scholarly journals Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

2018 ◽  
Author(s):  
Lucilla Pizzo ◽  
Matthew Jensen ◽  
Andrew Polyak ◽  
Jill A. Rosenfeld ◽  
Katrin Mannik ◽  
...  
Keyword(s):  
Family History ◽  
Genetic Background ◽  
Rare Variants ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Disease Genes ◽  
Complete Evaluation ◽  
Rare Cnvs ◽  
Complex Disorders

AbstractPurposeTo assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.MethodsWe analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.ResultsThe number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.ConclusionAccurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

scholarly journals A Systematic Review on Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

2020 ◽  
Author(s):  
Sana Amanat ◽  
Teresa Requena ◽  
Jose Antonio Lopez-Escamez
Keyword(s):  
Systematic Review ◽  
Candidate Genes ◽  
Rare Variants ◽  
De Novo ◽  
Complex Diseases ◽  
De Novo Mutations ◽  
Genetic Studies ◽  
Complex Disorders ◽  
Extreme Phenotype ◽  
Age Related

Exome sequencing has been commonly used in rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) to search 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 heritability in complex clinical traits. We have conducted a systematic review to find evidence supporting the use of EP strategies to search for rare variants in genetic studies of complex diseases, to highlight the contribution of rare variation to the genetic structure of multiallelic conditions. After performing the quality assessment of the retrieved records, we selected 19 genetic studies considering EP to demonstrate genetic association. All the studies successfully identified several rare variants, de novo mutations and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach in patients with an early onset of the 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.

scholarly journals A Systematic Review of Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 987
Author(s):  
Sana Amanat ◽  
Teresa Requena ◽  
Jose Antonio Lopez-Escamez
Keyword(s):  
Systematic Review ◽  
Candidate Genes ◽  
Rare Variants ◽  
De Novo ◽  
Complex Diseases ◽  
Genetic Studies ◽  
Complex Disorders ◽  
Extreme Phenotype ◽  
Disease Spectrum ◽  
Age Related

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.

scholarly journals Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 and ALYREF as new candidate risk genes

2021 ◽  
Author(s):  
Lu Qiao ◽  
Le Xu ◽  
Lan Yu ◽  
Julia Wynn ◽  
Rebecca Hernan ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Rare Variants ◽  
De Novo ◽  
Disease Genes ◽  
Risk Genes ◽  
Association Analyses ◽  
Significant Enrichment ◽  
Coding Variants

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (Lon Peptidase 1, Mitochondrial) and ALYREF (Aly/REF Export Factor) as novel candidate CDH genes based on de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 cases and 11,220 ancestry-matched population controls and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in familial cases. Approximately 3% of our CDH cohort was heterozygous with ultra-rare predicted damaging variants in LONP1 who have a range of clinical phenotypes including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium specific deletion of Lonp1 die immediately after birth and have reduced lung growth and branching that may at least partially explain the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

scholarly journals Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism

2013 ◽  
Vol 168 (4) ◽  
pp. 557-564 ◽  
Author(s):  
Ritika R Kapoor ◽  
Sarah E Flanagan ◽  
Ved Bhushan Arya ◽  
Julian P Shield ◽  
Sian Ellard ◽  
...  
Keyword(s):  
Family History ◽  
Positive Family History ◽  
Genetic Diagnosis ◽  
Clinical Information ◽  
Congenital Hyperinsulinism ◽  
Molecular Characterisation ◽  
Heterogeneous Condition ◽  
Diffuse Disease ◽  
Molecular Aspects ◽  
Inherited Mutations

BackgroundCongenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8,KCNJ11,GLUD1,GCK,HADH,SLC16A1,HNF4AandHNF1A) are known to cause CHI.AimTo characterise the clinical and molecular aspects of a large cohort of patients with CHI.MethodologyThree hundred patients were recruited and clinical information was collected before genotyping.ABCC8andKCNJ11genes were analysed in all patients. Mutations inGLUD1,HADH,GCKandHNF4Agenes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A).ResultsMutations were identified in 136/300 patients (45.3%). Mutations inABCC8/KCNJ11were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations inABCC8/KCNJ11were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in theABCC8/KCNJ11genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations inABCC8/KCNJ11(n=15),HNF4A(n=7),GLUD1(n=16) andHADH(n=3).ConclusionsA genetic diagnosis was made for 45.3% of patients in this large series. Mutations in theABCC8gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms.

scholarly journals Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009679
Author(s):  
Enrique Audain ◽  
Anna Wilsdon ◽  
Jeroen Breckpot ◽  
Jose MG Izarzugaza ◽  
Tomas W. Fitzgerald ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Congenital Heart ◽  
De Novo ◽  
Integrative Analysis ◽  
Disease Genes ◽  
Rare Cnvs ◽  
Genomic Deletions ◽  
Genomic Variants ◽  
New Associations

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.

scholarly journals Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes

2018 ◽  
Author(s):  
Suhas Ganesh ◽  
Ahmed P Husayn ◽  
Ravi Kumar Nadella ◽  
Ravi Prabhakar More ◽  
Manasa Sheshadri ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Exome Sequencing ◽  
Rare Variants ◽  
Association Studies ◽  
Mental Illnesses ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Genome Wide Association Studies ◽  
Complex Disorders ◽  
Family Based

AbstractIntroductionSevere Mental Illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing (NGS) may add to the understanding of genetic architecture of SMIs.MethodsWe analyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n=26; schizophrenia, n=4; schizoaffective disorder, n=1 schizophrenia like psychosis, n=1) from 8 multiplex families; and 33 healthy individuals by whole exome sequencing. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the controls and rarity in South Asian sample of Exome Aggregation Consortium.ResultsWe identified a total of 42 unique rare, non-synonymous deleterious variants in this study with an average of 5 variants per family. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes identified in this sample have been previously reported to contribute to the risk of neuropsychiatric syndromes. These include genes which are related to neurodevelopmental processes, or have been implicated in different monogenic syndromes with a severe neurodevelopmental phenotype.ConclusionNGS approaches in family based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The study further validates the phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of severe mental illnesses.

scholarly journals Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations

2010 ◽  
Vol 162 (5) ◽  
pp. 987-992 ◽  
Author(s):  
S E Flanagan ◽  
R R Kapoor ◽  
G Mali ◽  
D Cody ◽  
N Murphy ◽  
...  
Keyword(s):  
Family History ◽  
De Novo ◽  
Clinical Phenotype ◽  
Mutation Screening ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
Hyperinsulinemic Hypoglycemia ◽  
Neonatal Hypoglycemia ◽  
Family History Of Diabetes ◽  
History Of

ObjectiveThe phenotype associated with heterozygous HNF4A gene mutations has recently been extended to include diazoxide responsive neonatal hypoglycemia in addition to maturity-onset diabetes of the young (MODY). To date, mutation screening has been limited to patients with a family history consistent with MODY. In this study, we investigated the prevalence of HNF4A mutations in a large cohort of patients with diazoxide responsive hyperinsulinemic hypoglycemia (HH).Subjects and methodsWe sequenced the ABCC8, KCNJ11, GCK, GLUD1, and/or HNF4A genes in 220 patients with HH responsive to diazoxide. The order of genetic testing was dependent upon the clinical phenotype.ResultsA genetic diagnosis was possible for 59/220 (27%) patients. KATP channel mutations were most common (15%) followed by GLUD1 mutations causing hyperinsulinism with hyperammonemia (5.9%), and HNF4A mutations (5%). Seven of the 11 probands with a heterozygous HNF4A mutation did not have a parent affected with diabetes, and four de novo mutations were confirmed. These patients were diagnosed with HI within the first week of life (median age 1 day), and they had increased birth weight (median +2.4 SDS). The duration of diazoxide treatment ranged from 3 months to ongoing at 8 years.ConclusionsIn this large series, HNF4A mutations are the third most common cause of diazoxide responsive HH. We recommend that HNF4A sequencing is considered in all patients with diazoxide responsive HH diagnosed in the first week of life irrespective of a family history of diabetes, once KATP channel mutations have been excluded.

scholarly journals Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita

2021 ◽  
pp. jmedgenet-2020-107595
Author(s):  
Annie Laquerriere ◽  
Dana Jaber ◽  
Emanuela Abiusi ◽  
Jérome Maluenda ◽  
Dan Mejlachowicz ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
De Novo ◽  
Genetic Diagnosis ◽  
Added Value ◽  
Disease Genes ◽  
Arthrogryposis Multiplex Congenita ◽  
Pathogenic Variants ◽  
New Genes ◽  
Whole Exome ◽  
Disease Loci

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

scholarly journals Transcript expression-aware annotation improves rare variant discovery and interpretation

2019 ◽  
Author(s):  
Beryl B. Cummings ◽  
Konrad J. Karczewski ◽  
Jack A. Kosmicki ◽  
Eleanor G. Seaby ◽  
Nicholas A. Watts ◽  
...  
Keyword(s):  
Rare Variant ◽  
Developmental Disorders ◽  
De Novo ◽  
Disease Diagnosis ◽  
Autism Spectrum ◽  
Disease Genes ◽  
Loss Of Function ◽  
Tissue Samples ◽  
Complex Disorders ◽  
Alternative Mrna Splicing

AbstractThe acceleration of DNA sequencing in patients and population samples has resulted in unprecedented catalogues of human genetic variation, but the interpretation of rare genetic variants discovered using such technologies remains extremely challenging. A striking example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Through manual curation of putative loss of function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)(1), we show that one explanation for this paradox involves alternative mRNA splicing, which allows exons of a gene to be expressed at varying levels across cell types. Currently, no existing annotation tool systematically incorporates this exon expression information into variant interpretation. Here, we develop a transcript-level annotation metric, the proportion expressed across transcripts (pext), which summarizes isoform quantifications for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression project(2) (GTEx) and show that it clearly differentiates between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expression-based annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder (ASD) and developmental disorders and intellectual disability (DD/ID) to show that pLoF variants in weakly expressed regions have effect sizes similar to those of synonymous variants, while pLoF variants in highly expressed exons are most strongly enriched among cases versus controls. Our annotation is fast, flexible, and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for rare disease diagnosis, rare variant burden analyses in complex disorders, and curation and prioritization of variants in recall-by-genotype studies.

scholarly journals Screening for HNF1B Gene Mutations, in Four People with Typical Diabetes MODY5 Clinical Characteristics

2021 ◽  
Vol 8 (7) ◽  
Author(s):  
Alejandro de Dios ◽  
◽  
Sofia Irene Trobo ◽  
Anette Marianne Prior Gjesing ◽  
Torben Hansen ◽  
...  
Keyword(s):  
Family History ◽  
Genetic Screening ◽  
Clinical Characteristics ◽  
De Novo ◽  
Mutation Screening ◽  
Genetic Diagnosis ◽  
Gene Mutations ◽  
De Novo Mutations ◽  
Family History Of Diabetes ◽  
Bioinformatic Tools

Introduction: people with clinical characteristics of MODY benefit with a correct genetic diagnosis and are often only studied if having family history. In this work there were studied four people selected per their clinical characteristics of genitourinary abnormalities and MODY Diabetes, using the worldwide inclusion criteria for MODY5 except for a family history of diabetes or kidney disease. Methods: gene mutation screening in four people with clinical characteristics of MODY5 in search for alterations in the HNF1B gene with Sanger or NGS sequencing, and bioinformatic tools to analyze the results of the sequences. Results: from four people studied we found three mutations in the HNF1B gene, including a missense mutation previously described and two de novo whole gene deletions. The other person did not present any alteration in that gene even having clinical characteristics. Conclusions: people with clinical characteristics of MODY and having pancreatic, renal, kidney or genital located abnormalities are candidates for genetic screening of HNF1B. Yet, genetic screening of HNF1B should not only be restricted to such people but should also be considered in people without diabetes but having those other characteristics. We suggest also, the study of people even in the absence of family history, given that the possibility of occurrence of de novo mutations is underestimated.

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