Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes

Chapman, Nicola H.; Nato, Alejandro Q.; Bernier, Raphael; Ankenman, Katy; Sohi, Harkirat; Munson, Jeff; Patowary, Ashok; Archer, Marilyn; Blue, Elizabeth; Webb, Sara Jane; Coon, Hilary; Raskind, Wendy H.; Brkanac, Zoran

doi:10.1007/s00439-015-1585-y

Cited by 56 publications

(64 citation statements)

References 70 publications

(80 reference statements)

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“…present in family P1). Although we were quite liberal in selecting regions for further analysis (through including suggestive linkage signals), the observed pattern is similar to findings in previous linkage studies of ADHD [13,14] and other neurodevelopmental disorders (e.g., for ASDs [53]). …”

Section: Discussionsupporting

confidence: 82%

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Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

et al. 2018

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Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N total = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.

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Section: Discussionsupporting

confidence: 82%

“…With this in mind, our combined linkage and WES approach did help to efficiently limit the list of potentially causative variants in a data-driven way. Filtering WES variants by linkage analysis has earlier been shown to be an effective tool for prioritizing common and exome variants in extended families with ADHD [14] or ASD [53].…”

Section: Discussionmentioning

confidence: 99%

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

et al. 2018

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“…For each proband, available family members were genotyped to determine if they carry the variant allele. Primers for PCR amplification and sequencing were designed using Primer3 (v 4.0.0) and bidirectional sequencing on an ABI 3730 DNA analyzer (Applied Biosystems) was done as previously described 13 .…”

Section: Methodsmentioning

confidence: 99%

“…To identify genes involved in familial autism, new sequencing methods were initially applied in consanguineous affected individuals in order to detect recessive genes 10, 11 . More recently whole-exome sequencing (WES) has been used in multiplex families to identify heterozygous shared variants that are associated with ASD risk 12, 13 . Such studies identified additional candidate genes for autism but lacked statistical power and did not include replication 14 .…”

Section: Introductionmentioning

confidence: 99%

Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism

et al. 2016

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second and third degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes. Among these, a novel private missense C1143F variant in the second intracellular loop of the voltage-gated sodium channel NaV1.7, encoded by the SCN9A gene, was identified in one family. Through electrophysiological analysis, we show that NaV1.7C1143F exhibits partial loss-of-function effects, resulting in slower recovery from inactivation and decreased excitability in cultured cortical neurons. Furthermore, for the same intracellular loop of NaV1.7, we found an excess of rare variants in a case-control variant-burden study. Functional analysis of one of these variants, M932L/V991L, also demonstrated reduced firing in cortical neurons. However, while this variant is rare in Caucasians, it is frequent in Latino population, suggesting that genetic background can alter its effects on phenotype. While the involvement of the SCN1A and SCN2A genes encoding NaV1.1 and NaV1.2 channels in de novo ASD has previously been demonstrated, our study indicates the involvement of inherited SCN9A variants and partial loss of function of NaV1.7 channels in the etiology of rare familial ASD.

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“…In this context, next‐generation sequencing (NGS) technology, by evaluating rare genetic variants, has enabled a deeper examination of complex traits using alternate models of risk, such as the ‘oligogenic quasi‐Mendelian model’ and the ‘omnigenic models’ of inheritance. Several recent studies in autism, SCZ, BD, and depression have detected rare variants using NGS in case–control or family‐based designs, across different genes implicated to play a key role in critical biological pathways . Findings from such studies have shown that the majority of the rare variants identified are private to a family (Table S1), indicating the underlying heterogeneity in the genetic architecture of SMI.…”

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confidence: 99%

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

Ganesh

Pallikonda

Nadella

et al. 2018

Psychiatry Clin Neurosci

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Aim Severe 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 may add to the understanding of the genetic architecture of SMI. Methods We analyzed 32 ill subjects from eight multiplex families and 33 healthy individuals using whole‐exome sequencing. Prioritized variants were selected by a three‐step filtering process, which included: deleteriousness by five in silico algorithms; sharing within families by affected individuals; rarity in South Asian sample estimated using the Exome Aggregation Consortium data; and complete absence of these variants in control individuals from the same gene pool. Results We identified 42 rare, non‐synonymous deleterious variants (~5 per pedigree) in this study. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes were previously reported to contribute to the risk of diverse neuropsychiatric syndromes, nine (21.4%) of which were of Mendelian inheritance. These included genes carrying novel deleterious variants, such as the GRM1 gene implicated in spinocerebellar ataxia 44 and the NIPBL gene implicated in Cornelia de Lange syndrome. Conclusion Next‐generation sequencing approaches in family‐based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The findings of the study suggest a potential phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of SMI.

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Whole exome sequencing in extended families with autism spectrum disorder implicates four candidate genes

Cited by 56 publications

References 70 publications

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

Identification of ADHD risk genes in extended pedigrees by combining linkage analysis and whole-exome sequencing

Association of rare missense variants in the second intracellular loop of NaV1.7 sodium channels with familial autism

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

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