Four families with X-linked intellectual disability affected males: Novel deleterious variants and clinical features with the review of literature

Abstract

Introduction: Intellectual disability (ID) is a heterogeneous condition affecting brain development, function, and/or structure. The X-linked mode of inheritance of ID (X-linked intellectual disability; XLID) has a prevalence of 1.7 out of 1000 in males. Exome sequencing technology has revolutionized the process of disease-causing gene discovery in XLID. Nevertheless, so many of them still remain with unknown etiology. This study investigated four families with severe XLID to identify deleterious variants for possible diagnostics and prevention aims.Methods Nine male patients, their siblings, and the parents of four pedigrees were included in this study. The patients were studied genetically for Fragile X syndrome, followed by whole exome sequencing and analysis of intellectual disability-related genes variants. Sanger sequencing, co-segregation analysis, structural modeling, and in silico analysis were done to verify the causative variants. In addition, we collected data from previous studies to compare and situate our work in relation to existing knowledge.Results We found three novel deleterious variants in three different genes, including ZDHHC9 (p. Leu189Pro), ATP2B3 (p. Asp847Glu), and GLRA2 (p. Arg350Cys) with new clinical features and a reported pathogenic variant in the L1CAM (p. Glu309Lys) gene related to new clinical findings.Conclusion The current study's findings expand the existing knowledge of variants of the genes implicated in XLID and extend the spectrum of phenotypes associated with the related conditions. The data has implications for genetic diagnosis and counseling.