Characterization of patients referred for non-specific intellectual disability testing: the importance of autosomal genes for diagnosis

C A Tan; S Topper; D Del Gaudio; V Nelakuditi; O Shchelochkov; M J M Nowaczyk; S Zeesman; L Brady; L Russell; N Meeks; S Sastry; K Arndt; F Kobiernicki; R Shaw; S Das

doi:10.1111/cge.12575

Characterization of patients referred for non-specific intellectual disability testing: the importance of autosomal genes for diagnosis

Clin Genet. 2016 Apr;89(4):478-483. doi: 10.1111/cge.12575. Epub 2015 Mar 15.

Authors

C A Tan¹, S Topper¹, D Del Gaudio¹, V Nelakuditi¹, O Shchelochkov², M J M Nowaczyk³, S Zeesman⁴, L Brady⁴, L Russell⁵, N Meeks⁶, S Sastry⁷, K Arndt¹, F Kobiernicki¹, R Shaw¹, S Das¹

Affiliations

¹ Department of Human Genetics, University of Chicago, Chicago, IL, USA.
² Division of Genetics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
³ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
⁴ Department of Pediatrics, McMaster University, Hamilton, ON, Canada.
⁵ Department of Medical Genetics, Montreal General Hospital, Montreal, QC, Canada.
⁶ Department of Pediatrics, Section of Genetics, University of Colorado, Aurora, CO, USA.
⁷ Division of Genetic and Metabolic Disorders, Children's Hospital of Michigan, Detroit, MI, USA.

PMID: 25693842
DOI: 10.1111/cge.12575

Abstract

Genetic testing for non-specific intellectual disability (ID) presents challenges in daily clinical practice. Historically, the focus of the genetic elucidation of non-specific ID has been on genes on the X chromosome, and recent research has brought attention to the growing contribution of autosomal genes. In addition, next-generation sequencing (NGS) has greatly improved the ability to simultaneously analyze multiple genetic loci, making large panel testing a practical approach to testing for non-specific ID. We performed NGS analysis of a total of 90 genes implicated in non-specific ID. The 90 genes included 56 X-linked genes and 34 autosomal genes. Pathogenic variants were identified in 11 of 52 (21%) patient samples. Nine of the eleven cases harbored mutations in autosomal genes including AP4B1, STXB1, SYNGAP1, TCF4 and UBE3A. Our mutation-positive cases provide further evidence supporting the prevalence of autosomal mutations in patients referred for non-specific ID testing and the utility of their inclusion in multi-gene panel analysis.

Keywords: X-linked chromosome; autosomal; intellectual disability; next-generation sequencing; non-specific.