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Rahit, K. M. Tahsin Hassan, and Maja Tarailo-Graovac. "Genetic Modifiers and Rare Mendelian Disease." Genes 11, no. 3 (February 25, 2020): 239. http://dx.doi.org/10.3390/genes11030239.
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Despite advances in high-throughput sequencing that have revolutionized the discovery of gene defects in rare Mendelian diseases, there are still gaps in translating individual genome variation to observed phenotypic outcomes. While we continue to improve genomics approaches to identify primary disease-causing variants, it is evident that no genetic variant acts alone. In other words, some other variants in the genome (genetic modifiers) may alleviate (suppress) or exacerbate (enhance) the severity of the disease, resulting in the variability of phenotypic outcomes. Thus, to truly understand the disease, we need to consider how the disease-causing variants interact with the rest of the genome in an individual. Here, we review the current state-of-the-field in the identification of genetic modifiers in rare Mendelian diseases and discuss the potential for future approaches that could bridge the existing gap.
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Millán, José M., and Gema García-García. "Genetic Testing for Rare Diseases." Diagnostics 12, no. 4 (March 25, 2022): 809. http://dx.doi.org/10.3390/diagnostics12040809.
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Rasso, A., K. Boukhari, H. Baybay, S. Elloudi, Z. Douhi, and FZ Mernissi. "A Rare Genetic Diseases; Incontinentia Pigmenti: A Case Report." Journal of Clinical Research and Reports 3, no. 3 (March 6, 2020): 01–02. http://dx.doi.org/10.31579/2690-1919/060.
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A 3 years-old girl, born of a 25-year-old mother, and of 30-year-old father, with a 1st degree consanguineous marriage. She was born full term after an uneventful pregnancy. History of similar disease was not present in her family. The parents consulted pour management of skin lesion. with no associated functional signs including no mental retardation, no epilepsy. they report that her skin had been fiery red at the birth time and vesicles had developed shortly afterwards. Then the lesions had cleared gradually and left linear hypo-pigmentation. On clinical examination, showed a facial asymmetry, especially mandibular. Hypopigmented atrophic streaks were seen in her face abdomen, back and limbs, with a baschko-linear path. And she had a syndactyly from the toes of the feet. And. The disease was diagnosed as Incontinentia pigmenti (IP). The ophthalmic exam was normal. Her genetic counseling was otherwise normal. A dental radio-panoramic, and MRI of the cerebral, and lumbosacral spine have been requested.
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Walsh, Roddy, Rafik Tadros, and Connie R. Bezzina. "When genetic burden reaches threshold." European Heart Journal 41, no. 39 (April 29, 2020): 3849–55. http://dx.doi.org/10.1093/eurheartj/ehaa269.
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Abstract Rare cardiac genetic diseases have generally been considered to be broadly Mendelian in nature, with clinical genetic testing for these conditions predicated on the detection of a primary causative rare pathogenic variant that will enable cascade genetic screening in families. However, substantial variability in penetrance and disease severity among carriers of pathogenic variants, as well as the inability to detect rare Mendelian variants in considerable proportions of patients, indicates that more complex aetiologies are likely to underlie these diseases. Recent findings have suggested genetic variants across a range of population frequencies and effect sizes may combine, along with non-genetic factors, to determine whether the threshold for expression of disease is reached and the severity of the phenotype. The availability of increasingly large genetically characterized cohorts of patients with rare cardiac diseases is enabling the discovery of common genetic variation that may underlie both variable penetrance in Mendelian diseases and the genetic aetiology of apparently non-Mendelian rare cardiac conditions. It is likely that the genetic architecture of rare cardiac diseases will vary considerably between different conditions as well as between patients with similar phenotypes, ranging from near-Mendelian disease to models more akin to common, complex disease. Uncovering the broad range of genetic factors that predispose patients to rare cardiac diseases offers the promise of improved risk prediction and more focused clinical management in patients and their families.
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V Chandrasekhar. "Rare Diseases - Orphan Drugs." TELANGANA JOURNAL OF IMA 02, no. 02 (2022): 25–32. http://dx.doi.org/10.52314/tjima.2022.v2i2.82.
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Rare diseases (RDs) are a class of diseases that do not affect most of the population. Apart from the common diseases that affect most people, some severely rare diseases often pose unique challenges to society and the healthcare systems in India. According to the National Institute of Health (NIH), the F.D.A., and the National Organization for Rare Disorders (NORD), a rare disease is any disease, disorder, illness or condition affecting fewer than 200,000 people in the United States as defined by the Orphan Drug Designation Program. However, 95% of rare diseases currently have no treatment available. Healthcare Experts estimate that around 7000 rare diseases have been identified globally, out of which 450 have been reported in India, like hemophilia, thalas-semia, sickle cell anemia, and Pompe’s disease. Rare diseases come in many forms, including cancers and auto-immune diseases. Drugs for rare diseases are among the highest-priced medications on the market than other common drugs. A medical advisory board of nationally recognized and specialized physicians can help build in-depth case management tools and clinical decision support systems to develop and advance novel therapies. Recognition of carriers harbouring clinically pathogenic genetic vari-ations is essential to provide proper genetic counselling to the patient and management. The precise delineation of distinct RDs is possible through a meticulous clinical evaluation of the patients and their genetic screening. The Electronic Health Record (E.H.R.) helps foster collaboration and better outcomes. A holistic approach should be integrated across health care providers, both at the pharmacy and medical level, that helps improve patient experience and outcomes and reduce costs. Strong health poli-cies and initiatives are required both from private and government institutions for orphan drug development. A separate course on Clinical Genetics must be included in the academic curriculum of medical students in order to provide them knowledge on the basic concepts of genetics and its applications in human health.
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Bellen, Hugo J., Michael F. Wangler, and Shinya Yamamoto. "The fruit fly at the interface of diagnosis and pathogenic mechanisms of rare and common human diseases." Human Molecular Genetics 28, R2 (June 22, 2019): R207—R214. http://dx.doi.org/10.1093/hmg/ddz135.
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Abstract Drosophila melanogaster is a unique, powerful genetic model organism for studying a broad range of biological questions. Human studies that probe the genetic causes of rare and undiagnosed diseases using massive-parallel sequencing often require complementary gene function studies to determine if and how rare variants affect gene function. These studies also provide inroads to disease mechanisms and therapeutic targets. In this review we discuss strategies for functional studies of rare human variants in Drosophila. We focus on our experience in establishing a Drosophila core of the Model Organisms Screening Center for the Undiagnosed Diseases Network (UDN) and concurrent fly studies with other large genomic rare disease research efforts such as the Centers for Mendelian Genomics. We outline four major strategies that use the latest technology in fly genetics to understand the impact of human variants on gene function. We also mention general concepts in probing disease mechanisms, therapeutics and using rare disease to understand common diseases. Drosophila is and will continue to be a fundamental genetic model to identify new disease-causing variants, pathogenic mechanisms and drugs that will impact medicine.
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More, Avinash Narayan. "Gaucher’s disease : a rare genetic disorder." International Journal of Scientific and Research Publications 12, no. 10 (October 24, 2022): 321–24. http://dx.doi.org/10.29322/ijsrp.12.10.2022.p13044.
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Voelker, Rebecca. "First Drug for Rare Genetic Disease." JAMA 317, no. 5 (February 7, 2017): 466. http://dx.doi.org/10.1001/jama.2017.0028.
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Sannikova, A. V., R. M. Fayzullina, Z. A. Shangareeva, I. D. Sartaniya, and G. R. Bayazitova. "RARE GENETIC DISEASE: BORING – OPITZ SYNDROME." Научное обозрение. Медицинские науки (Scientific Review. Medical Sciences), no. 1 2025 (2025): 22–28. https://doi.org/10.17513/srms.1430.
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Kutsev, S. I., and S. Moiseev. "Family genetic screening in rare hereditary diseases." Clinical pharmacology and therapy 31, no. 4 (November 13, 2021): 6–12. http://dx.doi.org/10.32756/0869-5490-2021-4-6-12.
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Family genetic testing of probands with newly diagnosed rare hereditary diseases including Fabry disease improves early diagnosis and allows to initiate specific treatment, if available, at earlier stage in affected family members. Diagnosis of Fabry disease, an X-linked lysosomal storage disorder affecting kidneys, heart, brain and other organs, is usually late due to low awareness of physicians about rare diseases. Moreover, early symptoms can be non-specific (e.g. gastrointestinal disorders and autonomic neuropathy) or misleading (e.g. recurrent unexplained fever) whereas characteristic skin rash and keratopathy (cornea verticillata) are frequently overlooked. Undiagnosed patients with Fabry disease can be detected by screening in at-risk populations, such as patients with end-stage renal disease undergoing dialysis or renal transplantation, patients with unexplained left ventricular hypertrophy, and young adults with a history of stroke or transient ischemic attack who have a higher prevalence of the disease compared to general population. High-risk screening paves the way to family screening to identify affected relatives, including children, who can benefit from earlier treatment and genetic counselling. The major barriers to family screening include costs of testing, cultural and societal issues, stigma associated with a diagnosis of genetic disease, low contacts in the family, weak infrastructure, national regulations.
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Chen, Jing, Huan Xu, Anil Jegga, Kejian Zhang, Pete S. White, and Ge Zhang. "Novel phenotype–disease matching tool for rare genetic diseases." Genetics in Medicine 21, no. 2 (June 12, 2018): 339–46. http://dx.doi.org/10.1038/s41436-018-0050-4.
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Maroilley, Tatiana, and Maja Tarailo-Graovac. "Uncovering Missing Heritability in Rare Diseases." Genes 10, no. 4 (April 4, 2019): 275. http://dx.doi.org/10.3390/genes10040275.
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The problem of ‘missing heritability’ affects both common and rare diseases hindering: discovery, diagnosis, and patient care. The ‘missing heritability’ concept has been mainly associated with common and complex diseases where promising modern technological advances, like genome-wide association studies (GWAS), were unable to uncover the complete genetic mechanism of the disease/trait. Although rare diseases (RDs) have low prevalence individually, collectively they are common. Furthermore, multi-level genetic and phenotypic complexity when combined with the individual rarity of these conditions poses an important challenge in the quest to identify causative genetic changes in RD patients. In recent years, high throughput sequencing has accelerated discovery and diagnosis in RDs. However, despite the several-fold increase (from ~10% using traditional to ~40% using genome-wide genetic testing) in finding genetic causes of these diseases in RD patients, as is the case in common diseases—the majority of RDs are also facing the ‘missing heritability’ problem. This review outlines the key role of high throughput sequencing in uncovering genetics behind RDs, with a particular focus on genome sequencing. We review current advances and challenges of sequencing technologies, bioinformatics approaches, and resources.
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Nuha Majeed Farhan, Lubab Mohammed Awad, and Intisar Masier Abd. "The Role of Genetics in Neurological Disorders: From Rare Diseases to Common Conditions." Academic International Journal of Medical Update 2, no. 2 (October 16, 2024): 35–43. http://dx.doi.org/10.59675/u226.
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Neurological disorders result from neurological diseases affecting the brain, spinal cord and peripheral nerves and include rare genetic diseases like Huntington’s disease and spinal muscular atrophy, as well as common diseases such as Alzheimer’s, Parkinson’s disease and epilepsy. These conditions are strongly influenced by genetics, and genetics contribute to the onset, the progression of the disease, the severity of symptoms and treatment responsiveness. Genetics is relevant not only to inheritance, but also to de novo mutations, polygenic risk factors and gene environment interactions that contribute to the clinical phenotype of these disorders. Although the many mutations and heredity patterns of neurological conditions have not been worked out completely, genetic research has come a long way to help us learn more about these conditions. Single gene mutations are invaluable particularly for rare disorders for early diagnosis and targeted interventions. For instance, predictive gene testing such as checking for the HTT gene mutation linked to Huntington's disease allows people to learn if they are at risk of the disease early on — before their symptoms develop. On the other hand, most common neurological disorders involve genetic landscapes much more complicated, with small increases in risk due to more than one gene. Since epigenetic factors and certain environmental factors can further influence these risks, prevention is always in order. For example, people with APOE ε4 allele are more likely to develop Alzheimer’s disease but lifestyle factors such as dietary and exercise may reduce this risk. Such complexity emphasizes the necessity for complete studies, including genome wide association studies (GWAS), epigenetics, and transcriptomics to define molecular mechanisms of these multifactorial disorders. Genetic testing has recently become one of the most important tools in neurology, allowing us to make early diagnosis with great precision and to offer a comprehensive and personalized treatment plan, based on patients' genetic profile. For instance, these genetic mutations can help physicians choose the best medicines for patients with epilepsy. Gene based therapies, including gene replacement, antisense oligonucleotides (ASOs), and gene editing (e.g., CRISPR-Cas9) are newly emerging as potential treatments for human disease and as a therapeutic for spinal muscular atrophy and Duchenne muscular dystrophy. Indeed, as these therapies become more common, these must be addressed as ethical concerns, such as issues of genetic privacy, risk of genetic discrimination, and unintended consequences of genetic manipulation. The focus of this review is to give a brief but detailed account of the genetic components of neurological disorders, ranging from rare monogenic diseases to common multifactorial disorders. It describes key genetic discoveries and discusses developing genetic diagnostic and therapeutic strategies and the ethical implications related to these developments. The integration of genetic insights directly into clinical practice has the potential to provide a personal roadmap that could lead to individualizing the diagnostic, treatment and prevention approaches for neurological disorders and enhance patient outcomes.
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Bittmann, Stefan. "Genetic Treatment Approaches in Rare Pediatric Diseases." Asian Journal of Pediatric Research 14, no. 9 (August 26, 2024): 1–9. http://dx.doi.org/10.9734/ajpr/2024/v14i9382.
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Gene and cell therapies have been developed and approved for a growing number of pediatric diseases, with ongoing research for additional treatments. Each therapy is tailored to the specific disease and targets a specific genetic alteration or cell population. The development of new therapies is a complex and regulated process, with strict oversight at regional and European levels. Research begins in the laboratory and progresses through clinical trials to ensure safety and efficacy. Scientists are exploring novel therapies using human cells and tissues to model pediatric diseases. Clinical trials are conducted to evaluate the effectiveness of these therapies, and researchers are also investigating repurposing approved treatments for other diseases or aspects of the same disease.
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Koromina, Maria, Vasileios Fanaras, Gareth Baynam, Christina Mitropoulou, and George P. Patrinos. "Ethics and equity in rare disease research and healthcare." Personalized Medicine 18, no. 4 (July 2021): 407–16. http://dx.doi.org/10.2217/pme-2020-0144.
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Rapid advances in next-generation sequencing technology, particularly whole exome sequencing and whole genome sequencing, have greatly affected our understanding of genetic variation underlying rare genetic diseases. Herein, we describe ethical principles of guiding consent and sharing of genomics research data. We also discuss ethical dilemmas in rare diseases research and patient recruitment policies and address bioethical and societal aspects influencing the ethical framework for genetic testing. Moreover, we focus on addressing ethical issues surrounding research in low- and middle-income countries. Overall, this perspective aims to address key aspects and issues for building proper ethical frameworks, when conducting research involving genomics data with a particular emphasis on rare diseases and genetics testing.
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AZKUR, Dilek, Mustafa ERKOÇOĞLU, Ersoy CİVELEK, Gülen Eda ÜNİTE, and Can Naci KOCABAŞ. "A Rare Genetic Disease: Pachyonychia Congenita Type 2." Turkish Journal of Pediatric Disease 7, no. 4 (December 21, 2013): 193–95. http://dx.doi.org/10.12956/tjpd.2013.28.
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Momozawa, Yukihide, and Keijiro Mizukami. "Unique roles of rare variants in the genetics of complex diseases in humans." Journal of Human Genetics 66, no. 1 (September 18, 2020): 11–23. http://dx.doi.org/10.1038/s10038-020-00845-2.
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AbstractGenome-wide association studies have identified >10,000 genetic variants associated with various phenotypes and diseases. Although the majority are common variants, rare variants with >0.1% of minor allele frequency have been investigated by imputation and using disease-specific custom SNP arrays. Rare variants sequencing analysis mainly revealed have played unique roles in the genetics of complex diseases in humans due to their distinctive features, in contrast to common variants. Unique roles are hypothesis-free evidence for gene causality, a precise target of functional analysis for understanding disease mechanisms, a new favorable target for drug development, and a genetic marker with high disease risk for personalized medicine. As whole-genome sequencing continues to identify more rare variants, the roles associated with rare variants will also increase. However, a better estimation of the functional impact of rare variants across whole genome is needed to enhance their contribution to improvements in human health.
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Chia, Cara Lynn Marie N., Ma Teresita G. Gabriel, Leilani R. Senador, and Ciara Mae dela Cruz. "Darier-White disease: A rare genetic disorder." Journal of General-Procedural Dermatology & Venereology Indonesia 2, no. 3 (June 30, 2018): 89–92. http://dx.doi.org/10.19100/jdvi.v2i3.58.
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Castro-Sánchez, Sheila, María Álvarez-Satta, and Diana Valverde. "Bardet-Biedl syndrome: A rare genetic disease." Journal of Pediatric Genetics 02, no. 02 (July 27, 2015): 077–83. http://dx.doi.org/10.3233/pge-13051.
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Mohan, Leila S., Shabeeba Kannambalath, Vijayalakshmi Maneparambil, Soumya Nambiar, Kavitha Mohankumar, and Roohi A. Melarambath. "Brittle cornea syndrome—A rare genetic disease." Indian Journal of Ophthalmology - Case Reports 4, no. 2 (April 2024): 454–58. http://dx.doi.org/10.4103/ijo.ijo_1176_23.
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To report a case of an 8-year-old girl who presented with bluish discoloration of sclera, keratoconus, and progressive high myopia. She had a history of recurrent shoulder dislocation. A general physical examination showed a midfacial hypoplasia, upturned nares, thick and tented upper lip, and hyperextensible joints. The genetic analysis showed ZNF469 mutation suggestive of Brittle cornea syndrome 1 (BCS-1). We aim to highlight the importance of timely diagnosis and early provision of protective glasses seems to be the most important step in treating BCS.
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Enikanolaiye, Adebola, and Monica J. Justice. "Model systems inform rare disease diagnosis, therapeutic discovery and pre-clinical efficacy." Emerging Topics in Life Sciences 3, no. 1 (March 13, 2019): 1–10. http://dx.doi.org/10.1042/etls20180057.
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Abstract Model systems have played a large role in understanding human diseases and are instrumental in taking basic research findings to the clinic; however, for rare diseases, model systems play an even larger role. Here, we outline how model organisms are crucial for confirming causal associations, understanding functional mechanisms and developing therapies for disease. As diseases that have been studied extensively through genetics and molecular biology, cystic fibrosis and Rett syndrome are portrayed as primary examples of how genetic diagnosis, model organism development and therapies have led to improved patient health. Considering which model to use, yeast, worms, flies, fish, mice or larger animals requires a careful evaluation of experimental genetic tools and gene pathway conservation. Recent advances in genome editing will aid in confirming diagnoses and developing model systems for rare disease. Genetic or chemical screening for disease suppression may reveal functional pathway members and provide candidate entry points for developing therapies. Model organisms may also be used in drug discovery and as preclinical models as a prelude to testing treatments in patient populations. Now, model organisms will increasingly be used as platforms for understanding variation in rare disease severity and onset, thereby informing therapeutic intervention.
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Ergoren, Mahmut Cerkez, Elena Manara, Stefano Paolacci, Havva Cobanogullari, Gulten Tuncel, Meryem Betmezoglu, Matteo Bertelli, and Tamer Sanlidag. "The Biennial report: The collaboration between MAGI Research, Diagnosis and Treatment Center of Genetic and Rare Diseases and Near East University DESAM Institute." EuroBiotech Journal 4, no. 4 (October 21, 2020): 167–70. http://dx.doi.org/10.2478/ebtj-2020-0020.
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AbstractBackgroundScientific collaboration is more common now than it was before. In many areas of biomedical science, collaborations between researchers with different scientific backgrounds and perspectives have enabled researchers to address complicated questions and solve complex problems.Particularly, international collaborations and improvements in science and technology have shed light on solving the mechanisms that are involved in the etiology of many rare diseases. Hence, the diagnosis and treatment options have been improved for a number of rare diseases. The collaboration between Near East University DESAM Institute and MAGI Research, Diagnosis and Treatment Center of Genetic and Rare Diseases brought out significant results. Importantly, this collaboration contributed to the rare disease research by the identification of novel rare genetic disease-causing variations commonly in pediatric cases. Consequently, many pediatric unsolved cases have been diagnosed.The main scope of this article is to emphasize the outcomes of the collaboration between Near East University DESAM Institute and MAGI Research, Diagnosis and Treatment Center of Genetic and Rare Diseases which contributed greatly to the scientific literature by identifying novel rare genetic disease-causing variation.
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Elbagoury, Marwan, and Ohoud F. Kashari. "The Importance of Hematology Working Groups for Rare Genetic Diseases." Blood 136, Supplement 1 (November 5, 2020): 33–34. http://dx.doi.org/10.1182/blood-2020-140684.
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Rationale Around the globe, it is now understood that individuals with Rare genetic Diseases routinely face limitations to getting access to diagnosis. Plans have been created to improve the requirements of the patient's communities, including access to multidisciplinary care, and proposing new corrections or amendments to existing strategies. In the gulf region, numerous proposals have been established to tackle the diagnosis and management Rare genetic Diseases. Introduction and Background Rare genetic diseases are characterized as life-long, serious conditions that debilitate or compromise life. Almost 80% of Rare genetic diseases are diagnosed during the childhood. Absence of access to these assets affect patients and their families living with complex needs that may incorporate day in and day out observing, continuous serious physical and formative medicines, remaining in the training framework, and now and then costly strength meds1. The underlying etiology may stay obscure for many patients with rare genetic diseases despite multiple investigations. patients may be assigned an incorrect diagnosis and be referred to several specialties until a correct diagnosis can be made. A correct diagnosis of rare genetic diseases may impact not only the patient's care but may have further implications for management and/or counselling of family members as well2. Also, Early diagnosis leading to early treatment to prevent long-term damage. Global Landscape3 Rarity of diseases is most commonly defined based on prevalence and incidence within a jurisdiction, or in some cases by a combination of factors based on severity and the existence or feasibility of alternative therapeutic options. Globally, the following areas of focus aimed at improving the delivery of health care for the rare disease population: - Improve access to early diagnosis, timely intervention, coordinated care for rare genetic disease patients and developing referral pathways for rare genetic disease patients to facilitate efficient care deliver - Provide educational resources and knowledge exchange opportunities to health professionals to allow them to better identify, manage and treat rare disea - support integrated peer networks, patient organizations to ensure that rare disease patients, their family/caregivers and support them to make informed decisions about their condition. The importance of having working groups for Rare genetic Diseases in Gulf region 4 - Encourage improved coordination of care and access to particular information for rare genetic diseaseses. - Create a complete system services suppliers over Gulf states. Assets and Gaps analysis 1- Early Detection and Diagnostics 5 There are resources that assist the diagnostic capacity and early detection for rare genetic diseases. · Whole Exome sequencing are used mainly for research purposes, despite the fact that their use will reduced diagnostic odyssey. · Lack of the availability of testing is dependent on budget support in some hospitals. - Timely Access to Evidence-based care 6 - Family doctors may not be well equipped to meet the needs of patients with rare hematological genetic diseases, even after diagnosis. - Poor access supportive services for adult care. - Access to genetic counseling for patients and families outside major academic hospitals7. References 1. Sawyer, S. L. et al. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin. Genet.89, 275-284 (2016). 2. Undiagnosed Diseases Network Manual of Operations. (2018). 3. Richter, T. et al. Rare Disease Terminology and Definitions-A Systematic Global Review: Report of the ISPOR Rare Disease Special Interest Group. (2015). doi:10.1016/j.jval.2015.05.008 4. International Rare Disease Research Consortium& GUIDELINES Long version. (2013). 5. Clinical Handbook for Sickle Cell Disease Vaso-occlusive Crisis Provincial Council for Maternal and Child Health & Ministry of Health and Long-Term Care. (2017). 6. Therrell, B. L. et al. Current status of newborn screening worldwide: 2015. Seminars in Perinatology39, 171-187 (2015). 7. Stille, C. J. & Antonelli, R. C. Coordination of care for children with special health care needs. Current Opinion in Pediatrics16, 700-705 (2004). Figure Disclosures No relevant conflicts of interest to declare.
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Tasic, Velibor, Zoran Gucev, and Momir Polenakovic. "Rare Renal Disease in Macedonia – An Update." PRILOZI 38, no. 3 (December 1, 2017): 63–69. http://dx.doi.org/10.2478/prilozi-2018-0007.
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Abstract Rare renal diseases (RRD) are an important category of rare disease (RD) as they can do great damage to the patients, families and society. The patient may undergo years even decades of numerous investigations including invasive procedures and yet not have definitive and precise diagnose and therefore, no opportunity for appropriate treatment. The great progress in molecular genetic techniques characterized many Mendelian diseases on molecular level. This gave the possibility for appropriate prevention and treatment interventions, genetic counseling and prenatal diagnosis. Herein, we summarize the current status of RRD in Macedonia. The research interest of Macedonian clinicians and scientists is focused on the genetics of congenital anomalies of the kidney and urinary tract (CAKUT), steroid resistant nephrotic syndrome, nephrolithiasis and nephrocalcinosis, cystic diseases and cilliopathies with collaborations with eminent laboratories in Unites States and Europe. This collaboration resulted in detection of new genes and pathophysiological pathways published in The New England Journal of Medicine and in other high impact journals. Macedonian health professionals have knowledge and equipment for diagnosis of RRD. Unfortunately the lack of finances is great obstacle for early and appropriate diagnosis. Participation in the international registries, studies and trials should be encouraged. This would result in significant benefit for the patients, health professionals and science.
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Farhan, Sali M. K., and Robert A. Hegele. "Genetics 101 for Cardiologists: Rare Genetic Variants and Monogenic Cardiovascular Disease." Canadian Journal of Cardiology 29, no. 1 (January 2013): 18–22. http://dx.doi.org/10.1016/j.cjca.2012.10.010.
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Horváth, Emese, Nikoletta Nagy, and Márta Széll. "Difficulties of genetic counselling in rare, mainly neurogenetic disorders." Orvosi Hetilap 155, no. 31 (August 2014): 1221–27. http://dx.doi.org/10.1556/oh.2014.29957.
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Introduction: In recent decades methods used for the investigation of the genetic background of rare diseases showed a great improvement. Aim: The aim of the authors was to demonstrate difficulties of genetic counselling and investigations in case of five rare, mainly neurogenetic diseases. Method: During pre-test genetic counselling, the disease suspected from the clinical symptoms and the available genetic tests were considered. During post-test genetic counselling, the results of the genetic tests were discussed. Results: In three of the five cases genetic tests identified the disease-causing genetic abnormalities, while in two cases the causative abnormalities were not identified. Conclusions: Despite a great improvement of the available genetic methods, the causative genetic abnormalities cannot be identified in some cases. The genetic counsellor has a key role in the assessment and interpretation of the results and in helping the family planning. Orv. Hetil., 2014, 155(31), 1221–1227.
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Siddiqui, Mahmudur Rahman, Md Sahriar Mahbub, and Quazi Tarikul Islam. "Cerebrotendinous Xanthomatosis, A Rare Metabolic Disease." Journal of Medicine 13, no. 1 (March 12, 2012): 92–93. http://dx.doi.org/10.3329/jom.v13i1.8690.
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Cerebrotendinous xanthomatosis (CTX) is a rare genetic lipid storage disease. CTX is characterised by childhood-onset cataract, adolescent to young adult-onset tendon xanthomas and adult-onset progressive neurological dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs and seizures). A 32-year-old male patient presented to us with the features of this rare genetic metabolic disorder.DOI: http://dx.doi.org/10.3329/jom.v13i1.8690 JOM 2012; 13(1): 92-93
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Pfliegler, György, Erzsébet Kovács, György Kovács, Krisztián Urbán, Valéria Nagy, and Boglárka Brúgós. "Adult-onset rare diseases." Orvosi Hetilap 155, no. 9 (March 2014): 334–40. http://dx.doi.org/10.1556/oh.2014.29857.
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The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6–8000 “rare diseases” belong either to the scope of adult-care (e.g. internal medicine, neurology), or to “age-neutral” specialities such as ophtalmology, dermatology etc.). Orv. Hetil., 2014, 155(9), 334–340.
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Novakovic, K. E., V. L. Villemagne, C. C. Rowe, and C. L. Masters. "Rare genetically defined causes of dementia." International Psychogeriatrics 17, s1 (September 2005): S149—S194. http://dx.doi.org/10.1017/s1041610205002012.
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Several genetic disorders, though rare, are associated or present with dementia. Developments in the field of genetics are contributing to clarify and expand our knowledge of the complex physiopathological mechanisms leading to neurodegeneration and cognitive decline. Disorders associated with misfolded and aggregated proteins and lipid, metal or energy metabolism are examples of the multifarious disease processes converging in the clinical features of dementia, either as its predominant feature, as in cases of Alzheimer's disease (AD) or frontotemporal dementia (FTD), or as part of a cohort of accompanying or late-developing symptoms, as in Parkinson's disease (PD) or amyotrophic lateral sclerosis with dementia (ALS-D). Awareness of these disorders, allied with recent advances in genetic, biochemical and neuroimaging techniques, may lead to early diagnosis, successful treatment and better prognosis.
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Casas-Tintó, Sergio. "Drosophila as a Model for Human Disease: Insights into Rare and Ultra-Rare Diseases." Insects 15, no. 11 (November 6, 2024): 870. http://dx.doi.org/10.3390/insects15110870.
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Rare and ultra-rare diseases constitute a significant medical challenge due to their low prevalence and the limited understanding of their origin and underlying mechanisms. These disorders often exhibit phenotypic diversity and molecular complexity that represent a challenge to biomedical research. There are more than 6000 different rare diseases that affect nearly 300 million people worldwide. However, the prevalence of each rare disease is low, and in consequence, the biomedical resources dedicated to each rare disease are limited and insufficient to effectively achieve progress in the research. The use of animal models to investigate the mechanisms underlying pathogenesis has become an invaluable tool. Among the animal models commonly used in research, Drosophila melanogaster has emerged as an efficient and reliable experimental model for investigating a wide range of genetic disorders, and to develop therapeutic strategies for rare and ultra-rare diseases. It offers several advantages as a research model including short life cycle, ease of laboratory maintenance, rapid life cycle, and fully sequenced genome that make it highly suitable for studying genetic disorders. Additionally, there is a high degree of genetic conservation from Drosophila melanogaster to humans, which allows the extrapolation of findings at the molecular and cellular levels. Here, I examine the role of Drosophila melanogaster as a model for studying rare and ultra-rare diseases and highlight its significant contributions and potential to biomedical research. High-throughput next-generation sequencing (NGS) technologies, such as whole-exome sequencing and whole-genome sequencing (WGS), are providing massive amounts of information on the genomic modifications present in rare diseases and common complex traits. The sequencing of exomes or genomes of individuals affected by rare diseases has enabled human geneticists to identify rare variants and identify potential loci associated with novel gene–disease relationships. Despite these advances, the average rare disease patient still experiences significant delay until receiving a diagnosis. Furthermore, the vast majority (95%) of patients with rare conditions lack effective treatment or a cure. This scenario is enhanced by frequent misdiagnoses leading to inadequate support. In consequence, there is an urgent need to develop model organisms to explore the molecular mechanisms underlying these diseases and to establish the genetic origin of these maladies. The aim of this review is to discuss the advantages and limitations of Drosophila melanogaster, hereafter referred as Drosophila, as an experimental model for biomedical research, and the applications to study human disease. The main question to address is whether Drosophila is a valid research model to study human disease, and in particular, rare and ultra-rare diseases.
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Avdeev, S. N., E. I. Kondratyeva, L. S. Namazova-Baranova, and S. I. Kutsev. "Hereditary lung diseases and modern possibilities of genetic testing." PULMONOLOGIYA 33, no. 2 (April 12, 2023): 151–69. http://dx.doi.org/10.18093/0869-0189-2023-33-2-151-169.
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The European Respiratory Society website gives the following criterion for the disease to be classified as rare (orphan) - the disease occurs in 1 person per 2 000. One of the well-studied rare lung diseases is cystic fibrosis (CF), which is often considered a medical care model for patients with other orphan diseases. However, effective diagnostics and therapies have not yet been developed for many other rare diseases. Moreover, their true prevalence remains unknown because these diseases often go undiagnosed. One of the problems in diagnosing rare diseases is the lack of knowledge among physicians.The aim of this review is to provide a brief clinical and genetic description of rare hereditary lung diseases and to show modern genetic diagnostics to raise awareness among physicians. Data from 95 articles on hereditary lung diseases were used.Results. The results of the analysis of lung diseases associated with bronchiectasis, fibrosis, pneumothorax, and hereditary storage diseases are presented. Genetics and diagnostics, including the three-step molecular genetic testing for cystic fibrosis, are considered in detail. The diagnosis has been developed for both neonatal screening and clinical manifestations. The emergence of targeted therapy based on genetic diagnosis makes neonatal screening even more relevant and leads to an increase in life expectancy. A patient registry was established within 10 years. A detailed analysis of the diagnosis of primary ciliary dyskinesia (PCD) is given, taking into account the absence of a single “golden” standard for the diagnosis of PCD. The genetic basis of the most common hereditary diseases and modern possibilities of their diagnosis are discussed, including sequencing of genes responsible for the development of orphan diseases using standard Sanger sequencing methods and next-generation sequencing, and creating multigene panels.Conclusion. New molecular diagnostic methods will help to understand the nature of orphan lung diseases, study their epidemiology, and develop new diagnostic algorithms. The study of the genetic causes of rare diseases may serve as a basis for the development of targeted therapy.
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Yang, Qiong, Xin Xu, and Nan Laird. "Power Evaluations for Family-Based Tests of Association With Incomplete Parental Genotypes." Genetics 164, no. 1 (May 1, 2003): 399–406. http://dx.doi.org/10.1093/genetics/164.1.399.
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Abstract While a variety of methods have been developed to deal with incomplete parental genotype information in family-based association tests, sampling design issues with incomplete parental genotype data still have not received much attention. In this article, we present simulation studies with four genetic models and various sampling designs and evaluate power in family-based association studies. Efficiency depends heavily on disease prevalence. With rare diseases, sampling affecteds and their parents is preferred, and three sibs will be required to have close power if parents are unavailable. With more common diseases, sampling affecteds and two sibs will generally be more efficient than trios. When parents are unavailable, siblings need not be phenotyped if the disease is rare, but a loss of power will result with common diseases. Finally, for a class of complex traits where other genetic and environmental factors also cause phenotypic correlation among siblings, little loss of efficiency occurs to rare disease, but substantial loss of efficiency occurs to common disease.
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Lippi, Melania, Mattia Chiesa, Ciro Ascione, Matteo Pedrazzini, Saima Mushtaq, Davide Rovina, Daniela Riggio, et al. "Spectrum of Rare and Common Genetic Variants in Arrhythmogenic Cardiomyopathy Patients." Biomolecules 12, no. 8 (July 28, 2022): 1043. http://dx.doi.org/10.3390/biom12081043.
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Arrhythmogenic cardiomyopathy (ACM) is a rare inherited disorder, whose genetic cause is elusive in about 50–70% of cases. ACM presents a variable disease course which could be influenced by genetics. We performed next-generation sequencing on a panel of 174 genes associated with inherited cardiovascular diseases on 82 ACM probands (i) to describe and classify the pathogenicity of rare variants according to the American College of Medical Genetics and Genomics both for ACM-associated genes and for genes linked to other cardiovascular genetic conditions; (ii) to assess, for the first time, the impact of common variants on the ACM clinical disease severity by genotype-phenotype correlation and survival analysis. We identified 15 (likely) pathogenic variants and 66 variants of uncertain significance in ACM-genes and 4 high-impact variants in genes never associated with ACM (ABCC9, APOB, DPP6, MIB1), which deserve future consideration. In addition, we found 69 significant genotype-phenotype associations between common variants and clinical parameters. Arrhythmia-associated polymorphisms resulted in an increased risk of arrhythmic events during patients’ follow-up. The description of the genetic framework of our population and the observed genotype-phenotype correlation constitutes the starting point to address the current lack of knowledge in the genetics of ACM.
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Moon, Jangsup. "Rare genetic causes of meningitis and encephalitis." encephalitis 2, no. 2 (April 10, 2022): 29–35. http://dx.doi.org/10.47936/encephalitis.2021.00164.
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Differential diagnosis of meningitis and encephalitis is often very challenging because it cannot be determined based on symptoms, and the diseases have various causes. This article explains rare genetic causes of meningitis and encephalitis. Autoinflammatory disorders include cryopyrin-associated periodic syndromes, familial Mediterranean fever, and tumor necrosis factor receptor-associated periodic syndrome. Furthermore, other genetic disorders, such as complement factor I deficiency, phosphatidylinositol glycan anchor biosynthesis class T mutation, and neuronal intranuclear inclusion disease, can present as meningitis and encephalitis.
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Kim, Soo Yeon. "Navigating the landscape of clinical genetic testing: insights and challenges in rare disease diagnostics." Childhood Kidney Diseases 28, no. 1 (February 28, 2024): 8–15. http://dx.doi.org/10.3339/ckd.24.005.
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With the rapid evolution of diagnostic tools, particularly next-generation sequencing, the identification of genetic diseases, predominantly those with pediatric-onset, has significantly advanced. However, this progress presents challenges that span from selecting appropriate tests to the final interpretation of results. This review examines various genetic testing methodologies, each with specific indications and characteristics, emphasizing the importance of selecting the appropriate genetic test in clinical practice, taking into account factors like detection range, cost, turnaround time, and specificity of the clinical diagnosis. Interpretation of variants has become more challenging, often requiring further validation and significant resource allocation. Laboratories primarily classify variants based on the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science guidelines, however, this process has limitations. This review underscores the critical role of clinicians in matching patient phenotypes with reported genes/variants and considering additional factors such as variable expressivity, disease pleiotropy, and incomplete penetrance. These considerations should be aligned with specific gene-disease characteristics and segregation results based on an extended pedigree. In conclusion, this review aims to enhance understanding of the complexities of clinical genetic testing, advocating for a multidisciplinary approach to ensure accurate diagnosis and effective management of rare genetic diseases.
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McMahon, Mark S. "Novel Treatment of a Rare Genetic Bone Disease." Orthopedics 30, no. 2 (February 1, 2007): 91. http://dx.doi.org/10.3928/01477447-20070201-12.
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Bodmer, Walter F. "Genetic diversity and disease susceptibility." Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 352, no. 1357 (August 29, 1997): 1045–50. http://dx.doi.org/10.1098/rstb.1997.0083.
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The range of genetic diversity within human populations is enormous. Genetic susceptibility to common chronic disease is a significant part of this genetic diversity, which also includes a variety of rare, clear–cut, inherited diseases. Modern DNA–based genomic analysis can now routinely lead to the identification of genes involved in disease susceptibility, provides the basis for genetic counselling in affected families, and can be used more widely for a genetically targeted approach to disease prevention. This naturally raises problems concerning the use of information not just in an individulal's decisions, but also for employment, and health and life insurance.
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Vrijenhoek, T., N. Tonisson, H. Kääriäinen, L. Leitsalu, and T. Rigter. "Clinical genetics in transition—a comparison of genetic services in Estonia, Finland, and the Netherlands." Journal of Community Genetics 12, no. 2 (March 11, 2021): 277–90. http://dx.doi.org/10.1007/s12687-021-00514-7.
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AbstractGenetics has traditionally enabled the reliable diagnosis of patients with rare genetic disorders, thus empowering the key role of today’s clinical geneticists in providing healthcare. With the many novel technologies that have expanded the genetic toolkit, genetics is increasingly evolving beyond rare disease diagnostics. When placed in a transition context—like we do here—clinical genetics is likely to become a fully integral part of future healthcare and clinical genetic expertise will be required increasingly outside traditional clinical genetic settings. We explore transition effects on the thinking (culture), organizing (structure), and performing (practice) in clinical genetics, taking genetic healthcare in Estonia, Finland, and the Netherlands as examples. Despite clearly distinct healthcare histories, all three countries have initially implemented genetic healthcare in a rather similar fashion: as a diagnostic tool for predominantly rare congenital diseases, with clinical geneticists as the main providers. Dynamics at different levels, such as emerging technologies, biobanks and data infrastructure, and legislative frameworks, may require development of a new system attuned with the demands and (historic) context of specific countries. Here, we provide an overview of genetic service provisions in Estonia, Finland, and the Netherlands to consider the impact of historic and recent events on prospective developments in genetic healthcare.
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Elia, Davide, Olga Torre, Roberto Cassandro, Antonella Caminati, and Sergio Harari. "Ultra-rare cystic disease." European Respiratory Review 29, no. 157 (September 2, 2020): 190163. http://dx.doi.org/10.1183/16000617.0163-2019.
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Diffuse cystic lung diseases include a group of heterogeneous disorders characterised by the presence of cysts within the lung parenchyma, sometimes showing a characteristic computed tomography scan pattern that allows diagnosis. The pathogenetic mechanisms underlying cyst formation in the lung are still not clear and a number of hypotheses have been postulated according to the different aetiologies: ball-valve effect, ischaemic dilatation of small airways and alveoli related to infiltration and obstruction of small vessels and capillaries that supply the terminal bronchioles and connective tissue degradation by matrix metalloproteases. A wide number of lung cyst diseases have been classified into six diagnostic groups according to the aetiology: neoplastic, congenital/genetic, lymphoproliferative, infective, associated with interstitial lung diseases, and other causes. This article focuses on lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and Erdheim–Chester disease, Birt–Hogg–Dubé, follicular bronchiolitis and lymphocytic interstitial pneumonia, light-chain deposition disease and amyloidosis, congenital lung disease associated with aberrant lung development and growth, and cystic lung disease associated with neoplastic lesion. These cystic diseases are epidemiologically considered as ultra-rare conditions as they affect fewer than one individual per 50 000 or fewer than 20 individuals per million. Despite the rarity of this group of disorders, the increasing use of high-resolution computed tomography has improved the diagnostic yield, even in asymptomatic patients allowing prompt and correct therapy and management without the need for a biopsy.
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Amanat, Sana, Teresa Requena, and Jose Antonio Lopez-Escamez. "A Systematic Review of Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders." Genes 11, no. 9 (August 25, 2020): 987. http://dx.doi.org/10.3390/genes11090987.
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Exome sequencing has been commonly used to characterize rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) and searching for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to the heritability of complex clinical traits. We conducted a systematic review to find evidence supporting the use of EP strategies in the search for rare variants in genetic studies of complex diseases and highlight the contribution of rare variations to the genetic structure of polygenic conditions. After assessing the quality of the retrieved records, we selected 19 genetic studies considering EPs to demonstrate genetic association. All studies successfully identified several rare or de novo variants, and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach for patients with an early onset of a disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.
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Corigliano, K., M. Grandinetti, G. Mazzenga, F. Cammertoni, M. Nesta, N. Pavone, P. Bruno, A. Amodeo, and M. Massetti. "A MULTIDISCIPLINARY APPROACH TO RARE AND GENETIC AORTIC DISEASE." Journal of Cardiovascular Medicine 25, Supplement 1 (November 2024): e7. https://doi.org/10.2459/01.jcm.0001096196.55310.9a.
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Background and Aim: Considering the increasing number of genetical diagnosis regarding connective tissue syndromes (Marfan, Ehlers-Danlos, Loeys-Dietz), there is an increasing attention about young patients developing acute aortic syndromes, which can be catastrophic at times. Care of these patients represents a major challenge, due to the variability in timing and severity of the clinical presentation, also determined by the underlying genetic substrate. Methods: In this retrospective study we consider two groups of patients with known connective tissue disease who underwent aortic surgery and were followed at our institution: Group A and Group B, composed by 31 (from 2014 to 2024) and 36 patients (from 2000 to 2010), respectively. We retrieved data of all enrolled patients from the electronic archives of the Institution. Patients’ follow-up data were collected at 8-year average post-intervention. Results: There were no differences between the two groups regarding diagnosis, presence of preoperative risk factors and mortality at follow-up. Re-operation or urgent hospitalization were more frequent in Group B by 16.4% than in Group A (32.4%; N:12 vs 16%; N:5; p= 0.047). There was greater adherence to follow-up (and risk factors control) rate in Group A than Group B (p=0.038). Conclusions: A clinical pathway for rare genetic aortic disease is mandatory. Our team includes dedicated cardiac and vascular surgeons, cardiologists, genetics, radiologists, obstetrics, anesthesiologists. We created a shared tailored clinical protocol for these patients’ needs. Our preliminary experience showed that novel multidimensional approach plays a key role in clinical surveillance of this peculiar population.
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Ugwu, Okechukwu Paul Chima, Esther Ugo Alum, Moses Thembo, Okon Michael Ben, and Emmanuel Adie Awafung. "The Use of AI in Detecting Rare Diseases." Research Output Journal of Public Health and Medicine 3, no. 2 (September 1, 2024): 22–25. http://dx.doi.org/10.59298/rojphm/2024/322225.
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Rare diseases, affecting fewer than 1 in 2,000 individuals, present significant challenges in diagnosis and treatment due to their diversity, limited clinical data, and lack of awareness among healthcare professionals. Artificial intelligence (AI) is emerging as a valuable tool in rare disease detection, leveraging large datasets and machine learning algorithms to analyze symptoms, genetic data, and medical literature. This paper investigates how AI enhances diagnostic accuracy, shortens the diagnostic process, and addresses the complexities associated with rare diseases. Additionally, we examine case studies, discuss the ethical considerations of AI-based diagnosis, and highlight the potential for AI to revolutionize rare disease care. Keywords: Artificial Intelligence (AI), Rare Diseases, Machine Learning, Diagnosis, Genetic Testing.
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Callea, Michele, Diego Martinelli, Francisco Cammarata-Scalisi, Chiara Grimaldi, Houweyda Jilani, Piercesare Grimaldi, Colin Eric Willoughby, and Antonino Morabito. "Multisystemic Manifestations in Rare Diseases: The Experience of Dyskeratosis Congenita." Genes 13, no. 3 (March 11, 2022): 496. http://dx.doi.org/10.3390/genes13030496.
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Dyskeratosis congenital (DC) is the first genetic syndrome described among telomeropathies. Its classical phenotype is characterized by the mucocutaneous triad of reticulated pigmentation of skin lace, nail dystrophy and oral leukoplakia. The clinical presentation, however, is heterogeneous and serious clinical complications include bone marrow failure, hematological and solid tumors. It may also involve immunodeficiencies, dental, pulmonary and liver disorders, and other minor complication. Dyskeratosis congenita shows marked genetic heterogeneity, as at least 14 genes are responsible for the shortening of telomeres characteristic of this disease. This review discusses clinical characteristics, molecular genetics, disease evolution, available therapeutic options and differential diagnosis of dyskeratosis congenita to provide an interdisciplinary and personalized medical assessment that includes family genetic counseling.
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Chung, Brian K., and Tom H. Karlsen. "Genetic Discoveries Highlight Environmental Factors as Key Drivers of Liver Disease." Digestive Diseases 35, no. 4 (2017): 323–33. http://dx.doi.org/10.1159/000456583.
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Background: Over the last 50 years, genetic studies have uncovered a spectrum of rare and common alleles that confer susceptibility to both Mendelian and complex forms of liver disease. For disorders of Mendelian inheritance, identification of the causal variants has demonstrated that common environmental exposures can elicit severe liver pathogenesis in predisposed individuals. Specific environmental triggers for complex liver disorders are largely unknown; however, large-scale association studies indicate that environmental triggers are the predominant factors in driving liver pathophysiology. Key Messages: In Mendelian liver disorders, a single rare variant of major effect is often responsible for disease development. Gene-sequencing technologies have greatly facilitated the discovery of causal variants for Mendelian diseases and are increasingly utilized in molecular and clinical genetics for diagnostic and counselling purposes. By contrast, genetic susceptibility for complex liver disorders is heterogeneous, as many different genes acting on multiple distinct pathways influence disease onset and severity. Risk variants for complex liver disorders are relatively common, typically of small effect size and detected by genome-wide association studies (GWAS), which compare the genetic variation of specific loci using thousands of patients and healthy controls. Thus far, GWAS have detected dozens of unique and overlapping risk alleles for complex liver disease, but these account for less than a quarter of the overall disease liability. These observations emphasize that environmental exposures on a background of genetic predisposition are significant drivers of liver pathophysiology. Rare variants of large effect size, undetectable by GWAS, may also affect the development of complex disease on a case-to-case basis but evidence for such a scenario remains to be determined. Conclusions: Genetic technologies have identified numerous risk genes for Mendelian and complex liver disorders transforming disease recognition. For complex liver disorders, deciphering the interplay between genetic risk and environment determinants remains a significant challenge for unlocking the development of novel and personalized interventions.
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Mitsui, Jun. "Genetic basis of sponadic Parkinson disease: common disease-multiple rare variants." Rinsho Shinkeigaku 50, no. 11 (2010): 865–66. http://dx.doi.org/10.5692/clinicalneurol.50.865.
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Keogh, Michael J., Wei Wei, Juvid Aryaman, Ian Wilson, Kevin Talbot, Martin R. Turner, Chris-Anne McKenzie, et al. "Oligogenic genetic variation of neurodegenerative disease genes in 980 postmortem human brains." Journal of Neurology, Neurosurgery & Psychiatry 89, no. 8 (January 13, 2018): 813–16. http://dx.doi.org/10.1136/jnnp-2017-317234.
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BackgroundSeveral studies suggest that multiple rare genetic variants in genes causing monogenic forms of neurodegenerative disorders interact synergistically to increase disease risk or reduce the age of onset, but these studies have not been validated in large sporadic case series.MethodsWe analysed 980 neuropathologically characterised human brains with Alzheimer’s disease (AD), Parkinson’s disease-dementia with Lewy bodies (PD-DLB), frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) and age-matched controls. Genetic variants were assessed using the American College of Medical Genetics criteria for pathogenicity. Individuals with two or more variants within a relevant disease gene panel were defined as ‘oligogenic’.ResultsThe majority of oligogenic variant combinations consisted of a highly penetrant allele or known risk factor in combination with another rare but likely benign allele. The presence of oligogenic variants did not influence the age of onset or disease severity. After controlling for the single known major risk allele, the frequency of oligogenic variants was no different between cases and controls.ConclusionsA priori, individuals with AD, PD-DLB and FTD-ALS are more likely to harbour a known genetic risk factor, and it is the burden of these variants in combination with rare benign alleles that is likely to be responsible for some oligogenic associations. Controlling for this bias is essential in studies investigating a potential role for oligogenic variation in neurodegenerative diseases.
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Sharma, Abhay. "AN OVERVIEW OF PROGERIA: RARE DISEASE OF INDIA." Indian Journal of Health Care Medical & Pharmacy Practice 5, no. 2 (December 10, 2024): 53–57. https://doi.org/10.59551/ijhmp/25832069/2024.5.2.50.
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Rare diseases (RDs) are conditions that affect a small percentage of the population and are often chronic and life-threatening. With more than 350 million people worldwide suffering from over 8,000 RDs, progeria stands out as a rare genetic disorder causing premature aging. This disorder includes syndromes like Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford syndrome (HGPS), and others, with HGPS being the most studied. HGPS is linked to mutations in the LMNA gene, which codes for lamin A and lamin C proteins. HGPS is caused by mutations in the LMNA gene, resulting in the production of an abnormal protein called progerin, which destabilizes cells and accelerates aging associated with detrimental phenotypic features. Progerin accumulation leads to genomic instability, dysregulated gene expression, delibated nuclear morphology and deficits in DNA repair. Awareness and education about rare diseases like progeria are crucial. Collaborative efforts involving patients, advocates, healthcare professionals, researchers, the pharmaceutical industry, and the government are essential for advancing research and treatment. Additionally, the potential role of nutraceuticals in future therapies should not be overlooked. Based on the articles analyzed, etiology, prevalence in India, treatment and supportive therapies and limitations of the reported treatment regimens have been examined. Possible targets identification, strategies for clinical trials are avenues for future research prospects.
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Hogan Smith, Kay. "Review of Rare Diseases Resources: National Organization for Rare Disorders (NORD) Rare Disease Database, NIH Genetic and Rare Diseases Information Center, and Orphanet." Journal of Consumer Health on the Internet 21, no. 2 (April 3, 2017): 216–25. http://dx.doi.org/10.1080/15398285.2017.1311613.
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Hoehndorf, Robert, Paul N. Schofield, and Georgios V. Gkoutos. "An integrative, translational approach to understanding rare and orphan genetically based diseases." Interface Focus 3, no. 2 (April 6, 2013): 20120055. http://dx.doi.org/10.1098/rsfs.2012.0055.
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PhenomeNet is an approach for integrating phenotypes across species and identifying candidate genes for genetic diseases based on the similarity between a disease and animal model phenotypes. In contrast to ‘guilt-by-association’ approaches, PhenomeNet relies exclusively on the comparison of phenotypes to suggest candidate genes, and can, therefore, be applied to study the molecular basis of rare and orphan diseases for which the molecular basis is unknown. In addition to disease phenotypes from the Online Mendelian Inheritance in Man (OMIM) database, we have now integrated the clinical signs from Orphanet into PhenomeNet. We demonstrate that our approach can efficiently identify known candidate genes for genetic diseases in Orphanet and OMIM. Furthermore, we find evidence that mutations in the HIP1 gene might cause Bassoe syndrome, a rare disorder with unknown genetic aetiology. Our results demonstrate that integration and computational analysis of human disease and animal model phenotypes using PhenomeNet has the potential to reveal novel insights into the pathobiology underlying genetic diseases.
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Rabello, Flavia, Mariana Laís Silva Celestino, Natália Cristina Ruy Carneiro, Jennifer Reis-Oliveira, Heloísa Vieira Prado, Mauro Henrique Nogueira Guimarães de Abreu, and Ana Cristina Borges-Oliveira. "Oral Problems in Brazilian Individuals with Rare Genetic Diseases That Affect Skeletal Development." International Journal of Environmental Research and Public Health 21, no. 9 (September 18, 2024): 1227. http://dx.doi.org/10.3390/ijerph21091227.
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The present study aimed to compare the prevalence of oral problems between individuals with rare genetic diseases that affect skeletal development and individuals without rare diseases. A cross-sectional study was conducted with 210 individuals between two and fifty-four years of age: 105 with rare genetic diseases (27 with mucopolysaccharidosis [MPS] and 78 with osteogenesis imperfecta [OI]) and 105 without rare diseases. The rare genetic disease group was recruited from hospital units that provide care for patients with MPS and OI in five states of Brazil, and the other group was recruited from the same location. The participants were examined with regards to malocclusion, dental anomalies, dental caries, and gingivitis. A questionnaire was administered addressing individual, sociodemographic, and behavioral characteristics as well as dental history. A descriptive analysis was performed, followed by unadjusted and adjusted binary logistic regression analyses. The mean age was 14.1 ± 12.2 years. Individuals with a rare disease were 12.9-fold more likely to have some type of oral problem (95% CI: 3.7–44.7) compared to the group without rare diseases. The prevalence of oral problems was higher among Brazilians with MPS and OI compared to normotypical individuals.