Replication of a rare risk haplotype on 1p36.33 for autism spectrum disorder

Replication of a rare risk haplotype on 1p36.33 for autism spectrum disorder

Hundreds of genes have been implicated in autism spectrum disorders (ASDs). In genetically heterogeneous conditions, large families with multiple affected individuals provide strong evidence implicating a rare variant, and replication of the same variant in multiple families is unusual. We previousl...

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Bibliographic Details
Published in:Human genetics Vol. 137; no. 10; pp. 807 - 815
Main Authors: Chapman, N. H., Bernier, R. A., Webb, S. J., Munson, J., Blue, E. M., Chen, D.-H., Heigham, E., Raskind, W. H., Wijsman, Ellen M.
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-10-2018
Springer
Springer Nature B.V
Subjects:
Autism
Autism Spectrum Disorder - genetics
Biomedical and Life Sciences
Biomedicine
DNA nucleotidylexotransferase
DNA sequencing
Eye Proteins - genetics
Families & family life
Family
Female
Gene Function
Gene regulation
Genetic aspects
Genetic Loci
Genomes
Genomics
Haplotypes
Human Genetics
Humans
Male
Metabolic Diseases
Missense mutation
Molecular Medicine
Mutation, Missense
Nucleotide sequence
Original Investigation
Polymorphism, Genetic
Replication
Repressor Proteins - genetics
Risk Factors
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Summary:Hundreds of genes have been implicated in autism spectrum disorders (ASDs). In genetically heterogeneous conditions, large families with multiple affected individuals provide strong evidence implicating a rare variant, and replication of the same variant in multiple families is unusual. We previously published linkage analyses and follow-up exome sequencing in seven large families with ASDs, implicating 14 rare exome variants. These included rs200195897, which was transmitted to four affected individuals in one family. We attempted replication of those variants in the MSSNG database. MSSNG is a unique resource for replication of ASD risk loci, containing whole genome sequence (WGS) on thousands of individuals diagnosed with ASDs and family members. For each exome variant, we obtained all carriers and their relatives in MSSNG, using a TDT test to quantify evidence for transmission and association. We replicated the transmission of rs200195897 to four affected individuals in three additional families. rs200195897 was also present in three singleton affected individuals, and no unaffected individuals other than transmitting parents. We identified two additional rare variants (rs566472488 and rs185038034) transmitted with rs200195897 on 1p36.33. Sanger sequencing confirmed the presence of these variants in the original family segregating rs200195897. To our knowledge, this is the first example of a rare haplotype being transmitted with ASD in multiple families. The candidate risk variants include a missense mutation in SAMD11 , an intronic variant in NOC2L , and a regulatory region variant close to both genes. NOC2L is a transcription repressor, and several genes involved in transcription regulation have been previously associated with ASDs.
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ISSN:0340-6717
1432-1203
DOI:10.1007/s00439-018-1939-3