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Whole genome investigation of an atypical autism case identifies a novel ANOS1 mutation with subsequent diagnosis of Kallmann syndrome.

ABSTRACT: We report an actionable secondary finding from whole-genome sequencing (WGS) of a 10-year-old boy with autism. WGS identified non-synonymous variants in several genes, including a nonsense mutation in the ANOS1 gene which is an X-linked cause of Kallmann syndrome. WGS can provide insights into complex genetic disorders such as autism, and actionable incidental findings can offer the potential for therapeutic interventions.

SUBMITTER: Dawson PA

PROVIDER: S-EPMC7200310 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Whole genome investigation of an atypical autism case identifies a novel <i>ANOS1</i> mutation with subsequent diagnosis of Kallmann syndrome.

Dawson Paul A PA Lee Soohyun S Ewing Adam D AD Prins Johannes B JB Heussler Helen S HS

Molecular genetics and metabolism reports 20200429

We report an actionable secondary finding from whole-genome sequencing (WGS) of a 10-year-old boy with autism. WGS identified non-synonymous variants in several genes, including a nonsense mutation in the <i>ANOS1</i> gene which is an X-linked cause of Kallmann syndrome. WGS can provide insights into complex genetic disorders such as autism, and actionable incidental findings can offer the potential for therapeutic interventions. ...[more]

PMID: 32382505

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Project description:BackgroundKallmann syndrome (KS) is a common type of idiopathic hypogonadotropic hypogonadism. To date, more than 30 genes including ANOS1 and FGFR1 have been identified in different genetic models of KS without affirmatory genotype-phenotype correlation, and novel mutations have been found.MethodsA total of 35 unrelated patients with clinical features of disorder of sex development were recruited. Custom-panel sequencing or whole-exome sequencing was performed to detect the pathogenic mutations. Sanger sequencing was performed to verify single-nucleotide variants. Copy number variation-sequencing (CNV-seq) was performed to determine CNVs. The pathogenicity of the identified variant was predicted in silico. mRNA transcript analysis and minigene reporter assay were performed to test the effect of the mutation on splicing.ResultsANOS1 gene c.709 T > A and c.711 G > T were evaluated as pathogenic by several commonly used software, and c.1063-2 A > T was verified by transcriptional splicing assay. The c.1063-2 A > T mutation activated a cryptic splice acceptor site downstream of the original splice acceptor site and resulted in an aberrant splicing of the 24-basepair at the 5' end of exon 8, yielding a new transcript with c.1063-1086 deletion. FRFR1 gene c.1835delA was assessed as pathogenic according to the ACMG guideline. The CNV of del(8)(p12p11.22)chr8:g.36140000_38460000del was judged as pathogenic according to the ACMG & ClinGen technical standards.ConclusionsHerein, we identified three novel ANOS1 mutations and two novel FGFR1 variations in Chinese KS families. In silico prediction and functional experiment evaluated the pathogenesis of ANOS1 mutations. FRFR1 c.1835delA mutation and del(8)(p12p11.22)chr8:g.36140000_38460000del were assessed as pathogenic variations. Therefore, our study expands the spectrum of mutations associated with KS and provides diagnostic evidence for patients who carry the same mutation in the future.

Dataset Information

Whole genome investigation of an atypical autism case identifies a novel ANOS1 mutation with subsequent diagnosis of Kallmann syndrome.

Publications

Whole genome investigation of an atypical autism case identifies a novel <i>ANOS1</i> mutation with subsequent diagnosis of Kallmann syndrome.

Similar Datasets

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