Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability.
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ABSTRACT:
SUBMITTER: Thuresson AC
PROVIDER: S-EPMC6392105 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Whole genome sequencing of consanguineous families reveals novel pathogenic variants in intellectual disability.
Thuresson Ann-Charlotte AC Soussi Zander Cecilia C Zhao Jin J JJ Halvardson Jonatan J Maqbool Khurram K Månsson Else E Stenninger Eric E Holmlund Ulrika U Öhrner Ylva Y Feuk Lars L
Clinical genetics 20181207 3
Similar Datasets
Project description:Intellectual disability (ID) is a condition of significant limitation of cognitive functioning and adaptive behavior, with 50% of etiology attributed to genetic predisposition. We recruited two consanguineous Pakistani families manifesting severe ID and developmental delay. The probands were subjected to whole exome sequencing (WES) and variants were further prioritized based on population frequency, predicted pathogenicity and functional relevance. The WES data analysis identified homozygous pathogenic variants in genes MBOAT7 and TRAPPC9. The pathogenicity of the variants was supported by co-segregation analysis and in silico tool. The findings of this study expand mutation spectrum and provide additional evidence to the role of MBOAT7 and TRAPPC9 in causation of ID.
| S-EPMC9858807 | biostudies-literature
Project description:BackgroundIntellectual disability (ID) is both a clinically diverse and genetically heterogeneous group of disorder, with an onset of cognitive impairment before the age of 18 years. ID is characterized by significant limitations in intellectual functioning and adaptive behaviour. The identification of genetic variants causing ID and neurodevelopmental disorders using whole-exome sequencing (WES) has proven to be successful. So far more than 1222 primary and 1127 candidate genes are associated with ID.MethodsTo determine pathogenic variants causative of ID in three unrelated consanguineous Pakistani families, we used a combination of WES, homozygosity-by-descent mapping, de-deoxy sequencing and bioinformatics analysis.ResultsRare pathogenic single nucleotide variants identified by WES which passed our filtering strategy were confirmed by traditional Sanger sequencing and segregation analysis. Novel and deleterious variants in VPS53, GLB1, and MLC1, genes previously associated with variable neurodevelopmental anomalies, were found to segregate with the disease in the three families.ConclusionsThis study expands our knowledge on the molecular basis of ID as well as the clinical heterogeneity associated to different rare genetic causes of neurodevelopmental disorders. This genetic study could also provide additional knowledge to help genetic assessment as well as clinical and social management of ID in Pakistani families.
| S-EPMC7092478 | biostudies-literature
Project description:BackgroundIntellectual disability (ID) is a heterogeneous group of neurodevelopmental disorders that is characterized by significant impairment in intellectual and adaptive functioning with onset during the developmental period. Whole-exome sequencing (WES)-based studies in the consanguineous families with individuals affected with ID have shown a high burden of relevant variants. So far, over 700 genes have been reported in syndromic and non-syndromic ID. However, genetic causes in more than 50% of ID patients still remain unclear.MethodsWhole-exome sequencing was applied for investigation of various variants of ID, then Sanger sequencing and in silico analysis in ten patients from five Iranian consanguineous families diagnosed with autosomal recessive neurodevelopmental disorders, intellectual disability, performed for confirming the causative mutation within the probands. The most patients presented moderate-to-severe intellectual disability, developmental delay, seizure, speech problem, high level of lactate, and onset before 10 years.ResultsFiltering the data identified by WES, two novel homozygous missense variants in FBXO31 and TIMM50 genes and one previously reported mutation in the CEP290 gene in the probands were found. Sanger sequencing confirmed the homozygote variant's presence of TIMM50 and FBXO31 genes in six patients and two affected siblings in their respective families. Our computational results predicted that the variants are located in the conserved regions across different species and have the impacts on the protein stability.ConclusionHence, we provide evidence for the pathogenicity of two novel variants in the patients which will expand our knowledge about potential mutation involved in the heterogeneous disease.
| S-EPMC8842163 | biostudies-literature
Project description:Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.
| S-EPMC5658665 | biostudies-literature
Project description:Vitiligo is an autoimmune complex pigmentation disease characterized by non-pigmented patches on the surface of the skin that affect approximately 0.5-2% population worldwide. The exact etiology is still unknown; however, vitiligo is hypothesized to be a multifactorial and genetically heterogeneous condition. Therefore, the current study is designed to investigate the anthropometric presentation and genetic spectrum of vitiligo in fifteen consanguineous Pakistani families. The clinical evaluation of participating individuals revealed varying degrees of disease severity, with 23 years as the average age of disease onset. The majority of the affected individuals had non-segmental vitiligo (NSV). Whole exome sequencing analysis revealed clustering of rare variants of known vitiligo-associated genes. For instance, in the affected individuals of family VF-12, we identified three novel rare variants of PTPN22 (c.1108C>A), NRROS (c.197C>T) and HERC2 (c.10969G>A) genes. All three variants replaced evolutionarily conserved amino acid residues in encoded proteins, which are predicted to impact the ionic interactions in the secondary structure. Although various in silico algorithms predicted low effect sizes for these variants individually, the clustering of them in affected individuals increases the polygenic burden of risk alleles. To our knowledge, this is the first study that highlights the complex etiology of vitiligo and genetic heterogeneity in multiplex consanguineous Pakistani families.
| S-EPMC10218579 | biostudies-literature
Project description:Intellectual disability (ID) is characterized by significant limitations in both intellectual functioning and adaptive behaviors, originating before the age of 18 years. However, the genetic etiologies of ID are still incompletely elucidated due to the wide range of clinical and genetic heterogeneity. Whole genome sequencing (WGS) has been applied as a single-step clinical diagnostic tool for ID because it detects genetic variations with a wide range of resolution from single nucleotide variants (SNVs) to structural variants (SVs). To explore the causative genes for ID, we employed WGS in 45 patients from 44 unrelated Japanese families and performed a stepwise screening approach focusing on the coding variants in the genes. Here, we report 12 pathogenic and likely pathogenic variants: seven heterozygous variants of ADNP, SATB2, ANKRD11, PTEN, TCF4, SPAST, and KCNA2, three hemizygous variants of SMS, SLC6A8, and IQSEC2, and one homozygous variant in AGTPBP1. Of these, four were considered novel. Furthermore, a novel 76 kb deletion containing exons 1 and 2 in DYRK1A was identified. We confirmed the clinical and genetic heterogeneity and high frequency of de novo causative variants (8/12, 66.7%). This is the first report of WGS analysis in Japanese patients with ID. Our results would provide insight into the correlation between novel variants and expanded phenotypes of the disease.
| S-EPMC8247954 | biostudies-literature
Project description:BackgroundCystic fibrosis (CF) is an autosomal recessive disease caused by genetic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is a common hereditary disease in Caucasians while rare in the Chinese. Until now, only 87 Chinese patients have been reported with molecular confirmations. The variant spectrum and clinical features of Chinese CF patients are obviously different from those of Caucasians.Materials and methodsWhole-exome sequencing was applied to analyze the exome of three individuals who have only the typical CF phenotype in the respiratory system from two consanguineous families. The protein domain and structure analysis were applied to predict the impact of the variants. Sanger sequencing was applied to validate the candidate variants.ResultsA previously reported homozygous variant in CFTR (NM_000492.4: c.1000C > T, p.R334W) was identified in proband I. A novel homozygous variant in a polymorphic position (NM_000492.4: c.1409T > A, p.V470E) was identified in two individuals in the family II. The novel CFTR variant predicted to be disease-causing is the first, to the best of our knowledge, to be reported in CFTR. However, in vitro validation is still needed.ConclusionOur finding expands the variant spectrum of CFTR, reveals clearer clinical phenotype distinction and variant spectrum distinction between Chinese and Caucasian CF patients, and contributes to a more rapid genetic diagnosis and future genetic counseling.
| S-EPMC8283821 | biostudies-literature
Project description:BackgroundIntellectual disability (ID) affects 1-3% of the world population. The number of genes whose dysfunctions cause intellectual disability is increasing. In addition, new gene associations are constantly being discovered, as well as specific phenotypic features for already identified genetic alterations are being described. The aim of our study was to search for pathogenic variants in genes responsible for moderate to severe intellectual disability and epilepsy, using a panel of targeted next-generation sequencing (tNGS) for diagnosis.MethodsThe group of 73 patients (ID, n=32; epilepsy, n=21; ID and epilepsy, n=18) was enrolled in the nucleus DNA (nuDNA) study using a tNGS panel (Agilent Technologies, USA). In addition, high coverage mitochondrial DNA (mtDNA) was extracted from the tNGS data for 54 patients.ResultsFifty-two rare nuDNA variants, as well as 10 rare and 1 novel mtDNA variants, were found in patients in the study group. The 10 most damaging nuDNA variants were subjected to a detailed clinical analysis. Finally, 7 nuDNA and 1 mtDNA were found to be the cause of the disease.ConclusionsThis shows that still a very large proportion of patients remain undiagnosed and may require further testing. The reason for the negative results of our analysis may be a non-genetic cause of the observed phenotypes or failure to detect the causative variant in the genome. In addition, the study clearly shows that analysis of the mtDNA genome is clinically relevant, as approximately 1% of patients with ID may have pathogenic variant in mitochondrial DNA.
| S-EPMC10545623 | biostudies-literature
Project description:Although it has been a half-century since dioxin-contaminated herbicides were used to defoliate the landscape during the Vietnam War, dioxin contamination "hotspots" still remain in Vietnam. Environmental and health impacts of these hotspots need to be evaluated. Intellectual disability (ID) is one of the diseases found in the children of people exposed to the herbicides. This study aims to identify genetic alterations of a patient whose family lived in a dioxin hotspot. The patient's father had a highly elevated dioxin concentration. He was affected with undiagnosed moderate ID. To analyze de novo mutations and genetic variations, and to identify causal gene(s) for ID, we performed whole genome sequencing (WGS) of the proband and his parents. Two de novo missense mutations were detected, each one in ETS2 and ZNF408 genes, respectively. Compound heterozygosity was identified in CENPF and TTN genes. Existing knowledge on the genes and bioinformatics analyses suggest that EST2, ZNF408, and CENPF might be promising candidates for ID causative genes.
| S-EPMC6313569 | biostudies-literature
Project description:Non-specific intellectual disability of autosomal recessive inheritance (NS-ARID) represents an important fraction of severe cognitive dysfunction disorders. To date, only 10 genes have been identified, and further 24 linked-ARID loci have been reported, as well as others with suggestive linkage. To discover novel genes causing NS-ARID, we undertook genome-wide homozygosity mapping in 64 consanguineous multiplex families of Syrian descent. A total of 11 families revealed unique, significantly linked loci at 4q26-4q28 (MRT17), 6q12-q15 (MRT18), 18p11 (MRT19), 16p12-q12 (MRT20), 11p15 (MRT21), 11p13-q14 (MRT23), 6p12 (MRT24), 12q13-q15 (MRT25), 14q11-q12 (MRT26), 15q23-q26 (MRT27), and 6q26-q27 (MRT28), respectively. Loci ranged between 1.2 and 45.6?Mb in length. One family showed linkage to chromosome 8q24.3, and we identified a mutation in TRAPPC9. Our study further highlights the extreme heterogeneity of NS-ARID, and suggests that no major disease gene is to be expected, at least in this study group. Systematic analysis of large numbers of affected families, as presented here, will help discovering the genetic causes of ID.
| S-EPMC3198153 | biostudies-literature