Identification of candidate genes of intellectual disability by single-gene deletions/amplifications mapping using chromosomal microarray analysis

Abstract

Introduction Disease-causing deletions/amplifications may include a single gene, several exons or single/part of exon, contributing to detection of novel pathogenic genes. The localization of single-gene deletion/amplification within the gene can affect its clinical manifestation. Objectives Improvement of diagnosis of intellectual disability. Methods aCGH with 60K Agilent microarrays, qPCR. Results Among 1099 patients with intellectual disability potentially pathogenic single-gene deletions/amplifications were detected in 51 individuals (5%). qPCR was used to verify aberrations in 21 patients (41%). Ten mutations were of maternal origin, four - paternal, two - de novo, another two were confirmed without analysis of parents, and three could not be confirmed. Single-gene aberrations involving the AGBL4 (exon 2), ASMT (exon 9), CYP2C18 (whole gene), DDX10 (promoter, exons 1-13), GYPA (whole gene), LIG4 (exon 1), LSAMP (intron 1), PSD3 (promoter, exons 1-11), SNTB1 (intron 1), SPOCK3 (exons 6-12), STAG2 (exons 7-34), SYT10 (promoter, exons 1-2), TCAF2 (exon 8), TMPRSS15 (promoter, exons 1-12), and ZDHHC7 (promoter, exons 1-4) genes were described by us for the first time. Deletion or amplification of several exons within a gene can affect transcription as point mutation does, while the copy number change of a whole gene can lead to an abnormal amount of the protein. Conclusions Fifteen novel genes potentially responsible for mental health were identified. In most of them aberrations were partial deletions/duplications. Most of abnormalities were inherited from healthy parents indicating the possible presence of a point mutation on the second allele or some modifying factors. This study was supported by the Russian Science Foundation, grant 21-65-00017. Disclosure No significant relationships.

Keywords

• intellectual disability
• Single-gene deletion
• Single-gene amplification