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Zahir, Farah R.; Mwenifumbo, Jill C.; Chun, Hye-Jung E.; Lim, Emilia L.; Van Karnebeek, Clara D. M.; Couse, Madeline; Mungall, Karen L.; Lee, Leora; Makela, Nancy; Armstrong, Linlea; Boerkoel, Cornelius F.; Langlois, Sylvie L.; McGillivray, Barbara M.; Jones, Steven J. M.; Friedman, J. M. (Jan Marshall), 1947-; Marra, Marco, 1966-

BioMed Central

Background: Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients. Methods: We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches. Results: We verified de novo pathogenic single nucleotide variants (SNV) in ARID1B c.1595delG and PHF6 c.820C > T, potentially causative de novo two base indels in SQSTM1 c.115_116delinsTA and UPF1 c.1576_1577delinsA, and de novo SNVs in CACNB3 c.1289G > A, and SPRY4 c.508 T > A, of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including de novo genome assembly. We confirmed a likely contributory 165 kb de novo heterozygous 1q43 microdeletion missed by clinical microarray. The de novo assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation. Conclusion: This study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses.

Article

eng

Vancouver : University of British Columbia Library

10.14288/1.0361968

Medicine, Faculty of; Other UBC; Non UBC; Medical Genetics, Department of; Pediatrics, Department of

10.1186/s12864-017-3671-0

Faculty

http://creativecommons.org/licenses/by/4.0/