Tachycardia: an autosomal, monogenic, biallelic, recessive trait

A brief commentary of the genetics of blood pressure is presented. The importance of the mechanisms of blood pressure regulation, among which heart rate is relevant, is emphasized. The analysis of a small population to test the quantitative model of the trait heart rate, considered as a metric character, is presented. The analysis of heart rate fitting to a qualitative model of inheritance is carried out. The results displayed might support the hypothesis that tachycardia could be an autosomal, monogenic, biallelic recessive trait.     

Reevaluation of genetic variants previously associated with arrhythmogenic right ventricular cardiomyopathy integrating population-based cohorts and proteomics data

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is one of the most common causes of sudden cardiac death in young people. Patients diagnosed with ARVC may experience increased likelihood of development of anxiety and depression, emphasizing the need for accurate diagnosis. To assist future genetic diagnosis and avoidance of misdiagnosis, we evaluated the reported monogenic disease-causing variants in ARVD/C Genetic Variants Database, Human Gene Mutation Database, and ClinVar. Within the aforementioned databases, 630 monogenic disease-causing variants from 18 genes were identified. In the genome Aggregation Database, 226 of these were identified; 68 of which were found at greater than expected prevalence. Furthermore, 37/226 genetic variants were identified amongst the 409 000 UK biobank participants, 23 were not associated with ARVC. Among the 14 remaining variants, 13 were previously found with greater than expected prevalence for a monogenic variant. Nevertheless, they were associated with serious cardiac phenotypes, suggesting that these 13 variants may be disease-modifiers of ARVC, rather than monogenic disease-causing. In summary, more than 10% of variants previously reported to cause ARVC were found unlikely to be associated with highly penetrant monogenic forms of ARVC. Notably, all variants in OBSCN and MYBPC3 were found, making these unlikely to be monogenic causes of ARVC.     

The experience of 3 years of external quality assessment of preimplantation genetic diagnosis for cystic fibrosis

Preimplantation genetic diagnosis (PGD) was first performed over 20 years ago and has become an accepted part of genetic testing and assisted reproduction worldwide. The techniques and protocols necessary to carry out genetic testing at the single-cell level can be difficult to master and have been developed independently by the laboratories worldwide offering preimplantation testing. These factors indicated the need for an external quality assessment (EQA) scheme for monogenic disease PGD. Toward this end, the European Society for Human Reproduction and Embryology came together with United Kingdom National External Quality Assessment Services for Molecular Genetics, to create a pilot EQA scheme followed by practical EQA schemes for all interested parties. Here, we detail the development of the pilot scheme as well as development and findings from the practical (clinical) schemes that have followed. Results were generally acceptable and there was marked improvement in results and laboratory scores for those labs that participated in multiple schemes. Data from the first three schemes indicate that the EQA scheme is working as planned and has helped laboratories improve their techniques and result reporting. The EQA scheme for monogenic PGD will continue to be developed to offer assessment for other monogenic disorders.     

外显子组测序是发现单基因病致病基因的捷径

新一代测序技术的产生和发展为疾病研究带来了新的机遇.作为一种高效、快速和高性价比的研究方法,外显子组测序技术已经开始应用于单基因疾病等遗传病的研究.该技术已经得到国际学术界的广泛认可,也将越来越多地应用于单基因疾病的研究中.这将对单基因病致病基因的发现产生巨大推动作用.作者对国内外近两年应用外显子测序技术检测疾病相关基因的一些研究进行文献综述.     

Zero tolerance! A perspective on monogenic disorders with defective regulatory T cells and IBD‐like disease

Recently, several studies have investigated a number of rare monogenic autoimmune disorders, in which the causative genetic defects were identified and found to affect the development or function of regulatory T cells (Tregs). The studies of these disorders have facilitated a deeper understanding of the mechanisms involved in immune regulation and tolerance. Furthermore, these studies have highlighted the importance of Tregs in maintaining homeostasis at the mucosal interface between the host and microbiome. Here, we offer our perspective on these monogenic autoimmune disorders, highlighting their overlapping clinical features with inflammatory bowel disease.     

Polygenic risk score as a possible tool for identifying familial monogenic causes of complex diseases

PurposeThe study aimed to evaluate whether polygenic risk scores could be helpful in addition to family history for triaging individuals to undergo deep-depth diagnostic sequencing for identifying monogenic causes of complex diseases.MethodsAmong 44,550 exome-sequenced European ancestry UK Biobank participants, we identified individuals with a clinically reported or computationally predicted monogenic pathogenic variant for breast cancer, bowel cancer, heart disease, diabetes, or Alzheimer disease. We derived polygenic risk scores for these diseases. We tested whether a polygenic risk score could identify rare pathogenic variant heterozygotes among individuals with a parental disease history.ResultsMonogenic causes of complex diseases were more prevalent among individuals with a parental disease history than in the rest of the population. Polygenic risk scores showed moderate discriminative power to identify familial monogenic causes. For instance, we showed that prescreening the patients with a polygenic risk score for type 2 diabetes can prioritize individuals to undergo diagnostic sequencing for monogenic diabetes variants and reduce needs for such sequencing by up to 37%.ConclusionAmong individuals with a family history of complex diseases, those with a low polygenic risk score are more likely to have monogenic causes of the disease and could be prioritized to undergo genetic testing.     

Monogenic polyautoimmunity in primary immunodeficiency diseases

Primary immunodeficiency diseases (PIDs) consist of a large group of genetic disorders that affect distinct components of the immune system. PID patients are susceptible to infection and non-infectious complications, particularly autoimmunity. A specific group of monogenic PIDs are due to mutations in genes that are critical for the regulation of immunological tolerance and immune responses. This group of monogenic PIDs is at high risk of developing polyautoimmunity (i.e., the presence of more than one autoimmune disease in a single patient) because of their impaired immunity. In this review, we discuss the mechanisms of autoimmunity in PIDs and the characteristics of polyautoimmunity in the following PIDs: IPEX; monogenic IPEX-like syndrome; LRBA deficiency; CTLA4 deficiency; APECED; ALPS; and PKCδ deficiency.     

代谢性皮肤单基因病临床与分子遗传学研究进展

代谢性皮肤单基因病是由某些代谢性原因引起皮肤异常表现的单基因病,这类疾病具有遗传性、代谢异常以及皮肤异常表现等共同特点,主要涉及淀粉样蛋白、卟啉、铁、半乳糖苷酶、类脂蛋白以及苯丙氨酸等物质的代谢异常.常见的代谢性皮肤单基因病有家族性原发性皮肤淀粉样变、红细胞生成性原卟啉病、遗传性血色病、弥漫性躯体血管角皮病、类脂蛋白沉积症和苯丙酮尿症等.其中家族性原发性皮肤淀粉样变具有一定的遗传异质性,国内外很多家系尚未发现易感基因,未来需要继续探索.FECH基因的突变类型众多,这给明确红细胞生成性原卟啉病的突变位点和产前诊断带来一定困难.蛋白酶体抑制剂MG132和rhɑ-GLA联合应用可以显著恢复GLA酶的活性,未来可能有助于研发治疗弥漫性躯体血管角皮瘤的药物.     

Aicardi–Goutières syndrome: a model disease for systemic autoimmunity

Systemic autoimmunity is a complex disease process that results from a loss of immunological tolerance characterized by the inability of the immune system to discriminate self from non‐self. In patients with the prototypic autoimmune disease systemic lupus erythematosus (SLE), formation of autoantibodies targeting ubiquitous nuclear antigens and subsequent deposition of immune complexes in the vascular bed induces inflammatory tissue injury that can affect virtually any organ system. Given the extraordinary genetic and phenotypic heterogeneity of SLE, one approach to the genetic dissection of complex SLE is to study monogenic diseases, for which a single gene defect is responsible. Considerable success has been achieved from the analysis of the rare monogenic disorder Aicardi–Goutières syndrome (AGS), an inflammatory encephalopathy that clinically resembles in‐utero‐acquired viral infection and that also shares features with SLE. Progress in understanding the cellular and molecular functions of the AGS causing genes has revealed novel pathways of the metabolism of intracellular nucleic acids, the major targets of the autoimmune attack in patients with SLE. Induction of autoimmunity initiated by immune recognition of endogenous nucleic acids originating from processes such as DNA replication/repair or endogenous retro‐elements represents novel paradigms of SLE pathogenesis. These findings illustrate how investigating rare monogenic diseases can also fuel discoveries that advance our understanding of complex disease. This will not only aid the development of improved tools for SLE diagnosis and disease classification, but also the development of novel targeted therapeutic approaches.     

Pachygyria/hypogenitalism: A monogenic syndrome

We describe the clinical and neuroimaging findings of two severely retarded boys born to consanguineous parents. This appears to be a monogenic condition of abnormal neuronal migration associated with hypogenitalism. Reports of other monogenic syndromes of neuronal migration abnormalities are reviewed.     

Novel genomic techniques open new avenues in the analysis of monogenic disorders

The molecular genetic cause of over 3,000 monogenic disorders is currently unknown. This review discusses how novel genomic techniques like Next‐Generation DNA Sequencing (NGS) and genotyping arrays open new avenues in the elucidation of genetic defects causing monogenic disorders. They will not only speed up disease gene identification but will enable us to systematically tackle previously intractable monogenic disorders. These are mainly disorders not amenable to classic linkage analysis, for example, due to insufficient family size. Most monogenic diseases are caused by exonic mutations or splice‐site mutations changing the amino acid sequence of the affected gene. These mutations can be identified by sequencing of all exons in the human genome (exome sequencing) rendering whole genome sequencing unnecessary in most cases. Genotyping arrays containing 10⁵–2×10⁶ single nucleotide polymorphisms (SNPs) and nonpolymorphic markers allow highly accurate mapping of genomic deletions and duplications not detectable by exome sequencing, which are the second most common cause of monogenic disorders. However, several hundred rare, previously unknown sequence variants affecting the amino acid sequence of the encoded protein are found in the exome of every human individual. Therefore, the main challenge will be the differentiation between the many rare benign variants detected by novel genomic techniques and disease causing mutations. Hum Mutat 32:144–151, 2011. © 2011 Wiley‐Liss, Inc.     

Identification and quantification of oligogenic loss-of-function disorders

PurposeMonogenic disorders can present clinically heterogeneous symptoms. We hypothesized that in patients with a monogenic disorder caused by a large deletion, frequently additional loss-of-function (LOF)-intolerant genes are affected, potentially contributing to the phenotype.MethodsWe investigated the LOF-intolerant gene distribution across the genome and its association with benign population and pathogenic classified deletions from individuals with presumably monogenic disorders. For people with presumably monogenic epilepsy, we compared Human Phenotype Ontology terms in people with large and small deletions.ResultsWe identified LOF-intolerant gene dense regions that were enriched for ClinVar and depleted for population copy number variants. Analysis of data from >143,000 individuals with a suspected monogenic disorder showed that 2.5% of haploinsufficiency disorder–associated deletions can affect at least 1 other LOF-intolerant gene. Focusing on epilepsy, we observed that 13.1% of pathogenic and likely pathogenic ClinVar deletions <3 megabase pair, covering the diagnostically most relevant genes, affected at least 1 additional LOF-intolerant gene. Those patients have potentially more complex phenotypes with increasing deletion size.ConclusionWe could systematically show that large deletions frequently affected admditional LOF-intolerant genes in addition to the established disease gene. Further research is needed to understand how additional potential disease-relevant genes influence monogenic disorders to improve clinical care and the efficacy of targeted therapies.     

Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract

Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is a developmental disorder of the kidney and/or genito-urinary tract that results in end stage kidney disease (ESKD) in up to 50% of children. Despite the congenital nature of the disease, CAKUT accounts for almost 10% of adult onset ESKD. Multiple lines of evidence suggest that CAKUT is a Mendelian disorder, including the observation of familial clustering of CAKUT. Pathogenesis in CAKUT is embryonic in origin, with disturbances of kidney and urinary tract development resulting in a heterogeneous range of disease phenotypes. Despite polygenic and environmental factors being implicated, a significant proportion of CAKUT is monogenic in origin, with studies demonstrating single gene defects in 10%–20% of patients with CAKUT. Here, we review monogenic disease causation with emphasis on the etiological role of gene developmental pathways in CAKUT.     

Discovering monogenic patients with a confirmed molecular diagnosis in millions of clinical notes with MonoMiner

PurposeCohort building is a powerful foundation for improving clinical care, performing biomedical research, recruiting for clinical trials, and many other applications. We set out to build a cohort of all monogenic patients with a definitive causal gene diagnosis in a 3-million patient hospital system.MethodsWe define a subset (4461) of OMIM diseases that have at least 1 known monogenic causal gene. We then introduce MonoMiner, a natural language processing framework to identify molecularly confirmed monogenic patients from free-text clinical notes.ResultsWe show that ICD-10-CM codes cover only a fraction of monogenic diseases and that even where available, ICD-10-CM code?based patient retrieval offers 0.14 precision. Searching by causal gene symbol offers great recall but has an even worse 0.07 precision. MonoMiner achieves 6 to 11 times higher precision (0.80), with 0.87 precision on disease diagnosis alone, tagging 4259 patients with 560 monogenic diseases and 534 causal genes, at 0.48 recall.ConclusionMonoMiner enables the discovery of a large, high-precision cohort of patients with monogenic diseases with an established molecular diagnosis, empowering numerous downstream uses. Because it relies solely on clinical notes, MonoMiner is highly portable, and its approach is adaptable to other domains and languages.     

Preimplantation genetic diagnosis of monogenic diseases

Preimplantation genetic diagnosis (PGD) is an alternative to prenatal diagnosis allowing the detection of genetic diseases on IVF embryos before their transfer into the uterus and before the pregnancy. The aim of this procedure is to obtain unaffected or carrier embryos in order to avoid the burden of termination of pregnancy after prenatal diagnosis for couples at risk of transmitting particularly severe genetic disorders to their offspring. For monogenic diseases, PGD is most often based on single blastomere amplification by polymerase chain reaction (PCR). More than a decade after the first births, the possibilities of diagnosis for monogenic diseases have considerably increased. As for molecular biology and conventional diagnosis, the technologies and strategies for PGD are continually improved, with for instance introduction of fluorescent PCR or multiplex amplification. In this review, we describe several approaches for PGD of monogenic diseases, followed by an overview of the French practice, particularly in our lab.     

Current concepts in preimplantation genetic diagnosis (PGD): a molecular biologist's view

The first clinically applied preimplantation genetic diagnosis (PGD) was reported more than a decade ago and since then PGD has known an exponential growth. This first report described the use of PCR to sex embryos from couples at risk for X-linked diseases. Not surprisingly, in the first years, the development of PCR-based tests led to PGD for well-known monogenic diseases such as cystic fibrosis and thalassaemia. When fluorescent in-situ hybridization (FISH) was introduced it quickly replaced PCR-based methods, which had led to misdiagnoses, for sexing of embryos. FISH was also quickly introduced for aneuploidy screening, which has as its main aim the improvement of IVF results in patients with poor reproductive outcome, and later for PGD in translocation carriers. In this review, PGD for patients with a pre-existing genetic risk will be discussed, i.e. the monogenic diseases and the translocations, as well as different biopsy methods and promising new developments.     

An online compendium of treatable genetic disorders

More than 4,000 genes have been associated with recognizable Mendelian/monogenic diseases. When faced with a new diagnosis of a rare genetic disorder, health care providers increasingly turn to internet resources for information to understand the disease and direct care. Unfortunately, it can be challenging to find information concerning treatment for rare diseases as key details are scattered across a number of authoritative websites and numerous journal articles. The website and associated mobile device application described in this article begin to address this challenge by providing a convenient, readily available starting point to find treatment information. The site, Rx-genes.com ( https://www.rx-genes.com/ ), is focused on those conditions where the treatment is directed against the mechanism of the disease and thereby alters the natural history of the disease. The website currently contains 633 disease entries that include references to disease information and treatment guidance, a brief summary of treatments, the inheritance pattern, a disease frequency (if known), nonmolecular confirmatory testing (if available), and a link to experimental treatments. Existing entries are continuously updated, and new entries are added as novel treatments appear in the literature.     

性发育疾病新的分类和基因诊断

性发育疾病(Disorders of sex development,DSD)是性决定和性分化异常的一组异质性遗传病,是由于染色体畸变或单基因突变导致的性发育遗传和内分泌途径的改变。曾经用雌雄间体、假两性畸形、真两性畸形和性反转这些术语用于描述性发育疾病,但有轻蔑含义。2006年欧洲儿科内分泌协会(European Society for Pardiatric Endocrinology,ESPE)和Lawson Wilkins儿科内分泌协会(Lawson Wilkins Pardiatric Endocrine Society,LWPES)联合召开了由内分泌学家、外科学家、遗传学家、心理学家和患者支持小组成员参加的会议,提出了新的术语、分类标准和已知的突变基因。在此,与大家共同探讨。     

Monogenic autoimmune diseases - lessons of self-tolerance

The molecular defects recently identified in the rare monogenic autoimmune diseases (AIDs) have pinpointed critical steps in the pathways that contribute to the development of normal immune responses and self-tolerance. Recent studies of autoimmune polyendocrinopathy syndrome type 1, autoimmune lymphoproliferative syndrome, immunodysregulation, polyendocrinopathy and enteropathy, X-linked, IL-2 receptor alpha-chain deficiency, and, in particular, their corresponding mouse models, have revealed the details of the molecular mechanisms of normal immune tolerance, and exposed how defects in these mechanisms result in human autoimmunity. In addition to a deeper understanding of the immune system, detailed molecular characterization of monogenic AIDs will help us to understand the mechanisms behind common polygenic AIDs and, furthermore, to develop novel therapies and intervention strategies to treat them.