scholarly journals Quantifying the contribution of recessive coding variation to developmental disorders

2017 ◽  
Author(s):  
Hilary C. Martin ◽  
Wendy D. Jones ◽  
James Stephenson ◽  
Juliet Handsaker ◽  
Giuseppe Gallone ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Disease Gene ◽  
De Novo ◽  
European Ancestry ◽  
Compound Heterozygous ◽  
Clinical Genetics ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Dominant Disease ◽  
Coding Variants

Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained by de novo coding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction: EIF3F, KDM5B, and THOC6. EIF3F is a novel disease gene, and KDM5B has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.

scholarly journals Quantifying the contribution of recessive coding variation to developmental disorders

Science ◽  
2018 ◽  
Vol 362 (6419) ◽  
pp. 1161-1164 ◽  
Author(s):  
Hilary C. Martin ◽  
Wendy D. Jones ◽  
Rebecca McIntyre ◽  
Gabriela Sanchez-Andrade ◽  
Mark Sanderson ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
European Ancestry ◽  
Incomplete Penetrance ◽  
Cellular Models ◽  
Genome Wide ◽  
Coding Variants

We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

scholarly journals Non-coding variants upstream of MEF2C cause severe developmental disorder through three distinct loss-of-function mechanisms

2020 ◽  
Author(s):  
Caroline F Wright ◽  
Nicholas M Quaife ◽  
Laura Ramos-Hernández ◽  
Petr Danecek ◽  
Matteo P Ferla ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Developmental Disorder ◽  
De Novo ◽  
Diagnostic Yield ◽  
Severe Disease ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Clinical Genetic ◽  
Protein Coding ◽  
Coding Variants

AbstractClinical genetic testing of protein-coding regions identifies a likely causative variant in only ∼35% of severe developmental disorder (DD) cases. We screened 9,858 patients from the Deciphering Developmental Disorders (DDD) study for de novo mutations in the 5’untranslated regions (5’UTRs) of dominant haploinsufficient DD genes. We identify four single nucleotide variants and two copy number variants upstream of MEF2C that cause DD through three distinct loss-of-function mechanisms, disrupting transcription, translation, and/or protein function. These non-coding variants represent 23% of disease-causing variants identified in MEF2C in the DDD cohort. Our analyses show that non-coding variants upstream of known disease-causing genes are an important cause of severe disease and demonstrate that analysing 5’UTRs can increase diagnostic yield, even using existing exome sequencing datasets. We also show how non-coding variants can help inform both the disease-causing mechanism underlying protein-coding variants, and dosage tolerance of the gene.

scholarly journals A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Bernice Lo ◽  
Sara Tomei ◽  
Valentina Mattei ◽  
Samuel N. Young ◽  
...  
Keyword(s):  
Potential Role ◽  
Autosomal Dominant ◽  
Inflammatory Diseases ◽  
Diabetic Patients ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Healthy Sibling ◽  
Dominant Disease ◽  
Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

scholarly journals Hypertrophic Cardiomyopathy: An Overview of Genetics and Management

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 878 ◽  
Author(s):  
Polakit Teekakirikul ◽  
Wenjuan Zhu ◽  
Helen C. Huang ◽  
Erik Fung
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Current Knowledge ◽  
Diagnostic Testing ◽  
Left Ventricular ◽  
Clinical Genetics ◽  
Incomplete Penetrance ◽  
Cardiac Symptoms ◽  
Genetic Landscape ◽  
Dominant Disease ◽  
Muscle Disorder

Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous cardiac muscle disorder with a diverse natural history, characterized by unexplained left ventricular hypertrophy (LVH), with histopathological hallmarks including myocyte enlargement, myocyte disarray and myocardial fibrosis. Although these features can cause significant cardiac symptoms, many young individuals with HCM are asymptomatic or mildly symptomatic. Sudden cardiac death (SCD) may occur as the initial clinical manifestation. Over the past few decades, HCM has been considered a disease of sarcomere, and typically as an autosomal dominant disease with variable expressivity and incomplete penetrance. Important insights into the genetic landscape of HCM have enhanced our understanding of the molecular pathogenesis, empowered gene-based diagnostic testing to identify at-risk individuals, and offered potential targets for the development of therapeutic agents. This article reviews the current knowledge on the clinical genetics and management of HCM.

scholarly journals Human and mouse essentiality screens as a resource for disease gene discovery

2019 ◽  
Author(s):  
Pilar Cacheiro ◽  
Violeta Muñoz-Fuentes ◽  
Stephen A. Murray ◽  
Mary E. Dickinson ◽  
Maja Bucan ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Disease Gene ◽  
De Novo ◽  
Genetic Diseases ◽  
Gene Discovery ◽  
Tissue Expression ◽  
Human Cell Line ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Disease Gene Discovery

ABSTRACTAlthough genomic sequencing has been transformative in the study of rare genetic diseases, identifying causal variants remains a considerable challenge that can be addressed in part by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from the comprehensive viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and from human cell line essentiality screens. We propose a novel, cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing characteristics in the biological processes they regulate, tissue expression levels and human mutation rates. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented in the developmental lethal category, representing genes not essential for cell survival but required for organism development. Exploiting this finding, we have screened developmental disorder cases from three independent disease sequencing consortia and identified potentially pathogenic, de novo variants shared in different patients for several developmental lethal genes that have not previously been associated with rare disease. We therefore propose FUSIL as an efficient resource for disease gene discovery.

scholarly journals Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

2016 ◽  
Author(s):  
Jeremy F McRae ◽  
Stephen Clayton ◽  
Tomas W Fitzgerald ◽  
Joanna Kaplanis ◽  
Elena Prigmore ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Phenotypic Diversity ◽  
Diagnostic Yield ◽  
Dominant Negative ◽  
De Novo Mutation ◽  
Published Data ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Birth Prevalence

AbstractIndividuals with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,293 families with individuals with DDs, and meta-analysed these data with published data on 3,287 individuals with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the affected individual, the relatedness of their parents and the age of both father and mother. We identified 94 genes enriched for damaging de novo mutation at genome-wide significance (P < 7 × 10−7), including 14 genes for which compelling data for causation was previously lacking. We have characterised the phenotypic diversity among these genetic disorders. We demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42% of our cohort carry pathogenic DNMs (single nucleotide variants and indels) in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder resulting in altered-function (e.g. activating, dominant negative). We established that most haplo insufficient developmental disorders have already been identified, but that many altered-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that developmental disorders caused by DNMs have an average birth prevalence of 1 in 213 to 1 in 448 (0.22-0.47% of live births), depending on parental age.AbbreviationsPTVProtein-Truncating VariantDNMDe Novo MutationDDDevelopmental DisorderDDDDeciphering Developmental Disorders study

scholarly journals Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder

2021 ◽  
Author(s):  
Xiaoming Jia ◽  
Fernando S. Goes ◽  
Adam E. Locke ◽  
Duncan Palmer ◽  
Weiqing Wang ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Meta Analysis ◽  
Common Variant ◽  
European Ancestry ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Protein Coding ◽  
Significant Enrichment ◽  
Coding Variants

AbstractBipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

scholarly journals De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+ regulation

2021 ◽  
Vol 118 (52) ◽  
pp. e2115140118
Author(s):  
Matthew Halvorsen ◽  
Laura Gould ◽  
Xiaohan Wang ◽  
Gariel Grant ◽  
Raquel Moya ◽  
...  
Keyword(s):  
Sudden Death ◽  
Odds Ratio ◽  
Neuronal Excitability ◽  
De Novo ◽  
Sequence Data ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Sudden Unexplained Death ◽  
Unexplained Death

Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 “trios” (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10−4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C. Both RYR2 mutations are pathogenic (P = 1.7 × 10−7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10−7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.

scholarly journals Schizophrenia, autism spectrum disorders and developmental disorders share specific disruptive coding mutations

2020 ◽  
Author(s):  
Elliott Rees ◽  
Hugo Creeth ◽  
Hai-Gwo Hwu ◽  
Wei Chen ◽  
Ming Tsuang ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Intellectual Disability ◽  
Neurodevelopmental Disorders ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Risk Genes ◽  
Spectrum Disorders ◽  
Coding Variants ◽  
Shared Risk

Abstract Genes enriched for rare disruptive coding variants in schizophrenia overlap those in which disruptive mutations are associated with neurodevelopmental disorders (NDDs), particularly autism spectrum disorders and intellectual disability. However, it is unclear whether this implicates the same specific variants, or even variants with the same functional effects on shared risk genes. Here, we show that de novo mutations in schizophrenia are generally of the same functional category as those that confer risk for NDDs, and that the specific de novo mutations in NDDs are enriched in schizophrenia. These findings indicate that, in part, NDDs and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology. We also observe pleiotropic effects for variants known to be pathogenic for several syndromic developmental disorders, suggesting that schizophrenia should be included among the phenotypes associated with these mutations. Collectively, our findings support the hypothesis that at least some forms of schizophrenia lie within a continuum of neurodevelopmental disorders.

scholarly journals Distinct Epigenomic Patterns Are Associated with Haploinsufficiency and Predict Risk Genes of Developmental Disorders

2017 ◽  
Author(s):  
Xinwei Han ◽  
Siying Chen ◽  
Elise Flynn ◽  
Shuang Wu ◽  
Dana Wintner ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
De Novo ◽  
Population Data ◽  
Cell Types ◽  
Computational Method ◽  
Loss Of Function ◽  
Major Mechanism ◽  
Risk Variants ◽  
Sequencing Studies ◽  
New Applications

AbstractHaploinsufficiency is a major mechanism of genetic risk in developmental disorders. Accurate prediction of haploinsufficient genes is essential for prioritizing and interpreting deleterious variants in genetic studies. Current methods based on mutation intolerance in population data suffer from inadequate power for genes with short transcripts. Here we showed haploinsufficiency is strongly associated with epigenomic patterns, and then developed a new computational method (Episcore) to predict haploinsufficiency from epigenomic data from a broad range of tissue and cell types using machine learning methods. Based on data from recent exome sequencing studies of developmental disorders, Episcore achieved better performance in prioritizing loss of function de novo variants than current methods. We further showed that Episcore was less biased with gene size, and was complementary to mutation intolerance metrics for prioritizing loss of function variants. Our approach enables new applications of epigenomic data and facilitates discovery and interpretation of novel risk variants in studies of developmental disorders.

Sign in / Sign up

Export Citation Format

Share Document