Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability

• Published in: BMC genomics Vol. 18; no. 1; pp. 403 - 16
• Main Authors: 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, Jan M., Marra, Marco A.
• Format: Journal Article
• Language: English
• Published: London BioMed Central 24.05.2017; BioMed Central Ltd; Springer Nature B.V; BMC
• Subjects: Algorithms; Analysis; Animal Genetics and Genomics; ARID1B; Assembly; Biomedical and Life Sciences; Brain research; CACNB3; Child; Children; Children & youth; Data analysis; Deoxyribonucleic acid; Diagnosis; DNA; DNA sequencing; Etiology; Families & family life; Gene sequencing; Genes; Genetic analysis; Genetic aspects; Genetics; Genome, Human - genetics; Genomes; Genomic instability; Genomics; Human and rodent genomics; Humans; INDEL Mutation; Intellectual disabilities; Intellectual Disability; Intellectual Disability - genetics; Life Sciences; Microarrays; Microbial Genetics and Genomics; Mutation, Missense; Non-coding RNA; Nucleotide sequence; Nucleotides; Pathogenicity; Pathogens; Patients; PHF6; Plant Genetics and Genomics; Polymorphism, Single Nucleotide; Proteomics; Regulatory sequences; Research Article; Software; SPRY4; Whole Genome Sequencing; British Columbia Canada; Canada; 1q43 microdeletion; Genome assembly; Whole genome sequencing; Intellectual Disability; UPF1; CACNB3; SPRY4; ARID1B; PHF6; SQSTM1
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-017-3671-0

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.