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Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism.

ABSTRACT: Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination procedure based on groupwise association tests, and a hierarchical approach that can integrate sequencing data with diverse functional and evolutionary conservation annotations for individual variants. Using simulations, we show that incorporation of multiple bioinformatic predictors of deleteriousness, such as PolyPhen-2, SIFT and GERP++ scores, can improve the power to discover truly causal variants. As proof of principle, we apply the proposed methods to VPS13B, a gene mutated in the rare neurodevelopmental disorder called Cohen syndrome, and recently reported with recessive variants in autism. We identify a small set of promising candidates for causal variants, including two loss-of-function variants and a rare, homozygous probably-damaging variant that could contribute to autism risk.

SUBMITTER: Ionita-Laza I

PROVIDER: S-EPMC4263785 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism.

Ionita-Laza Iuliana I Capanu Marinela M De Rubeis Silvia S McCallum Kenneth K Buxbaum Joseph D JD

PLoS genetics 20141211 12

Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination procedure based on groupwise association tests, and a hierarchical approach that can integrate sequenc ...[more]

PMID: 25502226

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Project description:BackgroundCohen syndrome, an autosomal recessive syndrome, is a rare syndrome with diverse clinical manifestations including failure to thrive, hypotonia, hypermobile joints, microcephaly, intellectual disabilities, craniofacial and limb anomalies, neutropenia and a friendly character. It is associated with mutations of the vacuolar protein sorting 13 homolog B (VPS13B) gene, which is involved in the development of the ocular, hematological and central nervous systems. This gene encodes a transmembrane protein playing a crucial role in preserving the integrity of the Golgi complex. To date, more than 150 mutations of VPS13B have been reported in over 200 Cohen syndrome patients. Missense or nonsense mutations are the most common mutations.Case presentationA 4-year-old girl, born to consanguineous parents, was referred to the pediatric clinical immunology outpatient clinic for investigation of recurrent neutropenia with a history of recurrent infections in the past year. On physical examination, she had the characteristic facial features of Cohen syndrome, developmental delay and speech disorder. She had a cheerful disposition, and her mother gave a history of feeding difficulties in her first months of life. She did not present any ophthalmologic or cardiac abnormalities. Her lab results revealed moderate neutropenia. Serum IgG, IgM, IgA and IgE levels were normal. She fulfilled the clinical diagnostic criteria for Cohen syndrome. WES revealed a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49). Currently, she is not experiencing any severe problem, and she undergoes irregular medical treatment once her neutrophil count decreases under the normal limit. Her verbal and motor abilities have improved as a result of speech and occupational therapies.ConclusionWe reported a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49) in a 4-year-old girl with Cohen syndrome. Cohen syndrome should be considered in differential diagnosis of any child with intellectual disability and neutropenia.

Project description:BackgroundAutism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown.MethodsIn this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements.ResultsCombined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-β pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD.ConclusionsOur study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes.

Dataset Information

Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism.

Publications

Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in Cohen syndrome and autism.

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