Artículos de revistas: "Genes families"

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Parsons, Oscar A. y Sara Jo Nixon. "Alcohol, Families, (and Genes)". Contemporary Psychology: A Journal of Reviews 36, n.º 11 (noviembre de 1991): 1000. http://dx.doi.org/10.1037/030397.

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Knowles, Jonathan, Päivi Lehtovaara y Tuula Teeri. "Cellulase families and their genes". Trends in Biotechnology 5, n.º 9 (septiembre de 1987): 255–61. http://dx.doi.org/10.1016/0167-7799(87)90102-8.

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Goldin, Lynn R. y Susan L. Slager. "Familial CLL: Genes and Environment". Hematology 2007, n.º 1 (1 de enero de 2007): 339–45. http://dx.doi.org/10.1182/asheducation-2007.1.339.

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Abstract Families with multiple individuals affected with chronic lymphocytic leukemia (CLL) and other related B-cell tumors have been described in the literature. Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome. While some environmental factors (such as farming-related exposures and occupational chemicals) may increase risk of CLL, results of epidemiologic studies have been generally inconsistent. Rates of CLL in the population show significant international variation, with the highest rates in the U.S. and Europe and the lowest rates in Asia. Migrants from Asia to the U.S. also have low rates of CLL, which supports a greater role for genetic compared with environmental risk factors. Large, population-based case-control and cohort studies have also shown significant familial aggregation of CLL and related conditions including non-Hodgkin and Hodgkin lymphoma. Monoclonal B-cell lymphocytosis also aggregates in families with CLL. However, the clinical implication of familial aggregation is minimal given the overall rarity of CLL. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for loci that contribute to susceptibility, but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated immune function and other genes, but more studies are needed to verify these findings. The ability to conduct large-scale genomic studies will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate etiologic pathways.

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Weller, Claudia M., Nadine Pelzer, Boukje de Vries, Mercè Artigas López, Oriol De Fàbregues, Julio Pascual, María A. Ramos Arroyo et al. "Two novel SCN1A mutations identified in families with familial hemiplegic migraine". Cephalalgia 34, n.º 13 (4 de abril de 2014): 1062–69. http://dx.doi.org/10.1177/0333102414529195.

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Background Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura, characterized by motor auras. The majority of FHM families have mutations in the CACNA1A and ATP1A2 genes; less than 5% of FHM families are explained by mutations in the SCN1A gene. Here we screened two Spanish FHM families for mutations in the FHM genes. Methods We assessed the clinical features of both FHM families and performed direct sequencing of all coding exons (and adjacent sequences) of the CACNA1A, ATP1A2, PRRT2 and SCN1A genes. Results FHM patients in both families had pure hemiplegic migraine with highly variable severity and frequency of attacks. We identified a novel SCN1A missense mutation p.Ile1498Met in all three tested hemiplegic migraine patients of one family. In the other family, novel SCN1A missense mutation p.Phe1661Leu was identified in six out of eight tested hemiplegic migraine patients. Both mutations affect amino acid residues that either reside in an important functional domain (in the case of Ile1498) or are known to be important for kinetic properties of the NaV1.1 channel (in the case of Phe1661). Conclusions We identified two mutations in families with FHM. SCN1A mutations are an infrequent but important cause of FHM. Genetic testing is indicated in families when no mutations are found in other FHM genes.

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Zheng, Guoqiao, Calogerina Catalano, Obul Reddy Bandapalli, Nagarajan Paramasivam, Subhayan Chattopadhyay, Matthias Schlesner, Rolf Sijmons et al. "Cancer Predisposition Genes in Cancer-Free Families". Cancers 12, n.º 10 (27 de septiembre de 2020): 2770. http://dx.doi.org/10.3390/cancers12102770.

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Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free (‘cancer-free families’, CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible.

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Alda, Martin. "Bipolar Disorder: From Families to Genes". Canadian Journal of Psychiatry 42, n.º 4 (mayo de 1997): 378–87. http://dx.doi.org/10.1177/070674379704200404.

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Background: Genetic factors are known to contribute to the etiology of bipolar illness, but the actual genetic mechanisms remain to be clarified. Methods: This paper reviews the research undertaken to establish the genetic basis of bipolar illness and to elucidate the nature of its genetic predisposition. Results: The presented findings suggest that bipolar affective disorder is a heterogeneous condition characterized by a complex relationship between the genetic susceptibility and the clinical presentation. Linkage studies have generated promising and replicated findings on chromosomes 18 and 21. Conclusion: In spite of the methodological difficulties inherent in the genetic study of psychiatric disorders, recent investigations have made important advances and promise to identify specific susceptibility genes.

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Smith, Simon A. y Bruce A. J. Ponder. "Predisposing Genes in Breast and Ovarian Cancer: An Overview". Tumori Journal 79, n.º 5 (octubre de 1993): 291–96. http://dx.doi.org/10.1177/030089169307900501.

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The isolation of genes that predispose to familial disease is an important goal in cancer research. The identification of such genes « opens up » the possibility of genetic diagnosis in families so that individuals who are at risk of cancer through inheriting a predisposing mutation can be Identified. Genes that are involved in familial cancer syndromes may also be important in the pathogenesis of sporadic forms of the disease, which are often more common. In the search for genes that predispose to familial breast and ovarian cancer much recent progress has been made. A locus on the long arm of chromosome 17, in the interval 17q12-21, has been identified by genetic linkage, and appears to be responsible for disease in approximately 40 % of breast cancer families and most families that contain breast and ovarian cancer. The region containing this locus, which has been called BRCA1, has been narrowed to a 3-4 cM interval defined by THRA1, the thyroid hormone receptor locus alpha, and D17S183, an anonymous microsatellite polymorphism. Loci other than BRCA1 that have been identified appear not only to predispose to breast and/or ovarian tumors, but to tumors at other sites too. A new locus has been identified on chromosome 2 which is linked to hereditary non-polyposis colorectal cancer (HNPCC). Families with HNPCC are also at risk of endometrial cancer and tumors of the ovary, amongst other cancer sites. Finally, mutations in the p53 gene are inherited in families with Li-Fraumeni syndrome, a rare cancer syndrome predisposing to breast tumors, sarcomas, leukemia and other cancers. Li-Fraumeni syndrome is also the only inherited cancer syndrome that predisposes at least in part to breast cancer where the actual predisposing gene is known. For the other cancer syndromes, the cloning of the predisposing genes is eagerly awaited.

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Liu, Yaxuan, Hafdis T. Helgadottir, Pedram Kharaziha, Jungmin Choi, Francesc López-Giráldez, Shrikant M. Mane, Veronica Höiom, Carl Christofer Juhlin, Catharina Larsson y Svetlana Bajalica-Lagercrantz. "Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer". Biomedicines 10, n.º 5 (26 de abril de 2022): 1004. http://dx.doi.org/10.3390/biomedicines10051004.

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Breast cancer is the most prevalent malignancy among women worldwide and hereditary breast cancer (HBC) accounts for about 5–10% of the cases. Today, the most recurrent genes known are BRCA1 and BRCA2, accounting for around 25% of familial cases. Although thousands of loss-of-function variants in more than twenty predisposing genes have been found, the majority of familial cases of HBC remain unexplained. The aim of this study was to identify new predisposing genes for HBC in three non-BRCA families with autosomal dominant inheritance pattern using whole-exome sequencing and functional prediction tools. No pathogenic variants in known hereditary cancer-related genes could explain the breast cancer susceptibility in these families. Among 2,122 exonic variants with maximum minor allele frequency (MMAF) < 0.1%, between 17–35 variants with combined annotation-dependent depletion (CADD) > 20 segregated with disease in the three analyzed families. Selected candidate genes, i.e., UBASH3A, MYH13, UTP11L, and PAX7, were further evaluated using protein expression analysis but no alterations of cancer-related pathways were observed. In conclusion, identification of new high-risk cancer genes using whole-exome sequencing has been more challenging than initially anticipated, in spite of selected families with pronounced family history of breast cancer. A combination of low- and intermediate-genetic-risk variants may instead contribute the breast cancer susceptibility in these families.

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Hallamaa, K. M., G. F. Browning y S. L. Tang. "Lipoprotein Multigene Families in Mycoplasma pneumoniae". Journal of Bacteriology 188, n.º 15 (1 de agosto de 2006): 5393–99. http://dx.doi.org/10.1128/jb.01819-05.

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ABSTRACT In this study, reverse transcriptase PCR was employed to construct a transcriptional profile of Mycoplasma pneumoniae lipoprotein genes contained in six multigene families. Most genes were found to be expressed. Many truncated lipoprotein genes were expressed, often polycistronically with other truncated genes, indicating that these genes may still be functional.

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Chubb, Daniel, Peter Broderick, Matthew Frampton, Ben Kinnersley, Amy Sherborne, Steven Penegar, Amy Lloyd, Yussanne P. Ma, Sara E. Dobbins y Richard S. Houlston. "Genetic Diagnosis of High-Penetrance Susceptibility for Colorectal Cancer (CRC) Is Achievable for a High Proportion of Familial CRC by Exome Sequencing". Journal of Clinical Oncology 33, n.º 5 (10 de febrero de 2015): 426–32. http://dx.doi.org/10.1200/jco.2014.56.5689.

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Purpose Knowledge of the contribution of high-penetrance susceptibility to familial colorectal cancer (CRC) is relevant to the counseling, treatment, and surveillance of CRC patients and families. Patients and Methods To quantify the impact of germline mutation to familial CRC, we sequenced the mismatch repair genes (MMR) APC, MUTYH, and SMAD4/BMPR1A in 626 early-onset familial CRC cases ascertained through a population-based United Kingdom national registry. In addition, we evaluated the contribution of mutations in the exonuclease domain (exodom) of POLE and POLD1 genes that have recently been reported to confer CRC risk. Results Overall mutations (pathogenic, likely pathogenic) in MMR genes make the highest contribution to familial CRC (10.9%). Mutations in the other established CRC genes account for 3.3% of cases. POLE/POLD1 exodom mutations were identified in three patients with family histories consistent with dominant transmission of CRC. Collectively, mutations in the known genes account for 14.2% of familial CRC (89 of 626 cases; 95% CI = 11.5, 17.2). Conclusion A genetic diagnosis is feasible in a high proportion of familial CRC. Mainstreaming such analysis in clinical practice should enable the medical management of patients and their families to be optimized. Findings suggest CRC screening of POLE and POLD1 mutation carriers should be comparable to that afforded to those at risk of HNPCC. Although the risk of CRC associated with unexplained familial CRC is in general moderate, in some families the risk is substantive and likely to be the consequence of unidentified genes, as exemplified by POLE and POLD1. Our findings have utility in the design of genetic analyses to identify such novel CRC risk genes.

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An, Joon-Yong, Jae Ho Jung, Leejee Choi, Eric D. Wieben y Brian G. Mohney. "Identification of Possible Risk Variants of Familial Strabismus Using Exome Sequencing Analysis". Genes 12, n.º 1 (10 de enero de 2021): 75. http://dx.doi.org/10.3390/genes12010075.

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Purpose: To investigate candidate genes associated with familial strabismus and propose a theory of their interaction in familial strabismus associated with early neurodevelopment. Methods: Eighteen families, including 53 patients diagnosed with strabismus and 34 unaffected family members, were analyzed. All patients with strabismus and available unaffected family members were evaluated using whole exome sequencing. The primary outcome was to identify rare occurring variants among affected individuals and investigate the evidence of their genetic heterogeneity. These results were compared with exome sequencing analysis to build a comprehensive genetic profile of the study families. Results: We observed 60 variants from 58 genes in 53 patients diagnosed with strabismus. We prioritized the most credible risk variants, which showed clear segregation in family members affected by strabismus. As a result, we found risk variants in four genes (FAT3, KCNH2, CELSR1, and TTYH1) in five families, suggesting their role in development of familial strabismus. In other families, there were several rare genetic variants in affected cases, but we did not find clear segregation pattern across family members. Conclusion: Genomic sequencing holds great promise in elucidating the genetic causes of strabismus; further research with larger cohorts or other related approaches are warranted.

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An, Joon-Yong, Jae Ho Jung, Leejee Choi, Eric D. Wieben y Brian G. Mohney. "Identification of Possible Risk Variants of Familial Strabismus Using Exome Sequencing Analysis". Genes 12, n.º 1 (10 de enero de 2021): 75. http://dx.doi.org/10.3390/genes12010075.

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Purpose: To investigate candidate genes associated with familial strabismus and propose a theory of their interaction in familial strabismus associated with early neurodevelopment. Methods: Eighteen families, including 53 patients diagnosed with strabismus and 34 unaffected family members, were analyzed. All patients with strabismus and available unaffected family members were evaluated using whole exome sequencing. The primary outcome was to identify rare occurring variants among affected individuals and investigate the evidence of their genetic heterogeneity. These results were compared with exome sequencing analysis to build a comprehensive genetic profile of the study families. Results: We observed 60 variants from 58 genes in 53 patients diagnosed with strabismus. We prioritized the most credible risk variants, which showed clear segregation in family members affected by strabismus. As a result, we found risk variants in four genes (FAT3, KCNH2, CELSR1, and TTYH1) in five families, suggesting their role in development of familial strabismus. In other families, there were several rare genetic variants in affected cases, but we did not find clear segregation pattern across family members. Conclusion: Genomic sequencing holds great promise in elucidating the genetic causes of strabismus; further research with larger cohorts or other related approaches are warranted.

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Travis, J. "MS Families: It's Genes, Not a Virus". Science News 148, n.º 12 (16 de septiembre de 1995): 180. http://dx.doi.org/10.2307/3979296.

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Swanson, Willie J. "Adaptive evolution of genes and gene families". Current Opinion in Genetics & Development 13, n.º 6 (diciembre de 2003): 617–22. http://dx.doi.org/10.1016/j.gde.2003.10.007.

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Field, L. Leigh. "Genes predisposing to IDDM in multiplex families". Genetic Epidemiology 6, n.º 1 (1989): 101–6. http://dx.doi.org/10.1002/gepi.1370060119.

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Chang-Claude, Jenny, Heiko Becher, Maria Caligo, Diana Eccles, Gareth Evans, Neva Haites, Shirley Hodgson, Pål Møller, Bernhard H. F. Weber y Dominique Stoppa-Lyonnet. "Risk Estimation as a Decision-Making Tool for Genetic Analysis of the Breast Cancer Susceptibility Genes". Disease Markers 15, n.º 1-3 (1999): 53–65. http://dx.doi.org/10.1155/1999/238375.

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For genetic counselling of a woman on familial breast cancer, an accurate evaluation of the probability that she carries a germ-line mutation is needed to assist in making decisions about genetic-testing.We used data from eight collaborating centres comprising 618 families (346 breast cancer only, 239 breast or ovarian cancer) recruited as research families or counselled for familial breast cancer, representing a broad range of family structures. Screening was performed in affected women from 618 families for germ-line mutations in BRCA1 and in 176 families for BRCA2 mutations, using different methods including SSCP, CSGE, DGGE, FAMA and PTT analysis followed by direct sequencing. Germ-line BRCA1 mutations were detected in 132 families and BRCA2 mutations in 16 families. The probability of being a carrier of a dominant breast cancer gene was calculated for the screened individual under the established genetic model for breast cancer susceptibility, first, with parameters for age-specific penetrances for breast cancer only [7] and, second, with age-specific penetrances for ovarian cancer in addition [20]. Our results indicate that the estimated probability of carrying a dominant breast cancer gene gives a direct measure of the likelihood of detecting mutations in BRCA1 and BRCA2. For breast/ovarian cancer families, the genetic model according to Narod et al. [20] is preferable for calculating the proband's genetic risk, and gives detection rates that indicate a 50% sensitivity of the gene test. Due to the incomplete BRCA2 screening of the families, we cannot yet draw any conclusions with respect to the breast cancer only families.

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Narta, Kiran, Manoj Ramesh Teltumbade, Mansi Vishal, Samreen Sadaf, Mohd Faruq, Hodan Jama, Naushin Waseem et al. "Whole Exome Sequencing Reveals Novel Candidate Genes in Familial Forms of Glaucomatous Neurodegeneration". Genes 14, n.º 2 (15 de febrero de 2023): 495. http://dx.doi.org/10.3390/genes14020495.

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Glaucoma is the largest cause of irreversible blindness with a multifactorial genetic etiology. This study explores novel genes and gene networks in familial forms of primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) to identify rare mutations with high penetrance. Thirty-one samples from nine MYOC-negative families (five POAG and four PACG) underwent whole-exome sequencing and analysis. A set of prioritized genes and variations were screened in an independent validation cohort of 1536 samples and the whole-exome data from 20 sporadic patients. The expression profiles of the candidate genes were analyzed in 17 publicly available expression datasets from ocular tissues and single cells. Rare, deleterious SNVs in AQP5, SRFBP1, CDH6 and FOXM1 from POAG families and in ACACB, RGL3 and LAMA2 from PACG families were found exclusively in glaucoma cases. AQP5, SRFBP1 and CDH6 also revealed significant altered expression in glaucoma in expression datasets. Single-cell expression analysis revealed enrichment of identified candidate genes in retinal ganglion cells and corneal epithelial cells in POAG; whereas for PACG families, retinal ganglion cells and Schwalbe’s Line showed enriched expression. Through an unbiased exome-wide search followed by validation, we identified novel candidate genes for familial cases of POAG and PACG. The SRFBP1 gene found in a POAG family is located within the GLC1M locus on Chr5q. Pathway analysis of candidate genes revealed enrichment of extracellular matrix organization in both POAG and PACG.

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Skarp, Sini, Johanna Korvala, Jouko Kotimäki, Martti Sorri, Minna Männikkö y Elina Hietikko. "New Genetic Variants in CYP2B6 and SLC6A Support the Role of Oxidative Stress in Familial Ménière’s Disease". Genes 13, n.º 6 (1 de junio de 2022): 998. http://dx.doi.org/10.3390/genes13060998.

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The objective was to study the genetic etiology of Ménière’s disease (MD) using next-generation sequencing in three families with three cases of MD. Whole exome sequencing was used to identify rare genetic variants co-segregating with MD in Finnish families. In silico estimations and population databases were used to estimate the frequency and pathogenicity of the variants. Variants were validated and genotyped from additional family members using capillary sequencing. A geneMANIA analysis was conducted to investigate the functional pathways and protein interactions of candidate genes. Seven rare variants were identified to co-segregate with MD in the three families: one variant in the CYP2B6 gene in family I, one variant in GUSB and EPB42 in family II, and one variant in each of the SLC6A, ASPM, KNTC1, and OVCH1 genes in family III. Four of these genes were linked to the same co-expression network with previous familial MD candidate genes. Dysfunction of CYP2B6 and SLC6A could predispose to MD via the oxidative stress pathway. Identification of ASPM and KNTC1 as candidate genes for MD suggests dysregulation of mitotic spindle formation in familial MD. The genetic etiology of familial MD is heterogenic. Our findings suggest a role for genes acting on oxidative stress and mitotic spindle formation in MD but also highlight the genetic complexity of MD.

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Brown, Anna L., Milena Babic, Andreas Schreiber, Jinghua Feng, Julia Dobbins, Peer Arts, Paul Wang et al. "Familial Clustering of Hematological Malignancies: Harbingers of Wider Germline Cancer Susceptibility". Blood 134, Supplement_1 (13 de noviembre de 2019): 3794. http://dx.doi.org/10.1182/blood-2019-131642.

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Introduction. The Australian Familial Haematological Cancer Study (AFHCS) was founded in 2004 when only one familial haematological malignancy (FHM) gene was known, RUNX1 causing thrombocytopenia and predominantly an MDS/AML HM phenotype. Today, there are over a dozen known FHM genes, mostly characterized as predisposing to myeloid malignancies. Within our AFHCS cohort of over 200 families, this is also true with a significant proportion of families with predisposition to myeloid malignancies solved with our identification of germline mutations in genes such as GATA2, RUNX1,CEBPA and DDX41. In contrast the majority of unsolved families have a predominance of lymphoid malignancies, most commonly non-Hodgkin lymphoma and chronic lymphocytic leukaemia. In several of these families we have found known pathogenic mutations in genes involved in regulation of the homologous recombination (HR) DNA damage repair (DDR) pathway (e.g. BRCA2 Y1710fs* and PALB2 K142*) that are previously characterised with regard to their known solid tumour predisposition. In the AFHCS families with these mutations we observe a mixture of hematological tumors of mostly lymphoid origin as well as non-hematological tumours. This led us to hypothesise that there is a subset of families for which the predisposition to malignancy includes a spectrum of different malignancies, i.e. pan-cancer predisposition. Further, we hypothesise that these are associated with mutations in genes with roles in HR DNA repair. In light of this we undertook a review of the phenotypic and genetic characteristics of families in our AFHCS cohort. Methods. Malignancy phenotype data, with regard to the different tumor types observed in each AFHCS family was annotated and aggregated. Covariance matrix analysis was then used to compare the number of times different tumor types were observed occurring together in a family pedigree. Genetic data: we curated whole exome sequence data for damaging mutations in genes with a known role in HR DNA damage repair. Results. A phenotype review of our cohort found 52% of assessable FHM families also had multiple types of solid tumour and/or individuals with diagnosis of multiple malignancies, indicative of a 'pan-cancer' phenotype. Covariance analysis showed that Hodgkin and non-Hodgkin lymphoma most often occurred together and also co-occurred with non-HM tumors breast, melanoma, colorectal, prostate and ovarian subtypes, implying a possible shared genetic etiology (Figure 1A). Assessment of AFHCS families for mutations in DDR genes including DNA repair (e.g. FANC/BRCA pathway genes) and chromosome cohesion (RAD21 and related) identified 18 variants segregating with malignancy including 5 frameshift or stopgain mutations. These high impact mutations included genes previously characterised in the context of autosomal recessive predisposition to hematological malignancy such as PALB2/BRCA2 family (Fanconi Anemia, see Figure 1B), NBN1 (Nijmegen Breakage Syndrome), DDX11 (Warsaw Syndrome) and others. A further 18 variants segregated in families where pan-cancer status is still under investigation. Conclusions. Phenotypic and genetic analysis of unsolved HM predisposed families have identified that familial clustering of lymphoma in actuality identifies families with pan-cancer germline genetic susceptibility, characterised by mutations in DNA damage response genes. Collectively these mutations may have a significant impact on our understanding of germline cancer predisposition, a finding supported by recent genetic population studies on sporadic cohorts, including pediatric cancer cohorts, opening the door for the application of rational therapies as evidenced by the BRCA/PARP inhibitor paradigm. However, as each individual gene mutation is rare, international collaborative studies will be essential for accurate measurements of risk and prognostication to assist individuals in the clinic. Disclosures Branford: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Qiagen: Consultancy, Honoraria; Cepheid: Consultancy, Honoraria. Scott:Celgene: Honoraria.

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Terhune, Elizabeth A., Cambria I. Wethey, Melissa T. Cuevas, Anna M. Monley, Erin E. Baschal, Morgan R. Bland, Robin Baschal et al. "Whole Exome Sequencing of 23 Multigeneration Idiopathic Scoliosis Families Reveals Enrichments in Cytoskeletal Variants, Suggests Highly Polygenic Disease". Genes 12, n.º 6 (16 de junio de 2021): 922. http://dx.doi.org/10.3390/genes12060922.

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Adolescent idiopathic scoliosis (AIS) is a lateral spinal curvature >10° with rotation that affects 2–3% of healthy children across populations. AIS is known to have a significant genetic component, and despite a handful of risk loci identified in unrelated individuals by GWAS and next-generation sequencing methods, the underlying etiology of the condition remains largely unknown. In this study, we performed exome sequencing of affected individuals within 23 multigenerational families, with the hypothesis that the occurrence of rare, low frequency, disease-causing variants will co-occur in distantly related, affected individuals. Bioinformatic filtering of uncommon, potentially damaging variants shared by all sequenced family members revealed 1448 variants in 1160 genes across the 23 families, with 132 genes shared by two or more families. Ten genes were shared by >4 families, and no genes were shared by all. Gene enrichment analysis showed an enrichment of variants in cytoskeletal and extracellular matrix related processes. These data support a model that AIS is a highly polygenic disease, with few variant-containing genes shared between affected individuals across different family lineages. This work presents a novel resource for further exploration in familial AIS genetic research.

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Grangeon, Lou, Stéphanie Guey, Jan Claudius Schwitalla, Françoise Bergametti, Minh Arnould, Michaelle Corpechot, Jessica Hadjadj et al. "Clinical and Molecular Features of 5 European Multigenerational Families With Moyamoya Angiopathy". Stroke 50, n.º 4 (abril de 2019): 789–96. http://dx.doi.org/10.1161/strokeaha.118.023972.

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Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%. In European patients, data about familial occurrence are limited. The aim of this study was to characterize the clinical and molecular features of several European families with a parent-to-child transmission of MMA. Methods Out of 126 MMA probands referred, we identified 113 sporadic probands and 13 familial probands. Segregation analysis showed a vertical parent-to-child pattern of inheritance in the families of 5 of these probands. All 5 families were of German or Dutch ancestry. We investigated the clinical features of affected members and used whole-exome sequencing to screen RNF213 and 13 genes involved in Mendelian MMA and to identify genes recurrently mutated in these families. Results Twelve affected MMA patients were identified, including 9 females and 3 males. Age at clinical onset ranged from 11 to 65 years. In 3 of 5 families, associated livedo racemosa was found. We did not detect any deleterious variants in the 13 known MMA genes. RNF213 rare missense variants predicted to be pathogenic were detected in all affected members of 2 of these families, as well as 2 candidate variants of the PALD1 gene. Conclusions Nonsyndromic MMA was identified in 5 European families, including 2 to 3 clinically affected cases segregating with a parent-to-child pattern of inheritance in each family. Molecular screening detected rare deleterious variants within RNF213 and PALD1 in all affected members of 2 of these 5 families, as well as in some clinically unaffected members. Altogether these data raise the difficult and, to date unanswered, question of the medical indication of presymptomatic screening.

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Jiménez-Jiménez, Félix Javier, Hortensia Alonso-Navarro, Elena García-Martín, Ignacio Álvarez, Pau Pastor y José A. G. Agúndez. "Genomic Markers for Essential Tremor". Pharmaceuticals 14, n.º 6 (27 de mayo de 2021): 516. http://dx.doi.org/10.3390/ph14060516.

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There are many reports suggesting an important role of genetic factors in the etiopathogenesis of essential tremor (ET), encouraging continuing the research for possible genetic markers. Linkage studies in families with ET have identified 4 genes/loci for familial ET, although the responsible gene(s) have not been identified. Genome-wide association studies (GWAS) described several variants in LINGO1, SLC1A2, STK32B, PPARGC1A, and CTNNA3, related with ET, but none of them have been confirmed in replication studies. In addition, the case-control association studies performed for candidate variants have not convincingly linked any gene with the risk for ET. Exome studies described the association of several genes with familial ET (FUS, HTRA2, TENM4, SORT1, SCN11A, NOTCH2NLC, NOS3, KCNS2, HAPLN4, USP46, CACNA1G, SLIT3, CCDC183, MMP10, and GPR151), but they were found only in singular families and, again, not found in other families or other populations, suggesting that some can be private polymorphisms. The search for responsible genes for ET is still ongoing.

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Lopes, Luciana R., Mario Fernando Prieto Peres, Kaate R. J. Vanmolkot, Patrícia R. Tobo, Eliova Zukerman, Rune R. Frants, Arn M. J. M. van den Maagdenberg y Carlos Alberto Moreira-Filho. "Mutation analysis of CACNA1A and ATP1A2 genes in Brazilian FHM families". Arquivos de Neuro-Psiquiatria 64, n.º 3a (septiembre de 2006): 549–52. http://dx.doi.org/10.1590/s0004-282x2006000400001.

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Familial hemiplegic migraine (FHM) is a rare autosomal dominant form of migraine with aura. This disease has been associated with missense mutations in the CACNA1A and ATP1A2 genes. The aim of this study was to identify whether CACNA1A and ATP1A2 are or not related to Brazilian FHM. Here we screened four Brazilian FHM families (total of 26 individuals - 13 affected and 13 asymptomatic or normal) for mutations in both genes. We found an amino acid change in a member of family FHM-D (Arg2206Gly). However since this alteration is not present in all affected individuals and is present in one asymptomatic individual it should be considered a polymorphism. Further studies with additional families will be necessary to reveal the importance of both CACNA1A and ATP1A2 genes on the pathogeneses of FHM in Brazil and to test the third gene (SCN1A) in these FHM families.

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24

Cardenas, Ryan, Peter Prinsley, Carl Philpott, Mahmood F. Bhutta, Emma Wilson, Daniel S. Brewer y Barbara A. Jennings. "Whole exome sequencing study identifies candidate loss of function variants and locus heterogeneity in familial cholesteatoma". PLOS ONE 18, n.º 3 (15 de marzo de 2023): e0272174. http://dx.doi.org/10.1371/journal.pone.0272174.

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Cholesteatoma is a rare progressive disease of the middle ear. Most cases are sporadic, but some patients report a positive family history. Identifying functionally important gene variants associated with this disease has the potential to uncover the molecular basis of cholesteatoma pathology with implications for disease prevention, surveillance, or management. We performed an observational WES study of 21 individuals treated for cholesteatoma who were recruited from ten multiply affected families. These family studies were complemented with gene-level mutational burden analysis. We also applied functional enrichment analyses to identify shared properties and pathways for candidate genes and their products. Filtered data collected from pairs and trios of participants within the ten families revealed 398 rare, loss of function (LOF) variants co-segregating with cholesteatoma in 389 genes. We identified six genes DENND2C, DNAH7, NBEAL1, NEB, PRRC2C, and SHC2, for which we found LOF variants in two or more families. The parallel gene-level analysis of mutation burden identified a significant mutation burden for the genes in the DNAH gene family, which encode products involved in ciliary structure. Functional enrichment analyses identified common pathways for the candidate genes which included GTPase regulator activity, calcium ion binding, and degradation of the extracellular matrix. The number of candidate genes identified and the locus heterogeneity that we describe within and between multiply affected families suggest that the genetic architecture for familial cholesteatoma is complex.

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25

Coon, Hilary, Todd M. Darlington, Emily DiBlasi, W. Brandon Callor, Elliott Ferris, Alison Fraser, Zhe Yu et al. "Genome-wide significant regions in 43 Utah high-risk families implicate multiple genes involved in risk for completed suicide". Molecular Psychiatry 25, n.º 11 (23 de octubre de 2018): 3077–90. http://dx.doi.org/10.1038/s41380-018-0282-3.

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Abstract Suicide is the 10th leading cause of death in the United States. Although environment has undeniable impact, evidence suggests that genetic factors play a significant role in completed suicide. We linked a resource of ~ 4500 DNA samples from completed suicides obtained from the Utah Medical Examiner to genealogical records and medical records data available on over eight million individuals. This linking has resulted in the identification of high-risk extended families (7–9 generations) with significant familial risk of completed suicide. Familial aggregation across distant relatives minimizes effects of shared environment, provides more genetically homogeneous risk groups, and magnifies genetic risks through familial repetition. We analyzed Illumina PsychArray genotypes from suicide cases in 43 high-risk families, identifying 30 distinct shared genomic segments with genome-wide evidence (p = 2.02E-07–1.30E-18) of segregation with completed suicide. The 207 genes implicated by the shared regions provide a focused set of genes for further study; 18 have been previously associated with suicide risk. Although PsychArray variants do not represent exhaustive variation within the 207 genes, we investigated these for specific segregation within the high-risk families, and for association of variants with predicted functional impact in ~ 1300 additional Utah suicides unrelated to the discovery families. None of the limited PsychArray variants explained the high-risk family segregation; sequencing of these regions will be needed to discover segregating risk variants, which may be rarer or regulatory. However, additional association tests yielded four significant PsychArray variants (SP110, rs181058279; AGBL2, rs76215382; SUCLA2, rs121908538; APH1B, rs745918508), raising the likelihood that these genes confer risk of completed suicide.

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26

Helgadottir, Hafdis T., Jessada Thutkawkorapin, Anna Rohlin, Margareta Nordling, Kristina Lagerstedt‐Robinson y Annika Lindblom. "Identification of known and novel familial cancer genes in Swedish colorectal cancer families". International Journal of Cancer 149, n.º 3 (25 de marzo de 2021): 627–34. http://dx.doi.org/10.1002/ijc.33567.

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27

Iruzubieta, Pablo, David Campo-Caballero, Jon Equiza, Inés Albajar, Naroa Sulibarría, Raquel Sáez, Naiara Andrés et al. "Description of Two Families with New Mutations in Familial Cerebral Cavernous Malformations Genes". Journal of Stroke and Cerebrovascular Diseases 30, n.º 12 (diciembre de 2021): 106130. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106130.

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Slater, Emily P., Lisa M. Wilke, Lutz Benedikt Böhm, Konstantin Strauch, Manuel Lutz, Norman Gercke, Elvira Matthäi et al. "Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer". Journal of Personalized Medicine 11, n.º 7 (2 de julio de 2021): 631. http://dx.doi.org/10.3390/jpm11070631.

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Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10–15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants.

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29

Zbar, Berton, Richard Klausner y W. Marston Linehan. "Studying Cancer Families to Identify Kidney Cancer Genes". Annual Review of Medicine 54, n.º 1 (febrero de 2003): 217–33. http://dx.doi.org/10.1146/annurev.med.54.101601.152514.

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Daniels, Gary R. y Prescott L. Deininger. "Repeat sequence families derived from mammalian tRNA genes". Nature 317, n.º 6040 (octubre de 1985): 819–22. http://dx.doi.org/10.1038/317819a0.

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Christophides, George K., Evgeny Zdobnov, Carolina Barillas-Mury, Ewan Birney, Stephanie Blandin, Claudia Blass, Paul T. Brey et al. "Immunity-Related Genes and Gene Families inAnopheles gambiae". Science 298, n.º 5591 (4 de octubre de 2002): 159–65. http://dx.doi.org/10.1126/science.1077136.

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MAYER, G., A. LATTERMANN, G. MUELLER‐ECKHARDT, E. SVANBORG y K. MEIER‐EWERT. "Segregation of HLA genes in multicase narcolepsy families". Journal of Sleep Research 7, n.º 2 (junio de 1998): 127–33. http://dx.doi.org/10.1046/j.1365-2869.1998.00105.x.

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Alexandre, Sylvie, Pascale Paindavoine, Jacqueline Hanocq-Quertier, Francoise Paturiaux-Hanocq, Patricia Tebabi y Etienne Pays. "Families of adenylate cyclase genes in Trypanosoma brucei". Molecular and Biochemical Parasitology 77, n.º 2 (mayo de 1996): 173–82. http://dx.doi.org/10.1016/0166-6851(96)02591-1.

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34

Maeda, N. y O. Smithies. "The Evolution of Multigene Families: Human Haptoglobin Genes". Annual Review of Genetics 20, n.º 1 (diciembre de 1986): 81–108. http://dx.doi.org/10.1146/annurev.ge.20.120186.000501.

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35

Arehart-Treichel, Joan. "Genes May Hold Key, But Families Turn It". Psychiatric News 39, n.º 10 (21 de mayo de 2004): 36. http://dx.doi.org/10.1176/pn.39.10.0036.

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Sørensen, T. I. A. y A. J. Stunkard. "Does obesity run in families because of genes?." Acta Psychiatrica Scandinavica 87, S370 (abril de 1993): 67–72. http://dx.doi.org/10.1111/j.1600-0447.1993.tb05363.x.

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37

Barlassina, C. "Genetics of Essential Hypertension: From Families to Genes". Journal of the American Society of Nephrology 13, n.º 90003 (1 de noviembre de 2002): 155S—164. http://dx.doi.org/10.1097/01.asn.0000032524.13069.88.

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38

Mahaney, F. X. "Scientists Study Families in Pursuit of Cancer Genes". JNCI Journal of the National Cancer Institute 83, n.º 2 (16 de enero de 1991): 82–83. http://dx.doi.org/10.1093/jnci/83.2.82.

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39

Kaplan, Norman L. y Richard R. Hudson. "On the divergence of genes in multigene families". Theoretical Population Biology 31, n.º 1 (febrero de 1987): 178–94. http://dx.doi.org/10.1016/0040-5809(87)90028-1.

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40

Bianchi, Michele M., Geppo Sartori, Micheline Vandenbol, Aneta Kaniak, Daniela Uccelletti, Cristina Mazzoni, Jean-Paul di Rago, Giovanna Carignani, Piotr P. Slonimski y Laura Frontali. "How to bring orphan genes into functional families". Yeast 15, n.º 6 (abril de 1999): 513–26. http://dx.doi.org/10.1002/(sici)1097-0061(199904)15:6<513::aid-yea370>3.0.co;2-p.

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41

Høyer, Helle, Geir J. Braathen, Øyvind L. Busk, Øystein L. Holla, Marit Svendsen, Hilde T. Hilmarsen, Linda Strand, Camilla F. Skjelbred y Michael B. Russell. "Genetic Diagnosis of Charcot-Marie-Tooth Disease in a Population by Next-Generation Sequencing". BioMed Research International 2014 (2014): 1–13. http://dx.doi.org/10.1155/2014/210401.

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Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited neuropathy. Today more than 40 CMT genes have been identified. Diagnosing heterogeneous diseases by conventional Sanger sequencing is time consuming and expensive. Thus, more efficient and less costly methods are needed in clinical diagnostics. We included a population based sample of 81 CMT families. Gene mutations had previously been identified in 22 families; the remaining 59 families were analysed by next-generation sequencing. Thirty-two CMT genes and 19 genes causing other inherited neuropathies were included in a custom panel. Variants were classified into five pathogenicity classes by genotype-phenotype correlations and bioinformatics tools. Gene mutations, classified certainly or likely pathogenic, were identified in 37 (46%) of the 81 families. Point mutations in known CMT genes were identified in 21 families (26%), whereas four families (5%) had point mutations in other neuropathy genes,ARHGEF10, POLG, SETX,andSOD1. Eleven families (14%) carried thePMP22duplication and one family carried aMPZduplication (1%). Most mutations were identified not only in known CMT genes but also in other neuropathy genes, emphasising that genetic analysis should not be restricted to CMT genes only. Next-generation sequencing is a cost-effective tool in diagnosis of CMT improving diagnostic precision and time efficiency.

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42

Hahn, Christopher N., Milena Babic, Peter J. Brautigan, Parvathy Venugopal, Kerry Phillips, Julia Dobbins, Peer Arts et al. "Australian Familial Haematological Cancer Study - Findings from 15 Years of Aggregated Clinical, Genomic and Transcriptomic Data". Blood 134, Supplement_1 (13 de noviembre de 2019): 1439. http://dx.doi.org/10.1182/blood-2019-131686.

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The Australian Familial Haematological Cancer Study (AFHCS) was initiated in 2004 with the aim to define genes predisposing to hematological malignancy (HM) to offer better options for clinical decision making and genetic counselling, and to identify therapeutic targets. The study is a referral centre for Australia and New Zealand, and currently has 230 families with multiple cases of myeloid and/or lymphoid malignancies or early onset cases (Figure 1), and is growing as clinical awareness of a germline genetic basis for blood cancers increases. To date, we have identified families with causal germline variants in several predisposition genes (five GATA2, ten RUNX1, one CEBPA, ten DDX41, one SAMD9L) including novel single nucleotide variants, deletions and insertions in coding and intronic sequences using traditional Sanger sequencing and now genomic and transcriptomic technologies. Of these, one GATA2 and four DDX41 germline mutations were identified during the screening of "sporadic" MDS samples. All four DDX41 mutant samples also harbored a somatic DDX41 (R525H) variant on the other allele at a low variant allele frequency. A comprehensive clinical analysis of the RUNX1 families has uncovered segregating phenotypes, in addition to thrombocytopenia and myeloid and lymphoid malignancies, including skin disorders such as psoriasis. In an increasing number of individuals in these families, important clinical decisions have been made dependent on mutation carrier status. Recently, we have identified and characterized a unique myeloproliferative neoplasm (MPN)/acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) family with a germline Chr14q duplication that overlaps with duplications in two other reported MPN/AML families. This appears to be a unique genotypic/phenotypic entity when compared to other myeloid predisposition genes and their associated phenotypes. Interestingly, we have identified several families carrying heterozygous pathogenic/likely pathogenic variants in genes representing autosomal recessive genomic instability syndromes segregating with HM. Here mutations in the genes NBN, RECQL4, DDX11 and RAD21 appear to act in an autosomal dominant manner. Further, we have found DNA damage repair gene predicted pathogenic variants in PALB2 and BARD1 in families with both solid cancers and HM, predominantly lymphomas, implicating an expansion of the major predisposition phenotype of these gene perturbations. Familial cases of chronic lymphocytic leukemia (CLL) have been well recognized, but it has been particularly difficult to identify predisposing variants. We have identified a number of strong candidate genes/variants in CLL families including PRPF8 (Y208C and N400S) and SAMHD1 (R371H) although more families are required to confirm these. An integral part of the AFHCS is the continued generation of cell and animal models to help define mechanisms of action of predicted or known pathogenic variants, and functional model systems for testing of variants of unknown significance. To facilitate the collection of patient samples, we have adopted the use of hair bulbs as the main germline sample as they are easy to collect, can be easily sent long distance by mail at room temperature, require no culture, are quickly and cheaply processed and provide good quality DNA using automated procedures. Overall, collaborative efforts within Australia and New Zealand and internationally have been highly fruitful in solving familial cases of hematopoietic malignancies over the last 15 years, and even more concerted international efforts will be required in the future to uncover the familial basis of unsolved cases, particularly in the lymphoid lineage, and to clarify best approaches for clinical decision making and treatment options. Figure 1. Summary of AFHCS families with associated hematological malignancies. Figure Disclosures Scott: Celgene: Honoraria.

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Andrés-Zayas, Cristina, Julia Suárez-González, María Chicano-Lavilla, Mariana Bastos Oreiro, Gabriela Rodríguez-Macías, Patricia Font López, Santiago Osorio Prendes et al. "Novel Candidate loci and Pathogenic Germline Variants Involved in Familial Hematological Malignancies Revealed by Whole-Exome Sequencing". Cancers 15, n.º 3 (2 de febrero de 2023): 944. http://dx.doi.org/10.3390/cancers15030944.

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The familial occurrence of hematological malignancies has been underappreciated. Recent studies suggest that up to 15% of adults with myeloid neoplasms carry germline pathogenic variants in cancer-predisposing genes. This study aimed to identify the underlying germline predisposition variant in patients with a strong family or personal onco-hematological history using whole exome sequencing on sixteen uncharacterized individuals. It was carried out in two groups of patients, one with samples available from two affected relatives (Cohort A) and one with available samples from the index case (Cohort B). In Cohort A, six families were characterized. Two families shared variants in genes associated with DNA damage response and involved in cancer development (CHEK2 and RAD54L). Pathogenic or likely pathogenic germline variants were also found in novel candidate genes (NFATC2 and TC2N). In two families, any relevant pathogenic or likely pathogenic genomic variants were identified. In Cohort B, four additional index cases were analyzed. Three of them harbor clinically relevant variants in genes with a probable role in the development of inherited forms of hematological malignancies (GATA1, MSH4 and PRF1). Overall, whole exome sequencing is a useful approach to achieve a further characterization of these patients and their mutational spectra. Moreover, further investigations may help improve optimization for disease management of affected patients and their families.

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44

Turley, Tamiel N., Jeanne L. Theis, Jared M. Evans, Zachary C. Fogarty, Rajiv Gulati, Sharonne N. Hayes, Marysia S. Tweet y Timothy M. Olson. "Identification of Rare Genetic Variants in Familial Spontaneous Coronary Artery Dissection and Evidence for Shared Biological Pathways". Journal of Cardiovascular Development and Disease 10, n.º 9 (12 de septiembre de 2023): 393. http://dx.doi.org/10.3390/jcdd10090393.

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Rare familial spontaneous coronary artery dissection (SCAD) kindreds implicate genetic disease predisposition and provide a unique opportunity for candidate gene discovery. Whole-genome sequencing was performed in fifteen probands with non-syndromic SCAD who had a relative with SCAD, eight of whom had a second relative with extra-coronary arteriopathy. Co-segregating variants and associated genes were prioritized by quantitative variant, gene, and disease-level metrics. Curated public databases were queried for functional relationships among encoded proteins. Fifty-four heterozygous coding variants in thirteen families co-segregated with disease and fulfilled primary filters of rarity, gene variation constraint, and predicted-deleterious protein effect. Secondary filters yielded 11 prioritized candidate genes in 12 families, with high arterial tissue expression (n = 7), high-confidence protein-level interactions with genes associated with SCAD previously (n = 10), and/or previous associations with connective tissue disorders and aortopathies (n = 3) or other vascular phenotypes in mice or humans (n = 11). High-confidence associations were identified among 10 familial SCAD candidate-gene-encoded proteins. A collagen-encoding gene was identified in five families, two with distinct variants in COL4A2. Familial SCAD is genetically heterogeneous, yet perturbations of extracellular matrix, cytoskeletal, and cell–cell adhesion proteins implicate common disease-susceptibility pathways. Incomplete penetrance and variable expression suggest genetic or environmental modifiers.

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Grond-Ginsbach, Caspar, Tobias Brandt, Manja Kloss, Suna Su Aksay, Philipp Lyrer, Christopher Traenka, Philipp Erhart et al. "Next generation sequencing analysis of patients with familial cervical artery dissection". European Stroke Journal 2, n.º 2 (9 de febrero de 2017): 137–43. http://dx.doi.org/10.1177/2396987317693402.

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Background The cause of cervical artery dissection is not well understood. We test the hypothesis that mutations in genes associated with known arterial connective tissue disorders are enriched in patients with familial cervical artery dissection. Patients and methods Patient duos from nine pedigrees with familial cervical artery dissection were analyzed by whole exome sequencing. Single nucleotide variants in a panel of 11 candidate genes (ACTA2, MYH11, FBN1, TGFBR1, TGFBR2, TGFB2, COL3A1, COL4A1, SMAD3, MYLK and SLC2A10) were prioritized according to functionality (stop-loss, nonsense, and missense variants with polyphen-2 score ≥0.95). Variants classified as “benign” or “likely benign” in the ClinVar database were excluded from further analysis. For comparison, non-benign stop-loss, nonsense and missense variants with polyphen-2 score ≥0.95 in the same panel of candidate genes were identified in the European non-Finnish population of the ExAC database ( n = 33,370). Results Non-benign Single nucleotide variants in both affected patients were identified in four of the nine cervical artery dissection families (COL3A1; Gly324Ser, FBN1: Arg2554Trp, COL4A1: Pro116Leu, and TGFBR2: Ala292Thr) yielding an allele frequency of 22.2% (4/18). In the comparison group, 1782 variants were present in 33,370 subjects from the ExAC database (allele frequency: 1782/66,740 = 2.7%; p = 0.0008; odds ratio = 14.2; 95% confidence interval = 3.8–52.9). Conclusion Cervical artery dissection families showed enrichment for non-benign variants in genes associated with arterial connective tissue disorders. The observation that findings differed across families indicates genetic heterogeneity of familial cervical artery dissection.

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Tous, Cristina, Carmen Muñoz-Redondo, Nereida Bravo-Gil, Angela Gavilan, Raquel María Fernández, Juan Antiñolo, Elena Navarro-González, Guillermo Antiñolo y Salud Borrego. "Identification of Novel Candidate Genes for Familial Thyroid Cancer by Whole Exome Sequencing". International Journal of Molecular Sciences 24, n.º 9 (25 de abril de 2023): 7843. http://dx.doi.org/10.3390/ijms24097843.

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Thyroid carcinoma (TC) can be classified as medullary (MTC) and non-medullary (NMTC). While most TCs are sporadic, familial forms of MTC and NMTC also exist (less than 1% and 3–9% of all TC cases, respectively). Germline mutations in RET are found in more than 95% of familial MTC, whereas familial NMTC shows a high degree of genetic heterogeneity. Herein, we aimed to identify susceptibility genes for familial NMTC and non-RET MTC by whole exome sequencing in 58 individuals belonging to 18 Spanish families with these carcinomas. After data analysis, 53 rare candidate segregating variants were identified in 12 of the families, 7 of them located in previously TC-associated genes. Although no common mutated genes were detected, biological processes regulating functions such as cell proliferation, differentiation, survival and adhesion were enriched. The reported functions of the identified genes together with pathogenicity and structural predictions, reinforced the candidacy of 36 of them, suggesting new loci related to TC and novel genotype–phenotype correlations. Therefore, our strategy provides clues to possible molecular mechanisms underlying familial forms of MTC and NMTC. These new molecular findings and clinical data of patients may be helpful for the early detection, development of tailored therapies and optimizing patient management.

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Kuzmenko, N. B., A. A. Mukhina, Yu A. Rodina, A. L. Kozlova, E. V. Deripapa, E. A. Viktorova, D. V. Yukhacheva, E. V. Raykina, D. E. Pershin y A. Yu Shcherbina. "Analysis of familial cases of primary immunodeficiency in the context of genetic counseling". Pediatric Hematology/Oncology and Immunopathology 20, n.º 4 (21 de diciembre de 2021): 125–33. http://dx.doi.org/10.24287/1726-1708-2021-20-4-125-133.

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Primary immunodeficiencies (PID) are caused by defects in genes of immune system. The mutations may occur de novo or can be inherited. The frequency of familial PID cases varies in different populations and depends on multiple factors. The aim of this study was to analyze familial PID cases among pediatric patients from NMRCPHOI D. Rogachev. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. 1075 children from 1020 families with molecular PID diagnosis were analyzed retrospectively. One hundred and forty-six children had at least one relative with the same disorder; mutations were identified in 31 PID’s genes. The frequency of familial cases was 13.6%. The proportion of families with two or more affected children was 5.4%. Patients born in a consanguineous marriage made up 3% of the observed children. Autosomal dominant PID were typical for families with affected adult relatives. Because of the high amount of familial cases, all parents of children with PID as well as adult PID patients of childbearing age should seek a familial genetic counselling immediately after the corresponding diagnosis. Patients whose PID diagnosis has not been genetically verified, should be urgently tested to find an underlying molecular genetic cause of the disease. Prenatal/preimplantation diagnostic and screening of their close relatives are very important in these families.

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Wang, Yupeng, Ying Sun y Paule V. Joseph. "Diverse evolutionary rates and gene duplication patterns among families of functional olfactory receptor genes in humans". PLOS ONE 18, n.º 4 (20 de abril de 2023): e0282575. http://dx.doi.org/10.1371/journal.pone.0282575.

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In humans, odors are detected by ~400 functional olfactory receptor (OR) genes. The superfamily of functional OR genes can be further divided into tens of families. In large part, the OR genes have experienced extensive tandem duplications, which have led to gene gains and losses. However, whether different OR gene families have experienced distinct modes of gene duplication has yet to be reported. We conducted comparative genomic and evolutionary analyses for human functional OR genes. Based on analysis of human-mouse 1–1 orthologs, we found that human functional OR genes show higher-than-average evolutionary rates, and there are significant differences among families of functional OR genes. Via comparison with seven vertebrate outgroups, families of human functional OR genes show different extents of gene synteny conservation. Although the superfamily of human functional OR genes is enriched in tandem and proximal duplications, there are particular families which are enriched in segmental duplications. These findings suggest that human functional OR genes may be governed by different evolutionary mechanisms and that large-scale gene duplications have contributed to the early evolution of human functional OR genes.

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Díaz-Gay, Marcos, Sebastià Franch-Expósito, Coral Arnau-Collell, Solip Park, Fran Supek, Jenifer Muñoz, Laia Bonjoch et al. "Integrated Analysis of Germline and Tumor DNA Identifies New Candidate Genes Involved in Familial Colorectal Cancer". Cancers 11, n.º 3 (13 de marzo de 2019): 362. http://dx.doi.org/10.3390/cancers11030362.

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Colorectal cancer (CRC) shows aggregation in some families but no alterations in the known hereditary CRC genes. We aimed to identify new candidate genes which are potentially involved in germline predisposition to familial CRC. An integrated analysis of germline and tumor whole-exome sequencing data was performed in 18 unrelated CRC families. Deleterious single nucleotide variants (SNV), short insertions and deletions (indels), copy number variants (CNVs) and loss of heterozygosity (LOH) were assessed as candidates for first germline or second somatic hits. Candidate tumor suppressor genes were selected when alterations were detected in both germline and somatic DNA, fulfilling Knudson’s two-hit hypothesis. Somatic mutational profiling and signature analysis were also performed. A series of germline-somatic variant pairs were detected. In all cases, the first hit was presented as a rare SNV/indel, whereas the second hit was either a different SNV (3 genes) or LOH affecting the same gene (141 genes). BRCA2, BLM, ERCC2, RECQL, REV3L and RIF1 were among the most promising candidate genes for germline CRC predisposition. The identification of new candidate genes involved in familial CRC could be achieved by our integrated analysis. Further functional studies and replication in additional cohorts are required to confirm the selected candidates.

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Landgren, Ola, Sigurdur Y. Kristinsson, Xueying Sharon Liang, Ingemar Turesson, Magnus Bjorkholm, Neil E. Caporaso, Mary L. McMaster, Stephen Chanock y Lynn R. Goldin. "Germline Genes Specific to Chronic Lymphocytic Leukemia (CLL) and Genes Common to CLL, Lymphoplasmacytic Lymphoma/Waldenström’s Macroglobulinemia, and Other Non-Hodgkin Lymphomas Are Important in Susceptibility". Blood 112, n.º 11 (16 de noviembre de 2008): 3127. http://dx.doi.org/10.1182/blood.v112.11.3127.3127.

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Abstract Background. Evidence from multiply affected families, case-control and population-based registry studies implicate a role for genetic factors in chronic lymphocytic leukemia (CLL). Population-based studies have found CLL and non-Hodgkin lymphomas (NHLs) to aggregate in families. The aim of this study was to expand our understanding on the role of susceptibility genes in CLL and other lymphoproliferative malignancies. Methods. Using the population-based Swedish Population-, Cancer-, and Multigenerational registries, we identified all CLL patients (n=9,717) diagnosed from 1958–2004 with linkable first-degree relatives (N=26,947). We also obtained information on 38,159 matched controls and their 107,223 first-degree relatives. Cancer risks in relatives of CLL patients were compared with those in relatives of controls using marginal survival models. In parallel, we conducted a candidate gene association study in unrelated familial lymphoma cases (44 CLL, 71 Waldenström’s macroglobulinemia (WM)) from our clinical studies of high risk families (which were selected for having multiple cases of either CLL or WM) compared to 107 spouses from the same families. We tested 1536 single nucleotide polymorphisms (SNPs) in 152 candidate genes in several pathways including apoptosis, DNA repair, immune response, and oxidative stress using a custom Illumina genotyping platform. Results. In our population-based study, we found relatives of CLL patients to have an increased risk for CLL (relative risk [RR]=8.5, 95%CI=6.1–11.7), lymphoplasmacytic lymphoma (LPL)/WM (RR=4.0, 95%CI=2.0–8.2) and other NHLs (RR=1.7, 95%CI=1.4–2.2), but not for Hodgkin lymphoma, multiple myeloma, or other hematologic tumors. In our SNP-based study, we found several genes (e.g., IL-10, BCL-2, TRAIL, and TRAILR1) to be significantly associated with both familial CLL and WM. In particular, a SNP in the promoter region of IL-10 (rs1800890, −3575T>A), which has been previously detected in other NHL case-control studies, was associated with both CLL and WM. Conclusions. We conclude that germline genes specific to CLL and genes common to CLL, LPL/WM and other NHLs are important in susceptibility. We found consistent patterns in both our population-based study and our clinical high-risk families. Our findings for BCL-2, TRAIL, and TRAILR1 highlight the important role of apoptosis pathways in the etiology of these lymphomas. Better characterization of early genetic lesions will ultimately provide clues to pathogenesis and allow identification of novel molecular targets.

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