Articles de revues : « Risk variants »

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Han, Shengtong. « Bayesian Rare Variant Analysis Identifies Novel Schizophrenia Putative Risk Genes ». Journal of Personalized Medicine 14, n^o 8 (2 août 2024) : 822. http://dx.doi.org/10.3390/jpm14080822.

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The genetics of schizophrenia is so complex that it involves both common variants and rare variants. Rare variant association studies of schizophrenia are challenging because statistical methods for rare variant analysis are under-powered due to the rarity of rare variants. The recent Schizophrenia Exome meta-analysis (SCHEMA) consortium, the largest consortium in this field to date, has successfully identified 10 schizophrenia risk genes from ultra-rare variants by burden test, while more risk genes remain to be discovered by more powerful rare variant association test methods. In this study, we use a recently developed Bayesian rare variant association method that is powerful for detecting sparse rare risk variants that implicates 88 new candidate risk genes associated with schizophrenia from the SCHEMA case–control sample. These newly identified genes are significantly enriched in autism risk genes and GO enrichment analysis indicates that new candidate risk genes are involved in mechanosensory behavior, regulation of cell size, neuron projection morphogenesis, and plasma-membrane-bounded cell projection morphogenesis, that may provide new insights on the etiology of schizophrenia.

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Shah, Shrijal S., Herbert Lannon, Leny Dias, Jia-Yue Zhang, Seth L. Alper, Martin R. Pollak et David J. Friedman. « APOL1 Kidney Risk Variants Induce Cell Death via Mitochondrial Translocation and Opening of the Mitochondrial Permeability Transition Pore ». Journal of the American Society of Nephrology 30, n^o 12 (26 septembre 2019) : 2355–68. http://dx.doi.org/10.1681/asn.2019020114.

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BackgroundGenetic Variants in Apolipoprotein L1 (APOL1) are associated with large increases in CKD rates among African Americans. Experiments in cell and mouse models suggest that these risk-related polymorphisms are toxic gain-of-function variants that cause kidney dysfunction, following a recessive mode of inheritance. Recent data in trypanosomes and in human cells indicate that such variants may cause toxicity through their effects on mitochondria.MethodsTo examine the molecular mechanisms underlying APOL1 risk variant–induced mitochondrial dysfunction, we generated tetracycline-inducible HEK293 T-REx cells stably expressing the APOL1 nonrisk G0 variant or APOL1 risk variants. Using these cells, we mapped the molecular pathway from mitochondrial import of APOL1 protein to APOL1-induced cell death with small interfering RNA knockdowns, pharmacologic inhibitors, blue native PAGE, mass spectrometry, and assessment of mitochondrial permeability transition pore function.ResultsWe found that the APOL1 G0 and risk variant proteins shared the same import pathway into the mitochondrial matrix. Once inside, G0 remained monomeric, whereas risk variant proteins were prone to forming higher-order oligomers. Both nonrisk G0 and risk variant proteins bound components of the mitochondrial permeability transition pore, but only risk variant proteins activated pore opening. Blocking mitochondrial import of APOL1 risk variants largely eliminated oligomer formation and also rescued toxicity.ConclusionsOur study illuminates important differences in the molecular behavior of APOL1 nonrisk and risk variants, and our observations suggest a mechanism that may explain the very different functional effects of these variants, despite the lack of consistently observed differences in trafficking patterns, intracellular localization, or binding partners. Variant-dependent differences in oligomerization pattern may underlie APOL1’s recessive, gain-of-function biology.

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Bayley, Jean Pierre, Birke Bausch, Johannes Adriaan Rijken, Leonie Theresia van Hulsteijn, Jeroen C. Jansen, David Ascher, Douglas Eduardo Valente Pires et al. « Variant type is associated with disease characteristics in SDHB, SDHC and SDHD-linked phaeochromocytoma–paraganglioma ». Journal of Medical Genetics 57, n^o 2 (6 septembre 2019) : 96–103. http://dx.doi.org/10.1136/jmedgenet-2019-106214.

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BackgroundPathogenic germline variants in subunits of succinate dehydrogenase (SDHB, SDHC and SDHD) are broadly associated with disease subtypes of phaeochromocytoma–paraganglioma (PPGL) syndrome. Our objective was to investigate the role of variant type (ie, missense vs truncating) in determining tumour phenotype.MethodsThree independent datasets comprising 950 PPGL and head and neck paraganglioma (HNPGL) patients were analysed for associations of variant type with tumour type and age-related tumour risk. All patients were carriers of pathogenic germline variants in the SDHB, SDHC or SDHD genes.ResultsTruncating SDH variants were significantly over-represented in clinical cases compared with missense variants, and carriers of SDHD truncating variants had a significantly higher risk for PPGL (p<0.001), an earlier age of diagnosis (p<0.0001) and a greater risk for PPGL/HNPGL comorbidity compared with carriers of missense variants. Carriers of SDHB truncating variants displayed a trend towards increased risk of PPGL, and all three SDH genes showed a trend towards over-representation of missense variants in HNPGL cases. Overall, variant types conferred PPGL risk in the (highest-to-lowest) sequence SDHB truncating, SDHB missense, SDHD truncating and SDHD missense, with the opposite pattern apparent for HNPGL (p<0.001).ConclusionsSDHD truncating variants represent a distinct group, with a clinical phenotype reminiscent of but not identical to SDHB. We propose that surveillance and counselling of carriers of SDHD should be tailored by variant type. The clinical impact of truncating SDHx variants is distinct from missense variants and suggests that residual SDH protein subunit function determines risk and site of disease.

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Park, Jihye, Soo Youn Lee, Su Youn Baik, Chan Hee Park, Jun Hee Yoon, Brian Y. Ryu et Ju Han Kim. « Gene-Wise Burden of Coding Variants Correlates to Noncoding Pharmacogenetic Risk Variants ». International Journal of Molecular Sciences 21, n^o 9 (27 avril 2020) : 3091. http://dx.doi.org/10.3390/ijms21093091.

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Genetic variability can modulate individual drug responses. A significant portion of pharmacogenetic variants reside in the noncoding genome yet it is unclear if the noncoding variants directly influence protein function and expression or are present on a haplotype including a functionally relevant genetic variation (synthetic association). Gene-wise variant burden (GVB) is a gene-level measure of deleteriousness, reflecting the cumulative effects of deleterious coding variants, predicted in silico. To test potential associations between noncoding and coding pharmacogenetic variants, we computed a drug-level GVB for 5099 drugs from DrugBank for 2504 genomes of the 1000 Genomes Project and evaluated the correlation between the long-known noncoding variant-drug associations in PharmGKB, with functionally relevant rare and common coding variants aggregated into GVBs. We obtained the area under the receiver operating characteristics curve (AUC) by comparing the drug-level GVB ranks against the corresponding pharmacogenetic variants-drug associations in PharmGKB. We obtained high overall AUCs (0.710 ± 0.022–0.734 ± 0.018) for six different methods (i.e., SIFT, MutationTaster, Polyphen-2 HVAR, Polyphen-2 HDIV, phyloP, and GERP++), and further improved the ethnicity-specific validations (0.759 ± 0.066–0.791 ± 0.078). These results suggest that a significant portion of the long-known noncoding variant-drug associations can be explained as synthetic associations with rare and common coding variants burden of the corresponding pharmacogenes.

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Barbirou, Mouadh, Amanda A. Miller, Amel Mezlini, Balkiss Bouhaouala-Zahar et Peter J. Tonellato. « Variant Characterization of a Representative Large Pedigree Suggests “Variant Risk Clusters” Convey Varying Predisposition of Risk to Lynch Syndrome ». Cancers 15, n^o 16 (12 août 2023) : 4074. http://dx.doi.org/10.3390/cancers15164074.

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Recently, worldwide incidences of young adult aggressive colorectal cancer (CRC) have rapidly increased. Of these incidences diagnosed as familial Lynch syndrome (LS) CRC, outcomes are extremely poor. In this study, we seek novel familial germline variants from a large pedigree Tunisian family with 12 LS-affected individuals to identify putative germline variants associated with varying risk of LS. Whole-genome sequencing analysis was performed to identify known and novel germline variants shared between affected and non-affected pedigree members. SNPs, indels, and structural variants (SVs) were computationally identified, and their oncological influence was predicted using the Genetic Association of Complex Diseases and Disorders, OncoKB, and My Cancer Genome databases. Of 94 germline familial variants identified with predicted functional impact, 37 SNPs/indels were detected in 28 genes, 2 of which (MLH1 and PRH1-TAS2R14) have known association with CRC and 4 others (PPP1R13B, LAMA5, FTO, and NLRP14) have known association with non-CRC cancers. In addition, 48 of 57 identified SVs overlap with 43 genes. Three of these genes (RELN, IRS2, and FOXP1) have a known association with non-CRC digestive cancers and one (RRAS2) has a known association with non-CRC cancer. Our study identified 83 novel, predicted functionally impactful germline variants grouped in three “variant risk clusters” shared in three familiarly associated LS groups (high, intermediate and low risk). This variant characterization study demonstrates that large pedigree investigations provide important evidence supporting the hypothesis that different “variant risk clusters” can convey different mechanisms of risk and oncogenesis of LS-CRC even within the same pedigree.

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Cannon-Albright, Lisa Anne, Craig Carl Teerlink, Jeff Stevens, Franklin W. Huang, Csilla Sipeky, Johanna Schleutker, Rolando Hernandez, Julio Facelli, Neeraj Agarwal et Donald L. Trump. « A Rare Variant in ERF (rs144812092) Predisposes to Prostate and Bladder Cancers in an Extended Pedigree ». Cancers 13, n^o 10 (15 mai 2021) : 2399. http://dx.doi.org/10.3390/cancers13102399.

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Pairs of related bladder cancer cases who belong to pedigrees with an excess of bladder cancer were sequenced to identify rare, shared variants as candidate predisposition variants. Candidate variants were tested for association with bladder cancer risk. A validated variant was assayed for segregation to other related cancer cases, and the predicted protein structure of this variant was analyzed. This study of affected bladder cancer relative pairs from high-risk pedigrees identified 152 bladder cancer predisposition candidate variants. One variant in ERF (ETS Repressing Factor) was significantly associated with bladder cancer risk in an independent population, was observed to segregate with bladder and prostate cancer in relatives, and showed evidence for altering the function of the associated protein. This finding of a rare variant in ERF that is strongly associated with bladder and prostate cancer risk in an extended pedigree both validates ERF as a cancer predisposition gene and shows the continuing value of analyzing affected members of high-risk pedigrees to identify and validate rare cancer predisposition variants.

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Boddicker, Nicholas J., Raphael Mwangi, Dennis P. Robinson, Allison C. Rosenthal, Thomas M. Habermann, Andrew L. Feldman, Lisa M. Rimsza et al. « Abstract 5233 : Germline CHEK2 variants and risk of lymphoma ». Cancer Research 83, n^o 7_Supplement (4 avril 2023) : 5233. http://dx.doi.org/10.1158/1538-7445.am2023-5233.

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Abstract Lymphoma is the sixth most commonly diagnosed cancer in the US. Genome-wide association studies have identified common variants associated with risk of specific lymphoma subtypes, but less is known about the contribution of rare inherited variants in the genetic architecture of lymphoma risk. CHEK2 is important to DNA repair and 2 small studies have found evidence of an association between CHEK2 variants and risk of lymphoma. Here, we investigated loss of function (LoF) variants in CHEK2 with risk of lymphoma (overall and subtypes). The study population included newly diagnosed lymphoma cases from Mayo who were enrolled in the Lymphoma SPORE Molecular Epidemiology Resource (MER). Controls were from the Mayo Clinic Biobank, from which we excluded a prior hematologic malignancy. Whole exome sequencing was performed by Regeneron on an Illumina NovaSeq panel (mean coverage of 48X). Variants were called using GATK v4 and variant annotation was performed using BioR. All LoF variants (nonsense, frameshift and consensus splice sites) in CHEK2 with a minor allele frequency < 0.5% were included in the analyses. Logistic regression was used to estimate odds ratio (OR) and 95% confidence intervals (CI) for the association between CHEK2mutation status and risk of lymphoma overall, and by lymphoma subtypes that had more than 5 mutation carriers, which included diffuse large B-cell (DLBCL), follicular (FL), and T-cell lymphoma (TCL). All analyses were adjusted for age (at diagnosis for cases and at enrollment for controls) and sex. A total of 4,852 lymphoma cases and 49,724 controls were included in this analysis. Median age for both cases and controls was 62 years (range 18-99 years). Males accounted for 57.5% (n=2,789) of the cases and 40.6% (n=20,186) of the controls. The DLBCL (23.6% of cases) and FL (23.3% of cases) subtypes were the most common; 7.6% of cases had TCL. A total of 407 (0.7%) individuals had a LoF variant. The frequency of LoF variants was 1.2% in lymphoma cases and 0.7% in controls. LoF variants were associated with increased risk of lymphoma overall (OR=1.77; 95%CI: 1.32-2.33), DLBCL (OR=2.07; 95%CI: 1.20-3.13), and TCL (OR=2.78; 95%CI: 1.178-5.50), but not FL (OR=1.31; 95%CI: 0.65-2.34). CHEK2 c.1100delC was the most frequently mutated variant in this population, accounting for 76% of all LoF variants. Individuals with a c.1100delC variant had an increased risk of lymphoma overall (OR=1.90; 95%CI: 1.37-2.58), DLBCL (OR=2.06; 95%CI: 1.09-3.54), and TCL (OR=3.17; 95%CI:1.24-6.58), but not FL (OR=1.05; 95%CI: 0.41-2.15). When restricted to cases, there was no significant difference in age at diagnosis (P=0.62) or sex (P=0.53) between LoF variant carriers and non-carriers. In this large lymphoma case-control study, CHEK2 LoF variants were associated with increased risk of lymphoma, demonstrating that rare inherited variants may play an important role in the etiology of lymphoma. Additional work is needed to investigate missense variants in CHEK2 and risk of lymphoma. Citation Format: Nicholas J. Boddicker, Raphael Mwangi, Dennis P. Robinson, Allison C. Rosenthal, Thomas M. Habermann, Andrew L. Feldman, Lisa M. Rimsza, Rebecca L. King, Melissa C. Larson, Brianna J. Gysbers, Stephen M. Ansell, Jithma P. Abeykoon, Grzegorz S. Nowakowski, Thomas E. Witzig, Anne J. Novak, Susan L. Slager, James R. Cerhan. Germline CHEK2 variants and risk of lymphoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5233.

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Ament, Seth A., Szabolcs Szelinger, Gustavo Glusman, Justin Ashworth, Liping Hou, Nirmala Akula, Tatyana Shekhtman et al. « Rare variants in neuronal excitability genes influence risk for bipolar disorder ». Proceedings of the National Academy of Sciences 112, n^o 11 (17 février 2015) : 3576–81. http://dx.doi.org/10.1073/pnas.1424958112.

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We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genome-wide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABAA receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5′ and 3′ UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD.

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Tu, J. J., L. Kuhn, L. Denny, K. J. Beattie, A. Lorincz et T. C. Wright. « Molecular variants of human papillomavirus type 16 and risk for cervical neoplasia in South Africa ». International Journal of Gynecologic Cancer 16, n^o 2 (mars 2006) : 736–42. http://dx.doi.org/10.1136/ijgc-00009577-200603000-00043.

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Non-European variants of human papillomavirus (HPV) type 16 are generally associated with a greater risk of cervical neoplasia than European prototype variants. We investigated whether this association would persist in a population in which non-European HPV 16 variants were more common. We sequenced HPV 16 isolates in cervical samples collected from 93 Black South African women enrolled in a cervical cancer screening study and examined associations between cervical neoplasia identified though colposcopy with cervical biopsy and the specific HPV 16 variant identified. The European prototype variant (EP) was the most commonly identified variant in this population (47% of all isolates), but African variants (Af-1 and Af-2) were also quite common (41% of all isolates). In contrast to previous studies, we found no evidence that non-European variants were associated with an increased risk of neoplasia. Rather, most of the HPV 16–associated cancers were found in association with EP (71% of 14 cases). In this setting where African HPV 16 variants were common, no increased risk for cervical neoplasia was found among women with these variants compared with other HPV 16 variants.

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Vogan, Kyle. « Bladder exstrophy risk variants ». Nature Genetics 47, n^o 5 (28 avril 2015) : 429. http://dx.doi.org/10.1038/ng.3298.

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Iwaki, Hirotaka, Cornelis Blauwendraat, Hampton L. Leonard, Ganqiang Liu, Jodi Maple-Grødem, Jean-Christophe Corvol, Lasse Pihlstrøm et al. « Genetic risk of Parkinson disease and progression : ». Neurology Genetics 5, n^o 4 (9 juillet 2019) : e348. http://dx.doi.org/10.1212/nxg.0000000000000348.

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ObjectiveTo determine if any association between previously identified alleles that confer risk for Parkinson disease and variables measuring disease progression.MethodsWe evaluated the association between 31 risk variants and variables measuring disease progression. A total of 23,423 visits by 4,307 patients of European ancestry from 13 longitudinal cohorts in Europe, North America, and Australia were analyzed.ResultsWe confirmed the importance of GBA on phenotypes. GBA variants were associated with the development of daytime sleepiness (p.N370S: hazard ratio [HR] 3.28 [1.69–6.34]) and possible REM sleep behavior (p.T408M: odds ratio 6.48 [2.04–20.60]). We also replicated previously reported associations of GBA variants with motor/cognitive declines. The other genotype-phenotype associations include an intergenic variant near LRRK2 and the faster development of motor symptom (Hoehn and Yahr scale 3.0 HR 1.33 [1.16–1.52] for the C allele of rs76904798) and an intronic variant in PMVK and the development of wearing-off effects (HR 1.66 [1.19–2.31] for the C allele of rs114138760). Age at onset was associated with TMEM175 variant p.M393T (−0.72 [−1.21 to −0.23] in years), the C allele of rs199347 (intronic region of GPNMB, 0.70 [0.27–1.14]), and G allele of rs1106180 (intronic region of CCDC62, 0.62 [0.21–1.03]).ConclusionsThis study provides evidence that alleles associated with Parkinson disease risk, in particular GBA variants, also contribute to the heterogeneity of multiple motor and nonmotor aspects. Accounting for genetic variability will be a useful factor in understanding disease course and in minimizing heterogeneity in clinical trials.

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Vargas-Neri, Jessica L., Bruce Carleton, Colin J. Ross, Mara Medeiros, Gilberto Castañeda-Hernández et Patricia Clark. « Pharmacogenomic study of anthracycline-induced cardiotoxicity in Mexican pediatric patients ». Pharmacogenomics 23, n^o 5 (avril 2022) : 291–301. http://dx.doi.org/10.2217/pgs-2021-0144.

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Background: The aim of this study was to evaluate the association between well-defined genetic risk variants in SLC28A3, RARG and UGT1A6 and anthracycline-induced cardiotoxicity in Mexican pediatric patients. Methods: We tested a cohort of 79 children treated with anthracyclines for the presence of SLC28A3-rs7853758, RARG-rs2229774 and UGT1A6-rs17863783. Results: The SLC28A3-rs7853758 variant was more frequent in this cohort, while the UGT1A6-rs17863783 and RARG-rs2229774 variants were present at lower frequencies. A clinically important decrease of fractional shortening was associated with SLC28A3-rs7853758 variant. Conclusion: In this cohort, 39.2% of patients carried the protective SLC28A3 variant. A small number of tested patients have the risk variants of UGT1A6 and RARG. None of the patients shared the two risk variants.

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Gibson, Summer B., Jonathan M. Downie, Spyridoula Tsetsou, Julie E. Feusier, Karla P. Figueroa, Mark B. Bromberg, Lynn B. Jorde et Stefan M. Pulst. « The evolving genetic risk for sporadic ALS ». Neurology 89, n^o 3 (22 juin 2017) : 226–33. http://dx.doi.org/10.1212/wnl.0000000000004109.

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Objective:To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)–associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity.Methods:Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls.Results:Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls.Conclusions:Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.

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Reková, Petra, Gabriela Dostálová, David Kemlink, Jaroslava Paulasová Schwabová, Zora Dubská, Manuela Vaneckova, Martin Mašek et al. « Detailed Phenotype of GLA Variants Identified by the Nationwide Neurological Screening of Stroke Patients in the Czech Republic ». Journal of Clinical Medicine 10, n^o 16 (12 août 2021) : 3543. http://dx.doi.org/10.3390/jcm10163543.

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Fabry disease (FD) is a rare X-linked disorder of glycosphingolipid metabolism caused by pathogenic variants within the alpha-galactosidase A (GLA) gene, often leading to neurological manifestations including stroke. Multiple screening programs seeking GLA variants among stroke survivors lacked detailed phenotype description, making the interpretation of the detected variant’s pathogenicity difficult. Here, we describe detailed clinical characteristics of GLA variant carriers identified by a nationwide stroke screening program in the Czech Republic. A total of 23 individuals with 8 different GLA variants were included in the study. A comprehensive diagnostic workup was performed by a team of FD specialists. The investigation led to the suggestion of phenotype reclassification for the G325S mutation from late-onset to classical. A novel variant R30K was found and was classified as a variant of unknown significance (VUS). The typical manifestation in our FD patients was a stroke occurring in the posterior circulation with an accompanying pathological finding in the cerebrospinal fluid. Moreover, we confirmed that cornea verticillata is typically associated with classical variants. Our findings underline the importance of detailed phenotype description and data sharing in the correct identification of pathogenicity of gene variants detected by high-risk-population screening programs.

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Nomura, Akihiro, Connor A. Emdin, Hong Hee Won, Gina M. Peloso, Pradeep Natarajan, Diego Ardissino, John Danesh et al. « Heterozygous ABCG5 Gene Deficiency and Risk of Coronary Artery Disease ». Circulation : Genomic and Precision Medicine 13, n^o 5 (octobre 2020) : 417–23. http://dx.doi.org/10.1161/circgen.119.002871.

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Background: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency—homozygous loss-of-function (LoF) variants—in the ABCG5 or ABCG8 genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of ABCG5 or ABCG8 —as occurs in heterozygous carriers of LoF variants—on LDL-C and risk of coronary artery disease (CAD) has remained uncertain. Methods: We first recruited 9 sitosterolemia families, identified causative LoF variants in ABCG5 or ABCG8 , and evaluated the associations of these ABCG5 or ABCG8 LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in ABCG5 or ABCG8 in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in ABCG5 or ABCG8 with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in ABCG5 or ABCG8 . Results: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in ABCG5 and 2 pedigrees in ABCG8 . Homozygous LoF variants in either ABCG5 or ABCG8 led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of ABCG5 LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in ABCG5 and in ABCG8 was ≈0.1% each. ABCG5 heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14–35]; P =1.1×10 −6 ) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27–3.35]; P =0.004). By contrast, ABCG8 heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD. Conclusions: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in ABCG5 had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

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Kent, Jason, et Michael C. Heinrich. « Novel models for the functional characterization of SDHA germline variants to predict cancer risk. » Journal of Clinical Oncology 42, n^o 16_suppl (1 juin 2024) : 11532. http://dx.doi.org/10.1200/jco.2024.42.16_suppl.11532.

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11532 Background: SDHA mutations are the most common cause of SDH-deficient GIST. More than 80% of SDHA-mutant GIST are associated with heterozygous germline mutations. Enhanced cancer surveillance of individuals carrying a known pathogenic germline SDHA mutation has the potential to detect early-stage tumors, allowing for curative surgery. However, of the > 1000 SDHA missense variants listed in ClinVar, > 95% are VUS. We must improve our ability to interpret the significance of SDHA variants before genetic sequencing can be utilized to its fullest potential for assessing cancer risk. Methods: We generated a novel clonal SDHA knock out (SDHAKO) human cell line with complete loss of SDHA expression and enzymatic activity. We next generated a clonal cell line harboring one copy of a landing pad cassette, allowing for site-specific integration of transfected expression cassettes mediated by Bxb1 recombinase. We validated that wild-type SDHA cDNA restored SDHA expression and enzymatic activity to levels equivalent to the parental HAP1 cells. We then selected 17 known benign variants (B,LB) and 21 known cancer missense variants (P, LP). In addition, we selected six missense variants associated with primary mitochondrial disease rather than cancer. Lastly, we selected 22 missense VUS. We created a mutant cell line in our KO landing pad cell line for each SDHA variant, as well as a control nonsense variant (SDHAR31X). Cell lines were analyzed for normalized SDH activity measurements (SDHAWT activity score = 1) Results: As expected, benign variants were collectively WT-like, with a mean Activity Score of 0.917. However, there was substantial variability amongst individual variants, with SDHAY55H having the lowest score at 0.215. Although known PMD variants (mean Activity Score = 0.358) were associated with lower functionality than that of benign variants, the extent of SDH dysfunction corresponding to cancer variants (mean Activity Score = 0.007) was substantially lower. Notably, all but one cancer variant could be described as functionally amorphic, as their Activity Scores were not significantly different from that of a control null variant, SDHAR31X, whose mean Activity Score was 0.004. We used the Activity Scores of these clinical control variants to establish thresholds to classify "cancer-like" or "benign-like" variants, which meet ACMG/AMP criteria for PS3_strong and BS_3 strong evidence according to an OddsPath calculation. We biochemically profiled 22 cell lines expressing a SDHA VUS. Using functional data and ACMG criteria, 3 variants could be reclassified as "Likely Benign", 14 could be reclassified as "Likely Pathogenic", and 5 remained a VUS (77% successfully reclassified). Conclusions: Functional characterization of SDHA germline missense variants has the potential to identify individuals who will benefit from genetic counseling and enhanced cancer screening procedures.

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Asanomi, Yuya, Daichi Shigemizu, Shintaro Akiyama, Akinori Miyashita, Risa Mitsumori, Norikazu Hara, Takeshi Ikeuchi, Shumpei Niida et Kouichi Ozaki. « A functional variant of SHARPIN confers increased risk of late-onset Alzheimer’s disease ». Journal of Human Genetics 67, n^o 4 (5 novembre 2021) : 203–8. http://dx.doi.org/10.1038/s10038-021-00987-x.

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AbstractLate-onset Alzheimer’s disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. Six highly deleterious variants of SHARPIN, comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls (P = 0.0016, odds ratio = 1.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.

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Cannon-Albright, Lisa A., Jeff Stevens, Julio C. Facelli, Craig C. Teerlink, Kristina Allen-Brady et Neeraj Agarwal. « High-Risk Pedigree Study Identifies LRBA (rs62346982) as a Likely Predisposition Variant for Prostate Cancer ». Cancers 15, n^o 7 (31 mars 2023) : 2085. http://dx.doi.org/10.3390/cancers15072085.

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There is evidence for contribution of inherited factors to prostate cancer, and more specifically to lethal prostate cancer, but few responsible genes/variants have been identified. We examined genetic sequence data for 51 affected cousin pairs who each died from prostate cancer and who were members of high-risk prostate cancer pedigrees in order to identify rare variants shared by the cousins as candidate predisposition variants. Candidate variants were tested for association with prostate cancer risk in UK Biobank data. Candidate variants were also assayed in 1195 additional sampled Utah prostate cancer cases. We used 3D protein structure prediction methods to analyze structural changes and provide insights into mechanisms of pathogenicity. Almost 4000 rare (<0.005) variants were identified as shared in the 51 affected cousin pairs. One candidate variant was also significantly associated with prostate cancer risk among the 840 variants with data in UK Biobank, in the gene LRBA (p = 3.2 × 10−5; OR = 2.09). The rare risk variant in LRBA was observed to segregate in five pedigrees. The overall predicted structures of the mutant protein do not show any significant overall changes upon mutation, but the mutated structure loses a helical structure for the two residues after the mutation. This unique analysis of closely related individuals with lethal prostate cancer, who were members of high-risk prostate cancer pedigrees, has identified a strong set of candidate predisposition variants which should be pursued in independent studies. Validation data for a subset of the candidates identified are presented, with strong evidence for a rare variant in LRBA.

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Durward-Akhurst, Sian, Joy Stock, Freya Stein, Christopher Stauthammer et Samuel Dudley. « 451 Identification of candidate sudden arrhythmic death -causing variants in a spontaneous animal model ». Journal of Clinical and Translational Science 8, s1 (avril 2024) : 134. http://dx.doi.org/10.1017/cts.2024.386.

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OBJECTIVES/GOALS: 1. Identify candidate AN-SAD-causing variants. 2. Estimate the variant effect size of and genotypic relative risk for arrhythmias and AN-SAD. METHODS/STUDY POPULATION: We performed whole genome sequencing (WGS) on 59 Thoroughbred AN-SAD cases and 58 controls. WGS was mapped and variants identified using a modified version of the Genome Analysis Toolkit best practices. Variants will be selected based on case-control analysis using SnpSift and presence in candidate genes. The top 400 candidate AN-SAD-causing variants will be selected based on being common in cases and rare or absent in controls, and uncommon (allele frequency less than 10%) in a catalog of genetic variation for the horse. The 400 variants will be genotyped in our cohort of 1,200 racehorses to determine variant effect size and genotypic relative risk. RESULTS/ANTICIPATED RESULTS: 17,182,003 variants were identified. 230 variants had significantly different allele frequencies (AF) between cases and controls (SnpSift). 723 high and 4,824 moderate impact variants were identified in 1,072 candidate genes. 3,681 variants were present at an AF 10% in the equine variant catalog. Variant effect prediction is ongoing to select the final 400 variants. Cardiac phenotyping (cardiac auscultation and ECG before, during, and after exercise) was performed on 790 racehorses and we will have 1,200 racehorses with cardiac phenotypes and/or AN-SAD. We will genotype the top 400 candidate AN-SAD-causing variants in these 1,200 horses to identify variants of large effect size. DISCUSSION/SIGNIFICANCE: Identification of candidate AN-SAD variants in a spontaneous animal model can facilitate interpretation of candidate variants in humans and horses. This project will provide further support for the racehorse AN-SAD model and will support future work exploring the genetic and environmental risk factors contributing to AN-SAD in this animal model.

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Wickland, Daniel P., Yingxue Ren, Jason P. Sinnwell, Joseph S. Reddy, Cyril Pottier, Vivekananda Sarangi, Minerva M. Carrasquillo et al. « Impact of variant-level batch effects on identification of genetic risk factors in large sequencing studies ». PLOS ONE 16, n^o 4 (16 avril 2021) : e0249305. http://dx.doi.org/10.1371/journal.pone.0249305.

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Genetic studies have shifted to sequencing-based rare variants discovery after decades of success in identifying common disease variants by Genome-Wide Association Studies using Single Nucleotide Polymorphism chips. Sequencing-based studies require large sample sizes for statistical power and therefore often inadvertently introduce batch effects because samples are typically collected, processed, and sequenced at multiple centers. Conventionally, batch effects are first detected and visualized using Principal Components Analysis and then controlled by including batch covariates in the disease association models. For sequencing-based genetic studies, because all variants included in the association analyses have passed sequencing-related quality control measures, this conventional approach treats every variant as equal and ignores the substantial differences still remaining in variant qualities and characteristics such as genotype quality scores, alternative allele fractions (fraction of reads supporting alternative allele at a variant position) and sequencing depths. In the Alzheimer’s Disease Sequencing Project (ADSP) exome dataset of 9,904 cases and controls, we discovered hidden variant-level differences between sample batches of three sequencing centers and two exome capture kits. Although sequencing centers were included as a covariate in our association models, we observed differences at the variant level in genotype quality and alternative allele fraction between samples processed by different exome capture kits that significantly impacted both the confidence of variant detection and the identification of disease-associated variants. Furthermore, we found that a subset of top disease-risk variants came exclusively from samples processed by one exome capture kit that was more effective at capturing the alternative alleles compared to the other kit. Our findings highlight the importance of additional variant-level quality control for large sequencing-based genetic studies. More importantly, we demonstrate that automatically filtering out variants with batch differences may lead to false negatives if the batch discordances come largely from quality differences and if the batch-specific variants have better quality.

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Oliverio, Andreina, Eleonora Bruno, Mara Colombo, Angelo Paradiso, Stefania Tommasi, Antonella Daniele, Daniela Andreina Terribile et al. « BRCA1/2 Variants and Metabolic Factors : Results From a Cohort of Italian Female Carriers ». Cancers 12, n^o 12 (30 novembre 2020) : 3584. http://dx.doi.org/10.3390/cancers12123584.

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Women carriers of pathogenic variants (mutations) in the BRCA1/2 genes face a high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). However, metabolic factors may influence BRCA penetrance. We studied the association of metabolic factors with BRCA1/2 variants and the risk effect of metabolic exposures in relation to the position of the mutations within the BRCA1/2. Overall, 438 women carriers of BRCA1/2 mutations, aged 18–70, with or without a previous diagnosis of BC/OC and without metastases, who joined our randomized dietary trial, were included in the study. The pathogenic variants were divided, according to their predicted effect, into loss of function (LOF) and nonsynonymous variants. The association between metabolic exposures and variants were analyzed by a logistic regression model. LOF variant carriers showed higher levels of metabolic parameters compared to carriers of nonsynonymous variants. LOF variant carriers had significantly higher levels of plasma glucose and serum insulin than nonsynonymous variant carriers (p = 0.03 and p < 0.001, respectively). This study suggests that higher insulin levels are significantly associated with LOF variants. Further investigations are required to explore the association of metabolic factors with LOF variants and the mechanisms by which these factors may affect BRCA-related cancer risk.

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Bobbili, Dheeraj Reddy, Peter Banda, Rejko Krüger et Patrick May. « Excess of singleton loss-of-function variants in Parkinson’s disease contributes to genetic risk ». Journal of Medical Genetics 57, n^o 9 (13 février 2020) : 617–23. http://dx.doi.org/10.1136/jmedgenet-2019-106316.

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BackgroundParkinson’s disease (PD) is a neurodegenerative disorder with complex genetic architecture. Besides rare mutations in high-risk genes related to monogenic familial forms of PD, multiple variants associated with sporadic PD were discovered via association studies.MethodsWe studied the whole-exome sequencing data of 340 PD cases and 146 ethnically matched controls from the Parkinson’s Progression Markers Initiative (PPMI) and performed burden analysis for different rare variant classes. Disease prediction models were built based on clinical, non-clinical and genetic features, including both common and rare variants, and two machine learning methods.ResultsWe observed a significant exome-wide burden of singleton loss-of-function variants (corrected p=0.037). Overall, no exome-wide burden of rare amino acid changing variants was detected. Finally, we built a disease prediction model combining singleton loss-of-function variants, a polygenic risk score based on common variants, and family history of PD as features and reached an area under the curve of 0.703 (95% CI 0.698 to 0.708). By incorporating a rare variant feature, our model increased the performance of the state-of-the-art classification model for the PPMI dataset, which reached an area under the curve of 0.639 based on common variants alone.ConclusionThe main finding of this study is to highlight the contribution of singleton loss-of-function variants to the complex genetics of PD and that disease risk prediction models combining singleton and common variants can improve models built solely on common variants.

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Karantanos, Theodoros, Shruti Chaturvedi, Christopher D. Gocke, Donna Marie Williams, Alison R. Moliterno et Evan M. Braunstein. « ATM Germline Variant Increases the Risk of MPN Progression ». Blood 134, Supplement_1 (13 novembre 2019) : 835. http://dx.doi.org/10.1182/blood-2019-125362.

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Introduction: Chronic myeloproliferative neoplasms (MPN) share the same driver mutations but their disease course and prognosis varies significantly. Deficiency of DNA damage repair (DDR) due to germline mutation is known to predispose to certain cancer types and has been implicated in the biology of MPN. The aim of our study was to evaluate the impact of germline variants in DDR genes in the natural history and outcomes of MPN patients. Patients and Methods: 76 individuals who were diagnosed with MPN (essential thrombocytosis (ET), polycythemia vera (PV) and primary myelofibrosis (PMF)) at Johns Hopkins University Hospital were included in this study. Targeted sequencing of 63 genes implicated in myeloid malignancies was performed as part of a standard clinical evaluation. Germline variants were determined by a variant allele frequency between 40-60% in blood samples and presence in the dbSNP database. Only rare variants (minor allele frequency < 0.01) were included in this analysis. Regression analysis was used to determine the association of the presence of germline variants with disease phenotype, driver mutation, number of somatic mutations, age and sex. Cox regression and Kaplan-Meier were used to assess the implication of germline variants in the progression to MF. Results: Median time from diagnosis to enrollment and follow up were 6 and 11 years respectively. 22 patients (28.9%) had at least one variant in a DDR gene, with ATM the most frequent (11/76 patients, 14.5%). Other recurrently mutated DDR genes included RECQL4 (6/76 patients, 7.9%), ATRX and RAD50 (Figure 1A). Patients with an ATM germline variant had higher incidence of a second malignancy (OR 4.37, 95% CI 1.16 - 16.46, P=0.029), a non-significant trend toward positive family history of malignancy (OR 3.75, 95% CI 0.91 - 15.46, P=0.067) and higher incidence of both second malignancy and positive family history of cancer (OR 4.58, 95% CI 1.17 - 17.94, P=0.029) (Figure 1B). The presence of an ATM germline variant was associated with MF or AML as opposed to ET or PV at the time of sequencing (RRR 5.84, 95% CI 1.12 - 30.34, P=0.036) independently of driver mutation, number of additional somatic mutations, age and male sex (Figure 1C). We did not find a significant difference in the number of somatic mutations between patients with and without ATM variant, however there was a trend toward increased chromosomal abnormalities among patients with ATM variant (Figure 1D). Finally, the presence of ATM variant was associated with higher risk of MF transformation (HR 3.43, 95% CI 1.02 - 11.6, P=0.047) independently of driver mutation (JAK2 Ref, CALR - HR 0.79, 95% CI 0.21 - 2.94, P=0.73) and male sex (HR 1.4, 95% CI 0.52 - 3.76, P=0.68). Kaplan-Meier analysis confirmed that progression to MF-free survival was shorter in patients harboring an ATM variant (P=0.01) (Figure 1E). Conclusion: The presence of a DDR gene germline variant, particularly ATM, is relatively common among patients with MPN. Patients with ATM variants had higher incidence of additional cancers and family history of malignancy, as well as an association with MF/AML phenotype and early transformation to MF. These data suggest involvement of ATM signaling in the progression of MPN, potentially via accumulation of DNA damage and genomic instability. Figure 1. A. Frequency of germline variants in MPN patients. The graph includes the gene variants identified in at least 2 distinct patients. Of known DDR related genes (in red) ATM is the most frequent (11/76 patients, 14.5%), followed by RECQL4 (6/76 patients, 7.9%) and ATRX and RAD50. B. Personal and family history of cancer among patients with and without ATM variant. Patients with ATM germline variant have higher incidence of additional malignancy (OR 4.37, 95% CI 1.16 - 16.46, P=0.029), higher incidence of family history of malignancy (OR 3.75, 95% CI 0.91 - 15.46, P=0.067) and higher incidence of concurrent personal history of malignancy and family history of malignancy (OR 4.58, 95% CI 1.17 - 17.94, P=0.029). C. MPN subtype per ATM variant status. Patients with an ATM germline variant were more likely to have MF or AML at the time of sequencing independent of driver mutation, number of somatic mutations, age and sex. D. Patients with an ATM variant had higher number of chromosomal abnormalities. E. Kaplan-Meier analysis of progression to MF free survival(P=0.01). Disclosures Chaturvedi: Shire/Takeda: Research Funding; Alexion: Consultancy; Sanofi: Consultancy.

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Arning, Astrid, Astrid Jeibmann, Stephan Köhnemann, Benjamin Brokinkel, Christian Ewelt, Klaus Berger, Jürgen Wellmann et al. « ADAMTS genes and the risk of cerebral aneurysm ». Journal of Neurosurgery 125, n^o 2 (août 2016) : 269–74. http://dx.doi.org/10.3171/2015.7.jns154.

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OBJECTIVE Cerebral aneurysms (CAs) affect 2%–5% of the population, and familial predisposition plays a significant role in CA pathogenesis. Several lines of evidence suggest that genetic variations in matrix metalloproteinase genes (MMP) are involved in the etiopathology of CAs. The authors performed a case-control study to investigate the effect of 4 MMP variants from the ADAMTS family on the pathogenesis of CAs. METHODS To identify susceptible genetic variants, the authors investigated 8 single nucleotide polymorphisms (SNPs) in 4 genes from the ADAMTS family (ADAMTS2, -7, -12, and -13) known to be associated with vascular diseases. The study included 353 patients with CAs and 1055 healthy adults. RESULTS The authors found significant associations between CA susceptibility and genetic variations in 3 members of the ADAMTS family. The largest risk for CA (OR 1.32, p = 0.006) was observed in carriers of the ADAMTS2 variant rs11750568, which has been previously associated with pediatric stroke. Three SNPs under investigation are associated with a protective effect in CA pathogenesis (ADAMTS12 variant rs1364044: OR 0.65, p = 0.0001; and ADAMTS13 variants rs739469 and rs4962153: OR 0.77 and 0.63, p = 0.02 and 0.0006, respectively), while 2 other ADAMTS13 variants may confer a significant risk (rs2301612: OR 1.26, p = 0.011; rs2285489: OR 1.24, p = 0.02). CONCLUSIONS These results suggest that reduced integrity of the endothelial wall, as conferred by ADAMTS variants, together with inflammatory processes and defective vascular remodeling plays an important role in CA pathogenesis, although the mechanism of action remains unknown. The authors' findings may lead to specific screening of at-risk populations in the future.

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Li, Qingqin S., Chao Tian, David Hinds et Guy R. Seabrook. « The association of clinical phenotypes to known AD/FTD genetic risk loci and their inter-relationship ». PLOS ONE 15, n^o 11 (5 novembre 2020) : e0241552. http://dx.doi.org/10.1371/journal.pone.0241552.

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To elucidate how variants in genetic risk loci previously implicated in Alzheimer’s Disease (AD) and/or frontotemporal dementia (FTD) contribute to expression of disease phenotypes, a phenome-wide association study was performed in two waves. In the first wave, we explored clinical traits associated with thirteen genetic variants previously reported to be linked to disease risk using both the 23andMe and UKB cohorts. We tested 30 additional AD variants in UKB cohort only in the second wave. APOE variants defining ε2/ε3/ε4 alleles and rs646776 were identified to be significantly associated with metabolic/cardiovascular and longevity traits. APOE variants were also significantly associated with neurological traits. ABI3 variant rs28394864 was significantly associated with cardiovascular (e.g. (hypertension, ischemic heart disease, coronary atherosclerosis, angina) and immune-related trait asthma. Both APOE variants and CLU variant were significantly associated with nearsightedness. HLA- DRB1 variant was associated with diseases with immune-related traits. Additionally, variants from 10+ AD genes (BZRAP1-AS1, ADAMTS4, ADAM10, APH1B, SCIMP, ABI3, SPPL2A, ZNF232, GRN, CD2AP, and CD33) were associated with hematological measurements such as white blood cell (leukocyte) count, monocyte count, neutrophill count, platelet count, and/or mean platelet (thrombocyte) volume (an autoimmune disease biomarker). Many of these genes are expressed specifically in microglia. The associations of ABI3 variant with cardiovascular and immune-related traits are one of the novel findings from this study. Taken together, it is evidenced that at least some AD and FTD variants are associated with multiple clinical phenotypes and not just dementia. These findings were discussed in the context of causal relationship versus pleiotropy via Mendelian randomization analysis.

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Pramukarso, Dodik Tugasworo, Herlina Suryawati, Soetedjo Soetedjo, Jimmy Eko Budi Hartono, Trianggoro Budisulistyo, Arinta Puspita Wati, Aditya Kurnianto et Patria Adri Wibhawa. « The Association Between Variants of Angiotensin Converting Enzyme (ACE) Gene With Risk Factors in Patients with Ischemic Stroke at Dr. Kariadi Semarang ». Medica Hospitalia : Journal of Clinical Medicine 8, n^o 3 (5 novembre 2021) : 297–303. http://dx.doi.org/10.36408/mhjcm.v8i3.565.

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BACKGROUND : Stroke is the leading cause of death and disability in the world. The occurrence of ischemic stroke is indicated by genetic factors, environmental factors and the interaction between it. Angiotensin Converting Enzyme (ACE) genetic variant is associated with various characteristics of risk factors for ischemic stroke. OBJECTIVE : Identifying genetic variants of Angiotensin Converting Enzyme (ACE) with the Polymerase Chain Reaction (PCR) method and to find it’s correlation beetwen risk factor in patients with Ischemic Stroke at Dr. Kariadi Semarang METHOD : The subjects of the study were 72 patients with ishcemic stroke who were treated at the polyclinic of the Neurology Department Dr. Kariadi Semarang in January - December 2013. DNA extraction of research subjects was carried out at the Laboratory of the Center of Biomedical Research (CEBIOR), Faculty of Medicine, Diponegoro University from January to March 2020. Amplification using the Polymerase Chain Reaction (PCR) method was carried out using an Eppendorf thermocycler. Data were analyzed with SPSS for Windows Version 25 RESULT : 72 samples analyzed obtained genetic variants of ACE II 39 (54.2%) samples, genetic variants of ACE DI 30 samples (41.7%), and genetic variants of ACE DD 3 (4.2%) samples. Meanwhile, there was no significant relationship ( p>0,05 ) between genetic variants of ACE and the characteristics of risk factors for ischemic stroke, namely age, gender, Body Mass Index, smoking history, triglyceride levels, HDL levels, LDL levels, obesity and hypertension. CONCLUSION : There are three types of ACE genetic variants, including the ACE II genetic variant, the ACE DI genetic variant, and the ACE DD genetic variant. Among the three genetic variants, ACE II genetic variant is the most common variant and there is no significant relationship to the various risk factor characteristics found in ischemic stroke patients at Dr. Kariadi Gneeral Hospital Semarang.

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Krohn, Lynne, Jennifer A. Ruskey, Uladzislau Rudakou, Etienne Leveille, Farnaz Asayesh, Michele T. M. Hu, Isabelle Arnulf et al. « GBA variants in REM sleep behavior disorder ». Neurology 95, n^o 8 (26 juin 2020) : e1008-e1016. http://dx.doi.org/10.1212/wnl.0000000000010042.

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ObjectiveTo study the role of GBA variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.MethodsA total of 4,147 individuals were included: 1,061 patients with iRBD and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk of iRBD, age at onset (AAO), and conversion rates.ResultsGBA variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87–3.22; p = 1 × 10−10). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90–7.14; p = 3.5 × 10−5), while for severe variant carriers it was 17.55 (95% CI, 2.11–145.9; p = 0.0015). Carriers of severe GBA variants had an average AAO of 52.8 years, 7–8 years earlier than those with mild variants or noncarriers (p = 0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers (p = 0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution.ConclusionsGBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.

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Waller, Rosalie G., Karen Curtin, Djordje Atanackovic, Guido J. Tricot, Steven M. Lipkin et Nicola J. Camp. « Exome Sequencing in Myeloma Pedigrees Implicates RAS1 and NOTCH Signaling Are Involved in Inherited Myeloma Risk ». Blood 126, n^o 23 (3 décembre 2015) : 2976. http://dx.doi.org/10.1182/blood.v126.23.2976.2976.

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Abstract Multiple Myeloma (MM) is a cancer of plasma cells with poor prognosis. Although, MM has been shown to be highly heritable in genealogy studies, no inherited risk-alleles have been identified. We hypothesize MM heritability is in part due to rare, germline variation that can be discovered in high-risk pedigrees. High-risk MM pedigrees were identified using the Utah Population Database which contains both genealogical and state cancer records. High-risk pedigrees were defined to have statistical excess of MM (p < 0.05). In this study we whole-exome sequenced germline DNA from 42 MM cases from high-risk pedigrees. Best practice variant calling, joint genotyping, and quality control were performed on the cases, a set of background controls from the 1000 Genome Project (1000G), and a small set of local controls (for technical artifacts), and resulted in 607,908 variants. We prioritized variants that were: 1) shared by at least 3 related MM cases, 2) absent in local controls, and 3) rare (frequency ≤ 0.01 in 1000G). This prioritization resulted in 116 variants of interest. Of the 116 variants, 3 MM cases in one high-risk pedigree shared multiple variants on chromosome 1p36.11-35.1. To formally assess whether these variants were inherited from a common founder we performed shared genome segment analysis using high-density SNP genotyping. We identified a region at 1p36.11-35.1, 8.9 Mb in length (p = 6.0 × 10-4; 22,000 simulations), providing positive evidence for segregation from a common founder. The segregating variants identified from exome sequencing in this region are in the genes CNKSR1, ARID1A, and SDC3. All three variants are individually predicted to be moderately deleterious. The variant in CNKSR1 falls in a splice region and has minor allele frequency of 0.004 in the 1000G Europeans. This variant was also observed in 3 additional cases in our sequencing set, indicating a strong enrichment of this variant in our high-risk MM cases (6/42 = 0.143). CNKSR1 is involved in the RAS1 and NOTCH signaling pathways and is a known target for cancer therapy. The variants in ARID1A and SDC3 both result in non-synonymous codon changes. ARID1A is commonly mutated across cancers and has been associated with accelerated tumor growth in hepatocellular carcinomas. SDC3 also interacts with NOTCH signaling, a pathway involved in MM growth (especially in patients with MAF translocations) and osteoclastogenesis. The variants in ARID1A and SDC3 are not carried by other cases in our sequencing set, which may indicate the combination of these variants is important to confer risk in the pedigree, or merely that the variants are hitchhikers on the segregating chromosome. Germline risk-alleles will shed light on the genetic factors involved in MM susceptibility and ultimately may provide new avenues for screening, diagnosis and treatment. Here we have identified evidence for segregating variants in a high-risk pedigree that implicate the RAS1 and NOTCH signaling pathways as involved in MM risk. Future work includes confirmation sequencing in the pedigree and a broader set of MM cases, and functional follow-up of the variants and their role in disruption of the genes and pathways. Disclosures No relevant conflicts of interest to declare.

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Nurmi, Anna K., Maija Suvanto, Joe Dennis, Kristiina Aittomäki, Carl Blomqvist et Heli Nevanlinna. « Pathogenic Variant Spectrum in Breast Cancer Risk Genes in Finnish Patients ». Cancers 14, n^o 24 (14 décembre 2022) : 6158. http://dx.doi.org/10.3390/cancers14246158.

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Recurrent pathogenic variants have been detected in several breast and ovarian cancer (BC/OC) risk genes in the Finnish population. We conducted a gene-panel sequencing and copy number variant (CNV) analysis to define a more comprehensive spectrum of pathogenic variants in BRCA1, BRCA2, PALB2, CHEK2, ATM, BARD1, RAD51C, RAD51D, BRIP1, and FANCM genes in Finnish BC patients. The combined frequency of pathogenic variants in the BRCA1/2 genes was 1.8% in 1356 unselected patients, whereas variants in the other genes were detected altogether in 8.3% of 1356 unselected patients and in 12.9% of 699 familial patients. CNVs were detected in 0.3% of both 1137 unselected and 612 familial patients. A few variants covered most of the pathogenic burden in the studied genes. Of the BRCA1/2 carriers, 70.8% had 1 of 10 recurrent variants. In the other genes combined, 92.1% of the carrier patients had at least 1 of 11 recurrent variants. In particular, PALB2 c.1592delT and CHEK2 c.1100delC accounted for 88.9% and 82.9%, respectively, of the pathogenic variation in each gene. Our results highlight the importance of founder variants in the BC risk genes in the Finnish population and could be used in the designing of population screening for the risk variants.

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Soufir, N., L. Bagait Miss, C. Oudin Miss, P. Wolkenstein, V. Descamps, N. Dupin, C. Lebbé, N. Basset-Seguin, P. Saiag et B. Grandchamp. « MC1R variants and melanoma risk : First study on Melan-Cohort ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 10524. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.10524.

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10524 Background: The presence of functional variants of MC1R, has been shown to be associated with melanoma (MM) risk in different populations worldwide. We had previously shown in a first case - control pilot study that MC1R variants were associated the risk of melanoma (MM) in France. Methods: In order to confirm and precise these results on a larger sample, we performed a case-control study with patients from Melan-Cohort, a prospective cohort from the Paris’ region. After signature of informed consents and extraction of blood DNAs, MC1R variants were sought by automatic sequencing in 270 patients (95 familial MM, 54 multiple sporadic MM, and 121 ‘single‘ MM) and in 154 controls sex, age, and ethnic matched. Usual statistical calculations (Chi2, odd ratios, logistic regression) were carried out. Results: MC1R functional variants were present in 73% of the patients versus 43% of controls (p<0.0001). The presence of only one variant was significantly associated with melanoma risk (OR 2.9 [1.88–4.5]), and the presence of two variants doubled the risk (OR, 6.91 [3.33–14.3]). Furthermore, each of the seven variants, RHC (i.e associated with the Red Hair Phenotype; R142H, R151C, R160W, D294H) or non-RHC (V92M, V60L, R163Q) was individually associated with melanoma risk (OR ranging from 2.8 to 14). The frequency of variants was similar in each sub-group of MM examined (familial, multiple sporadic, or ‘single‘). However, RHC variants were significantly more frequent in the familial subgroup (p = 0.0045) and non RHC were significantly more frequent in the “single” MM subgroup (p = 0.0006). In addition, we confirm that the risk related to MC1R largely persisted after stratification on each clinical risk factor: hair and eyes color, skin type, and nevi count. On the other hand, there was no association between the presence of MC1R variant and the histological type of MM, the age at diagnosis, and the Breslow index. Conclusion: Our results confirm the important role of MC1R on melanoma risk in France and this independently of clinical risk factors. Surprisingly, both RHC and non-RHC variants were associated with melanoma risk, but RHC variants have possibly a higher penetrance. Finally, the presence of MC1R variants does not seem to be correlated with the speed of evolution (Breslow index) of melanoma. No significant financial relationships to disclose.

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Acharya, Ratna, et Kiran Upadhyay. « Early recurrence of focal segmental glomerulosclerosis in a kidney transplant recipient withAPOL1one risk variant ». BMJ Case Reports 16, n^o 5 (mai 2023) : e254593. http://dx.doi.org/10.1136/bcr-2023-254593.

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Apolipoprotein 1(APOL1) risk variants (G1 and G2) are associated with focal segmental glomerulosclerosis (FSGS) in patients of African ancestry. The prevalence ofAPOL1two risk variants is lower in Hispanics and very rare in European and Asian populations.APOL1two risk variants in donor kidneys is associated with recipient kidney graft loss, however the effect of recipient risk variant in the kidney transplant outcome is unclear. Here, we present a late adolescent male with FSGS and end stage renal disease with oneAPOL1risk variant (G2) who had immediate recurrence of FSGS in the post-KT period. There was an excellent response to few sessions of plasmapheresis and Rituximab with no further recurrence of FSGS in the 1 year follow-up period. It needs to be seen whether the recipientAPOL1single risk variant causes increased susceptibility to kidney graft loss on a long run via recurrent or de novo pathologies.

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Veyrat-Durebex, Charlotte, Nathalie Bouzamondo, Morgane Le Mao, Juan Manuel Chao de la Barca, Céline Bris, Xavier Dieu, Gilles Simard et al. « Metabolomics signatures of a subset of RET variants according to their oncogenic risk level ». Endocrine-Related Cancer 26, n^o 3 (mars 2019) : 379–89. http://dx.doi.org/10.1530/erc-18-0314.

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Thirty percent of medullary thyroid carcinomas (MTCs) are related to dominant germline pathogenic variants in the RET proto-oncogene. According to their aggressiveness, these pathogenic variants are classified in three risk levels: ‘moderate’, ‘high’ and ‘highest’. The present study compares the metabolomics profiles of five pathogenic variants, whether already classified or not. We have generated six stable murine fibroblast cell lines (NIH3T3) expressing the WT allele or variants of the human RET gene, with different levels of pathogenicity, including the M918V variant that is yet to be accurately classified. We carried out a targeted metabolomics study of the cell extracts with a QTRAP mass spectrometer, using the Biocrates Absolute IDQ p180 kit, which allows the quantification of 188 endogenous molecules. The data were then subjected to multivariate statistical analysis. One hundred seventy three metabolites were accurately measured. The metabolic profiles of the cells expressing the RET variants were found to be correlated with their oncogenic risk. In addition, the statistical model we constructed for predicting the oncogenic risk attributed a moderate risk to the M918V variant. Our results indicate that metabolomics may be useful for characterizing the pathogenicity of the RET gene variants and their levels of aggressiveness.

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Nguyen-Dumont, Tú, James G. Dowty, Jason A. Steen, Anne-Laure Renault, Fleur Hammet, Maryam Mahmoodi, Derrick Theys et al. « Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2 : Findings from the Australian Breast Cancer Family Registry ». Cancers 13, n^o 6 (18 mars 2021) : 1378. http://dx.doi.org/10.3390/cancers13061378.

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Case-control studies of breast cancer have consistently shown that pathogenic variants in CHEK2 are associated with about a 3-fold increased risk of breast cancer. Information about the recurrent protein-truncating variant CHEK2 c.1100delC dominates this estimate. There have been no formal estimates of age-specific cumulative risk of breast cancer for all CHEK2 pathogenic (including likely pathogenic) variants combined. We conducted a population-based case-control-family study of pathogenic CHEK2 variants (26 families, 1071 relatives) and estimated the age-specific cumulative risk of breast cancer using segregation analysis. The estimated hazard ratio for carriers of pathogenic CHEK2 variants (combined) was 4.9 (95% CI 2.5–9.5) relative to non-carriers. The HR for carriers of the CHEK2 c.1100delC variant was estimated to be 3.5 (95% CI 1.02–11.6) and the HR for carriers of all other CHEK2 variants combined was estimated to be 5.7 (95% CI 2.5–12.9). The age-specific cumulative risk of breast cancer was estimated to be 18% (95% CI 11–30%) and 33% (95% CI 21–48%) to age 60 and 80 years, respectively. These findings provide important information for the clinical management of breast cancer risk for women carrying pathogenic variants in CHEK2.

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Foley, Georgea R., James R. Marthick, Sionne E. Lucas, Kelsie Raspin, Annette Banks, Janet L. Stanford, Elaine A. Ostrander, Liesel M. FitzGerald et Joanne L. Dickinson. « Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants ». Cancers 16, n^o 13 (7 juillet 2024) : 2482. http://dx.doi.org/10.3390/cancers16132482.

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Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rare ERCC3 (rs145201970, p = 2.57 × 10−4) and BRIP1 (rs4988345, p = 0.025) variants were significantly associated with PrCa risk. A PARP2 (rs200603922, p = 0.028) variant in the Australian dataset and a MUTYH (rs36053993, p = 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.

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Olabisi, Opeyemi A., Jia-Yue Zhang, Lynn VerPlank, Nathan Zahler, Salvatore DiBartolo, John F. Heneghan, Johannes S. Schlöndorff et al. « APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases ». Proceedings of the National Academy of Sciences 113, n^o 4 (23 décembre 2015) : 830–37. http://dx.doi.org/10.1073/pnas.1522913113.

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Two specific genetic variants of the apolipoprotein L1 (APOL1) gene are responsible for the high rate of kidney disease in people of recent African ancestry. Expression in cultured cells of these APOL1 risk variants, commonly referred to as G1 and G2, results in significant cytotoxicity. The underlying mechanism of this cytotoxicity is poorly understood. We hypothesized that this cytotoxicity is mediated by APOL1 risk variant-induced dysregulation of intracellular signaling relevant for cell survival. To test this hypothesis, we conditionally expressed WT human APOL1 (G0), the APOL1 G1 variant, or the APOL1 G2 variant in human embryonic kidney cells (T-REx-293) using a tetracycline-mediated (Tet-On) system. We found that expression of either G1 or G2 APOL1 variants increased apparent cell swelling and cell death compared with G0-expressing cells. These manifestations of cytotoxicity were preceded by G1 or G2 APOL1-induced net efflux of intracellular potassium as measured by X-ray fluorescence, resulting in the activation of stress-activated protein kinases (SAPKs), p38 MAPK, and JNK. Prevention of net K+ efflux inhibited activation of these SAPKs by APOL1 G1 or G2. Furthermore, inhibition of SAPK signaling and inhibition of net K+ efflux abrogated cytotoxicity associated with expression of APOL1 risk variants. These findings in cell culture raise the possibility that nephrotoxicity of APOL1 risk variants may be mediated by APOL1 risk variant-induced net loss of intracellular K+ and subsequent induction of stress-activated protein kinase pathways.

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Zenteno, Juan C., Oscar F. Chacón-Camacho, Vianey Ordoñez-Labastida, Antonio Miranda-Duarte, Camila Del Castillo, Jessica Nava, Fatima Mendoza, Luis Montes-Almanza, Germán Mora-Roldán et Karlen Gazarian. « Identification of Genetic Variants for Diabetic Retinopathy Risk Applying Exome Sequencing in Extreme Phenotypes ». BioMed Research International 2024 (13 janvier 2024) : 1–8. http://dx.doi.org/10.1155/2024/2052766.

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Background. Diabetic retinopathy (DR) risk has been shown to vary depending on ethnic backgrounds, and thus, it is worthy that underrepresented populations are analyzed for the potential identification of DR-associated genetic variants. We conducted a case-control study for the identification of DR-risk variants in Mexican population. Methods. We ascertained 60 type 2 diabetes mellitus (T2DM) patients. Cases (n=30) were patients with advanced proliferative DR (PDR) with less than 15 years after a T2DM diagnosis while controls (n=30) were patients with no DR 15 years after the diagnosis of T2DM. Exome sequencing was performed in all patients, and the frequency of rare variants was compared. In addition, the frequency of variants occurring in a set of 169 DR-associated genes were compared. Results. Statistically significant differences were identified for rare missense and splice variants and for rare splice variants occurring more than once in either group. A strong statistical difference was observed when the number of rare missense variants with an aggregated prediction of pathogenicity and occurring more than once in either group was compared (p=0.0035). Moreover, 8 variants identified more than once in either group, occurring in previously identified DR-associated genes were recognized. The p.Pro234Ser KIR2DS4 variant showed a strong protective effect (OR=0.04 [0.001–0.36]; p=0.04). Conclusions. Our study showed an enrichment of rare splice acceptor/donor variants in patients with PDR and identified a potential protective variant in KIR2DS4. Although statistical significance was not reached, our results support the replication of 8 previously identified DR-associated genes.

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Hawkins, Gregory A., David J. Friedman, Lingyi Lu, David R. McWilliams, Jeff W. Chou, Satria Sajuthi, Jasmin Divers et al. « Re-Sequencing of the APOL1-APOL4 and MYH9 Gene Regions in African Americans Does Not Identify Additional Risks for CKD Progression ». American Journal of Nephrology 42, n^o 2 (2015) : 99–106. http://dx.doi.org/10.1159/000439448.

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Background: In African Americans (AAs), APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci, since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant, and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants. Methods: Re-sequencing was performed across a ∼275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant. Results: Sequencing identified 3,246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions. No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1,571 AA ESKD cases and 1,334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1,139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p = 0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes did not replicate this association. Conclusion: Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.

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Reilly, Christopher R., Mikko Myllymäki, Robert Redd, Shilpa Padmanaban, Druha Karunakaran, Valerie Tesmer, Frederick D. Tsai et al. « The clinical and functional effects of TERT variants in myelodysplastic syndrome ». Blood 138, n^o 10 (21 mai 2021) : 898–911. http://dx.doi.org/10.1182/blood.2021011075.

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Abstract Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (P < .001) and younger age at MDS diagnosis (52 vs 59 years, P = .03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (P = .034) driven by an increased incidence of nonrelapse mortality (NRM; P = .015). Death from a noninfectious pulmonary cause was more frequent among patients with a TERT rare variant. Most variants were missense substitutions and classified as variants of unknown significance. Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90% of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein–RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.

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Zavaleta, Elizabeth, Nelly Solis, Maria Isabel Palacios, Liz Elva Zevallos-Escobar, Edison Vasquez Corales, Juan Carlos Bazo-Alvarez, Constantino Dominguez-Barrera et al. « Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru ». Cancers 14, n^o 22 (15 novembre 2022) : 5603. http://dx.doi.org/10.3390/cancers14225603.

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Background: Genetic testing for hereditary cancers is inconsistently applied within the healthcare systems in Latin America. In Peru, the prevalence and spectrum of cancer-predisposing germline variants is thus poorly characterized. Purpose: To determine the spectrum and prevalence of cancer-predisposing germline variants and variants of uncertain significance (VUS) in high-risk individuals located in a Peruvian low-resource setting city. Methods: Individuals presenting clinical criteria for hereditary cancer syndromes or being unaffected with familial history of cancer were included in the study. Samples from a total of 84 individuals were subjected to a high-throughput DNA sequencing assay that targeted a panel of 94 cancer predisposition genes. The pathogenicity of detected germline variants was classified according to the established American College of Medical Genetics and Genomics (ACMG) criteria. All pathogenic variants were validated by cycling temperature capillary electrophoresis. Results: We identified a total of eight pathogenic variants, found in 19 out of 84 individuals (23%). Pathogenic variants were identified in 24% (10/42) of unaffected individuals with family history of cancer and in 21% (9/42) of individuals with a cancer diagnosis. Pathogenic variants were identified in eight genes: RET (3), BRCA1 (3), SBDS (2), SBDS/MLH1 (4), MLH1 (4), TP53 (1), FANCD2 (1), DDB2/FANCG (1). In cancer cases, all colon cancer cases were affected by pathogenic variants in MLH1 and SBDS genes, while 20% (2/10) of the thyroid cancer cases by RET c.1900T>C variants were affected. One patient with endometrial cancer (1/3) had a double heterozygous pathogenic variant in DDB2 and FANCG genes, while one breast cancer patient (1/14) had a pathogenic variant in TP53 gene. Overall, each individual presented at least 17 VUS, totaling 1926 VUS for the full study population. Conclusion: We describe the first genetic characterization in a low-resource setting population where genetic testing is not yet implemented. We identified multiple pathogenic germline variants in clinically actionable predisposition genes, that have an impact on providing an appropriate genetic counselling and clinical management for individuals and their relatives who carry these variants. We also reported a high number of VUS, which may indicate variants specific for this population and may require a determination of their clinical significance.

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Trottier, Amy M., Lawrence J. Druhan, Ira L. Kraft, Amanda Lance, Simone Feurstein, Maria Helgeson, Jeremy P. Segal, Soma Das, Belinda R. Avalos et Lucy A. Godley. « Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies ». Blood Advances 4, n^o 20 (27 octobre 2020) : 5269–84. http://dx.doi.org/10.1182/bloodadvances.2020002013.

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Abstract Colony-stimulating factor 3 receptor (CSF3R) encodes the receptor for granulocyte colony-stimulating factor (G-CSF), a cytokine vital for granulocyte proliferation and differentiation. Acquired activating heterozygous variants in CSF3R are the main cause of chronic neutrophilic leukemia, a hyperproliferative disorder. In contrast, biallelic germ line hypomorphic variants in CSF3R are a rare cause of severe congenital neutropenia, a hypoproliferative condition. The impact of heterozygous germ line CSF3R variants, however, is unknown. We identified CSF3R as a new germ line hematologic malignancy predisposition gene through analysis of 832 next-generation sequencing tests conducted in 632 patients with hematologic malignancies. Among germ line CSF3R variants, 3 were abnormal in functional testing, indicating their deleterious nature. p.Trp547* was identified in 2 unrelated men with myelodysplastic syndromes diagnosed at 76 and 33 years of age, respectively. p.Trp547* is a loss-of-function nonsense variant in the extracellular domain that results in decreased CSF3R messenger RNA expression and abrogation of CSF3R surface expression and proliferative responses to G-CSF. p.Ala119Thr is a missense variant found in 2 patients with multiple myeloma and acute lymphoblastic leukemia, respectively. This variant is located between the extracellular immunoglobulin-like and cytokine receptor homology domains and results in decreased G-CSF sensitivity. p.Pro784Thr was identified in a 67-year-old man with multiple myeloma. p.Pro784Thr is a missense variant in the cytoplasmic domain that inhibits CSF3R internalization, producing a gain-of-function phenotype and G-CSF hypersensitivity. Our findings identify germ line heterozygous CSF3R variants as risk factors for development of myeloid and lymphoid malignancies.

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Hostetler, Ellen M., Ellen S. Regalado, Dong-Chuan Guo, Nadine Hanna, Pauline Arnaud, Laura Muiño-Mosquera, Bert Louis Callewaert et al. « SMAD3 pathogenic variants : risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium ». Journal of Medical Genetics 56, n^o 4 (19 janvier 2019) : 252–60. http://dx.doi.org/10.1136/jmedgenet-2018-105583.

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BackgroundPathogenic variants in SMAD3 cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Here, we examined differences in clinical presentation of aortic events (dissection or surgical repair of an aneurysm) with respect to age and variant type in an international cohort of individuals with SMAD3 variants.MethodsAortic status and events, vital status and clinical features were abstracted through retrospective review of medical records of 212 individuals with 51 unique SMAD3 variants, including haploinsufficiency (HI) and missense substitutions in the MH2 domain, as well as novel in-frame deletions and missense variants in the MH1 domain.ResultsAortic events were documented in 37% of cases, with dissections accounting for 70% of events. The median age at first aortic event was significantly lower in individuals with SMAD3 MH2 missense variants than those with HI variants (42years vs 49 years; p=0.003), but there was no difference in frequency of aortic events by variant type. The cumulative risk of an aortic event was 50% at 54 years of age. No aortic events in childhood were observed.ConclusionsSMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. Of the covariates examined, the type of underlying SMAD3 variant was responsible for some of this variation. Later onset of aortic events and the absence of aortic events in children associated with SMAD3 variants support gene-specific management of this disorder.

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Bryant, Nicole, Nicole Malpeli, Julia Ziaee, Cornelis Blauwendraat, Zhiyong Liu et Andrew B. West. « Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson’s disease cohort ». Human Molecular Genetics 30, n^o 6 (27 février 2021) : 454–66. http://dx.doi.org/10.1093/hmg/ddab058.

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Abstract Pathogenic missense variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified through linkage analysis in familial Parkinson disease (PD). Subsequently, other missense variants with lower effect sizes on PD risk have emerged, as well as non-coding polymorphisms (e.g. rs76904798) enriched in PD cases in genome-wide association studies. Here we leverage recent whole-genome sequences from the Accelerating Medicines Partnership-Parkinson’s Disease (AMP-PD) and the Genome Aggregation (gnomAD) databases to characterize novel missense variants in LRRK2 and explore their relationships with known pathogenic and PD-linked missense variants. Using a computational prediction tool that successfully classifies known pathogenic LRRK2 missense variants, we describe an online web-based resource that catalogs characteristics of over 1200 LRRK2 missense variants of unknown significance. Novel high-pathogenicity scoring variants, some identified exclusively in PD cases, tightly cluster within the ROC-COR-Kinase domains. Structure–function predictions support that some of these variants exert gain-of-function effects with respect to LRRK2 kinase activity. In AMP-PD participants, all p.R1441G carriers (N = 89) are also carriers of the more common PD-linked variant p.M1646T. In addition, nearly all carriers of the PD-linked p.N2081D missense variant are also carriers of the LRRK2 PD-risk variant rs76904798. These results provide a compendium of LRRK2 missense variants and how they associate with one another. While the pathogenic p.G2019S variant is by far the most frequent high-pathogenicity scoring variant, our results suggest that ultra-rare missense variants may have an important cumulative impact in increasing the number of individuals with LRRK2-linked PD.

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Ozarkar, Snehal, Adelle McFarland et Ram Savan. « Functional characterization of IRF5 exon 6 variants in SLE risk ». Journal of Immunology 198, n^o 1_Supplement (1 mai 2017) : 207.22. http://dx.doi.org/10.4049/jimmunol.198.supp.207.22.

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Abstract The goal of the proposed research is to determine how the interferon regulatory factor 5(IRF5) lupus risk variant translates into biological risk of systemic lupus erythematosus (SLE). Genome wide association studies (GWAS) have identified IRF5 as one of the most strongly associated genes with susceptibility to SLE. Although the genetic association of IRF5 with lupus is clear, the exact mechanism by which IRF5 risk variant promotes susceptibility for lupus is still unknown. We are investigating negative regulatory factors of IRF5 activity under normal conditions, which are unable to regulate IRF5 exon 6 risk variants thereby activating type I IFNs leading to aberrant immune activation. We have characterized IRF5 exon 6 variants in pDCs using molecular and biochemical approaches, and investigated the effect of negative regulators on IRF5 exon 6 variants. This will be a significant step to gain the mechanistic understanding of aberrant production type I IFNs and immune activation in lupus.

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Rice, Terri, Daniel H. Lachance, Annette M. Molinaro, Jeanette E. Eckel-Passow, Kyle M. Walsh, Jill Barnholtz-Sloan, Quinn T. Ostrom et al. « Understanding inherited genetic risk of adult glioma – a review ». Neuro-Oncology Practice 3, n^o 1 (25 août 2015) : 10–16. http://dx.doi.org/10.1093/nop/npv026.

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Abstract During the past six years, researchers have made major progress identifying common inherited genetic variation that increases risk for primary adult glioma. This paper summarizes knowledge about rare familial cancer syndromes that include adult glioma and reviews the available literature on the more recently discovered common inherited variation. Ten independent inherited variants in eight chromosomal regions have been convincingly associated with increased risk for adult glioma. Most of these variants increase relative risk of primary adult glioma by 20% to 40%, but the TP53 variant rs78378222 confers a two-fold relative risk (ie, 200%), and rs557505857 on chromosome 8 confers a six-fold relative risk of IDH-mutated astrocytomas and oligodendroglial tumors (ie, 600%). Even with a six-fold relative risk, the overall risk of developing adult glioma is too low for screening for the high-risk variant on chromosome 8. Future studies will help clarify which inherited adult glioma risk variants are associated with subtypes defined by histology and/or acquired tumor mutations. This review also provides an information sheet for primary adult glioma patients and their families.

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Cieślak, Adrianna, Grzegorz Galita, Michał Mik, Łukasz Dziki, Adam Dziki, Igor Sokołowski, Tomasz Popławski et Ireneusz Majsterek. « Association of GEMIN4 gene polymorphisms with the risk of colorectal cancer in the Polish population ». Polish Journal of Surgery 93, SUPLEMENT (17 novembre 2021) : 40–45. http://dx.doi.org/10.5604/01.3001.0015.5164.

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Aim: Gem-associated protein 4 (GEMIN4), a member of the GEMIN gene family, is a key compound of the regulating factors responsible for miRNA biogenesis. Genetic variability within this gene can alter the risk for development of colorectal cancer (CRC) as was shown for other genes involved in miRNA biogenesis. Therefore, presented study was intended to identify genetic variants of three single nucleotide polymorphisms (SNPs) in the GEMIN4 gene (rs1062923, rs2740348 and rs910925) and their relationship with CRC. Methods: The study comprised 203 patients and 179 age and sex matched controls. Genotyping of GEMIN4 gene variants was done using Taqman® assay. The association of GEMIN4 variants with CRC was done by odds ratio analysis. Haplotype analysis was done to see the combined effect of studied variants on CRC. Results: Patients carrying all variant genotypes for GEMIN4 rs1062923 (odds ratio [OR]= 0.205; 95% confidence interval [CI] = 0.1034–0.4065 for CC variant and [OR] = 0.1436; [CI] = 0.0869–0.2373 for CT variant, respectively) and GEMIN4 rs2740348 (odds ratio [OR] = 0.4498; 95% confidence interval [CI] = 0.2342–0.8637 for CC variant and [OR] = 0.3986; [CI] = 0.2043–0.7776 for CG variant, respectively) showed significant association in lower occurrence of cancer, whereas in case of GEMIN4 G/C rs910925 variant genotype, no significance correlation was found. Conclusion: Our study gives a substantive support for the association between the GEMIN4 gene variants/miRNA biogenesis and CRC risk.

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AI-Ghalayini, Kamal W., Mohammed A. Salama, Hadia Bassam Al Mahdi, Sameer Al-Harthi, Wesam A. Alhejily, Mirvat A. Alasnag, Noura O. Tasbhji, Diana A. H. Al-Quwaie, Panos Deloukas et Sherif Edris. « Identification of Genetic Variants Associated With Myocardial Infarction in Saudi Arabia ». Heart Surgery Forum 23, n^o 4 (23 juillet 2020) : E517—E523. http://dx.doi.org/10.1532/hsf.2955.

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The genetic variants associated with various genetic disorders have not been identified decisively in Saudi Arabia. Among these variants, six known for their association with coronary artery disease or myocardial infarction (MI) were studied on Saudi patients. Reference single nucleotide polymorphisms (SNPs) of these variants are rs5174, rs11591147, rs2259816, rs111245230, rs3782886 and rs2259820, referring to genes LRP8, PCSK9, HNF1A, SVEP1, BRAP and HNF1A, respectively. The analysis employed polymerase chain reaction panel coupled with mini-sequencing (SNapShot multiplex system) in order to identify these variants. A total of 100 MI patients and 103 healthy control individuals participated in this study. The six variants (SNPs) were evaluated for the risk of developing MI in the Saudi patients. Analysis of allele frequencies indicated that A allele of rs11591147 variant can be a protective allele, thus, is associated with the decreased risk of MI in Saudi individuals. Rare allele of rs111245230 variant (e.g., C allele) was extremely reduced, while rare allele of rs3782886 variant (e.g., G allele) does not exist in the ethnic signature of the Saudi population. This study elucidates the possible prediction of risk factors associated with severe diseases in Saudi population utilizing SNapShot multiplex system.

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Frank, Bernd, Peter Meyer, Melanie Barbara Boettger, Kari Hemminki, Henrike Stapelmann, Andreas Gast, Christina Schmitt, Rajiv Kumar, Consolato Sergi et Barbara Burwinkel. « ARLTS1 variants and melanoma risk ». International Journal of Cancer 119, n^o 7 (2006) : 1736–37. http://dx.doi.org/10.1002/ijc.22008.

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Reiner, Anne S., Mark E. Robson, Lene Mellemkjær, Marc Tischkowitz, Esther M. John, Charles F. Lynch, Jennifer D. Brooks et al. « Radiation Treatment, ATM, BRCA1/2, and CHEK2*1100delC Pathogenic Variants and Risk of Contralateral Breast Cancer ». JNCI : Journal of the National Cancer Institute 112, n^o 12 (2 mars 2020) : 1275–79. http://dx.doi.org/10.1093/jnci/djaa031.

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Abstract Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer–associated genes is unknown. In a population-based case-control study, we examined the association between RT; variants in ATM, BRCA1/2, or CHEK2*1100delC; and CBC risk. We analyzed 708 cases of women with CBC and 1399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2000 and aged younger than 55 years at diagnosis and screened for variants in breast cancer–associated genes. Rate ratios (RR) and 95% confidence intervals (CIs) were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (eg, BRCA1/2 pathogenic variant carriers without RT: RR = 3.52, 95% CI = 1.76 to 7.01; BRCA1/2 pathogenic variant carriers with RT: RR = 4.46, 95% CI = 2.96 to 6.71), suggesting that modifying RT plans for young women with breast cancer is unwarranted. Rare ATM missense variants, not currently identified as pathogenic, were associated with increased risk of RT-associated CBC (carriers of ATM rare missense variants of uncertain significance without RT: RR = 0.38, 95% CI = 0.09 to 1.55; carriers of ATM rare missense variants of uncertain significance with RT: RR = 2.98, 95% CI = 1.31 to 6.80). Further mechanistic studies will aid clinical decision-making related to RT.

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Zhou, Xiaopu, Yu Chen, Kin Y. Mok, Qianhua Zhao, Keliang Chen, Yuewen Chen, John Hardy et al. « Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis ». Proceedings of the National Academy of Sciences 115, n^o 8 (5 février 2018) : 1697–706. http://dx.doi.org/10.1073/pnas.1715554115.

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Alzheimer’s disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10−14), two common variants, GCH1 (rs72713460, P = 4.36 × 10−5) and KCNJ15 (rs928771, P = 3.60 × 10−6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype–phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.

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Liyanarachchi, Sandya, Julius Gudmundsson, Egil Ferkingstad, Huiling He, Jon G. Jonasson, Vinicius Tragante, Folkert W. Asselbergs et al. « Assessing thyroid cancer risk using polygenic risk scores ». Proceedings of the National Academy of Sciences 117, n^o 11 (4 mars 2020) : 5997–6002. http://dx.doi.org/10.1073/pnas.1919976117.

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Genome-wide association studies (GWASs) have identified at least 10 single-nucleotide polymorphisms (SNPs) associated with papillary thyroid cancer (PTC) risk. Most of these SNPs are common variants with small to moderate effect sizes. Here we assessed the combined genetic effects of these variants on PTC risk by using summarized GWAS results to build polygenic risk score (PRS) models in three PTC study groups from Ohio (1,544 patients and 1,593 controls), Iceland (723 patients and 129,556 controls), and the United Kingdom (534 patients and 407,945 controls). A PRS based on the 10 established PTC SNPs showed a stronger predictive power compared with the clinical factors model, with a minimum increase of area under the receiver-operating curve of 5.4 percentage points (P≤ 1.0 × 10−9). Adding an extended PRS based on 592,475 common variants did not significantly improve the prediction power compared with the 10-SNP model, suggesting that most of the remaining undiscovered genetic risk in thyroid cancer is due to rare, moderate- to high-penetrance variants rather than to common low-penetrance variants. Based on the 10-SNP PRS, individuals in the top decile group of PRSs have a close to sevenfold greater risk (95% CI, 5.4–8.8) compared with the bottom decile group. In conclusion, PRSs based on a small number of common germline variants emphasize the importance of heritable low-penetrance markers in PTC.

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