Whole-genome Sequencing of Quartet Families with Autism Spectrum Disorder

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2015 Jan 27

PMID 25621899

Citations 266

Authors

Ryan K C Yuen

Bhooma Thiruvahindrapuram

Daniele Merico

Susan Walker

Kristiina Tammimies

Ny Hoang

Christina Chrysler

Thomas Nalpathamkalam

Giovanna Pellecchia

Yi Liu

Matthew J Gazzellone

Lia DAbate

Eric Deneault

Jennifer L Howe

Richard S C Liu

Ann Thompson

Mehdi Zarrei

Mohammed Uddin

Christian R Marshall

Robert H Ring

Lonnie Zwaigenbaum

Peter N Ray

Rosanna Weksberg

Melissa T Carter

Bridget A Fernandez

Wendy Roberts

Peter Szatmari

Stephen W Scherer

Affiliations

Soon will be listed here.

Abstract

Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics.

Citing Articles

Quantifying the effects of computational filter criteria on the accurate identification of de novo mutations at varying levels of sequencing coverage.

Milhaven M, Garg A, Versoza C, Pfeifer S Heredity (Edinb). 2025; .

PMID: 40082647 DOI: 10.1038/s41437-025-00754-0.

Shared rare genetic variants in multiplex autism families suggest a social memory gene under selection.

Lee K, Lee T, Kim M, Ignatova E, Ban H, Sung M Sci Rep. 2025; 15(1):696.

PMID: 39753649 PMC: 11698849. DOI: 10.1038/s41598-024-83839-w.

Prenatal gene-environment interactions mediate the impact of advanced maternal age on mouse offspring behavior.

Zietek M, Jaszczyk A, Stankiewicz A, Sampino S Sci Rep. 2024; 14(1):31733.

PMID: 39738558 PMC: 11685589. DOI: 10.1038/s41598-024-82070-x.

Genetic variants in DDX53 contribute to autism spectrum disorder associated with the Xp22.11 locus.

Scala M, Bradley C, Howe J, Trost B, Salazar N, Shum C Am J Hum Genet. 2024; 112(1):154-167.

PMID: 39706195 PMC: 11739878. DOI: 10.1016/j.ajhg.2024.11.003.

Roles of ANK2/ankyrin-B in neurodevelopmental disorders: Isoform functions and implications for autism spectrum disorder and epilepsy.

Yoon S, Penzes P Curr Opin Neurobiol. 2024; 90:102938.

PMID: 39631164 PMC: 11839328. DOI: 10.1016/j.conb.2024.102938.

References

Campbell I, Yuan B, Robberecht C, Pfundt R, Szafranski P, McEntagart M . Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am J Hum Genet. 2014; 95(2):173-82. PMC: 4129404. DOI: 10.1016/j.ajhg.2014.07.003. View

Betancur C . Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2010; 1380:42-77. DOI: 10.1016/j.brainres.2010.11.078. View

Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L . Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014; 94(5):677-94. PMC: 4067558. DOI: 10.1016/j.ajhg.2014.03.018. View

Bae B, Tietjen I, Atabay K, Evrony G, Johnson M, Asare E . Evolutionarily dynamic alternative splicing of GPR56 regulates regional cerebral cortical patterning. Science. 2014; 343(6172):764-8. PMC: 4480613. DOI: 10.1126/science.1244392. View

Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T . Strong association of de novo copy number mutations with autism. Science. 2007; 316(5823):445-9. PMC: 2993504. DOI: 10.1126/science.1138659. View

Gilissen C, Hehir-Kwa J, Tjwan Thung D, van de Vorst M, van Bon B, Willemsen M . Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014; 511(7509):344-7. DOI: 10.1038/nature13394. View

Carnevali P, Baccash J, Halpern A, Nazarenko I, Nilsen G, Pant K . Computational techniques for human genome resequencing using mated gapped reads. J Comput Biol. 2011; 19(3):279-92. DOI: 10.1089/cmb.2011.0201. View

Blake J, Bult C, Eppig J, Kadin J, Richardson J . The Mouse Genome Database: integration of and access to knowledge about the laboratory mouse. Nucleic Acids Res. 2013; 42(Database issue):D810-7. PMC: 3964950. DOI: 10.1093/nar/gkt1225. View

Tennessen J, Bigham A, OConnor T, Fu W, Kenny E, Gravel S . Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science. 2012; 337(6090):64-9. PMC: 3708544. DOI: 10.1126/science.1219240. View

10.

Solomon B, Nguyen A, Bear K, Wolfsberg T . Clinical genomic database. Proc Natl Acad Sci U S A. 2013; 110(24):9851-5. PMC: 3683745. DOI: 10.1073/pnas.1302575110. View

11.

Toma C, Torrico B, Hervas A, Valdes-Mas R, Tristan-Noguero A, Padillo V . Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations. Mol Psychiatry. 2013; 19(7):784-90. DOI: 10.1038/mp.2013.106. View

12.

Numata S, Ye T, Hyde T, Guitart-Navarro X, Tao R, Wininger M . DNA methylation signatures in development and aging of the human prefrontal cortex. Am J Hum Genet. 2012; 90(2):260-72. PMC: 3276664. DOI: 10.1016/j.ajhg.2011.12.020. View

13.

Veltman J, Brunner H . De novo mutations in human genetic disease. Nat Rev Genet. 2012; 13(8):565-75. DOI: 10.1038/nrg3241. View

14.

Moran C, Agostini M, Visser W, Schoenmakers E, Schoenmakers N, Offiah A . Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: clinical, biochemical, and genetic analyses of three related patients. Lancet Diabetes Endocrinol. 2014; 2(8):619-26. PMC: 5989926. DOI: 10.1016/S2213-8587(14)70111-1. View

15.

Szatmari P, Paterson A, Zwaigenbaum L, Roberts W, Brian J, Liu X . Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007; 39(3):319-28. PMC: 4867008. DOI: 10.1038/ng1985. View

16.

Pang A, MacDonald J, Yuen R, Hayes V, Scherer S . Performance of high-throughput sequencing for the discovery of genetic variation across the complete size spectrum. G3 (Bethesda). 2013; 4(1):63-5. PMC: 3887540. DOI: 10.1534/g3.113.008797. View

17.

Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh J . A mutation in the thyroid hormone receptor alpha gene. N Engl J Med. 2011; 366(3):243-9. DOI: 10.1056/NEJMoa1110296. View

18.

Ronald A, Hoekstra R . Autism spectrum disorders and autistic traits: a decade of new twin studies. Am J Med Genet B Neuropsychiatr Genet. 2011; 156B(3):255-74. DOI: 10.1002/ajmg.b.31159. View

19.

Reva B, Antipin Y, Sander C . Determinants of protein function revealed by combinatorial entropy optimization. Genome Biol. 2007; 8(11):R232. PMC: 2258190. DOI: 10.1186/gb-2007-8-11-r232. View

20.

Marshall C, Noor A, Vincent J, Lionel A, Feuk L, Skaug J . Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008; 82(2):477-88. PMC: 2426913. DOI: 10.1016/j.ajhg.2007.12.009. View