Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis

Intellectual disability (ID) and autism spectrum disorder (ASD) are complex neurodevelopmental disorders with high heritability. To search for the genetic deficits in two siblings affected with ID and ASD in a family, we first performed a genome-wide copy number variation (CNV) analysis using chromosomal microarray analysis (CMA). We found a 3.7 Mb microdeletion at 22q13.3 in the younger sister. This de novo microdeletion resulted in the haploinsufficiency of SHANK3 and several nearby genes involved in neurodevelopment disorders. Hence, she was diagnosed with Phelan-McDermid syndrome (PMS, OMIM#606232). We further performed whole-genome sequencing (WGS) analysis in this family. We did not detect pathogenic mutations with significant impacts on the phenotypes of the elder brother. Instead, we identified several rare, likely pathogenic variants in seven genes implicated in neurodevelopmental disorders: KLHL17, TDO2, TRRAP, EIF3F, ATP10A, DICER1, and CDH15. These variants were transmitted from his unaffected parents, indicating these variants have only moderate clinical effects. We propose that these variants worked together and led to the clinical phenotypes in the elder brother. We also suggest that the combination of multiple genes with moderate effects is part of the genetic mechanism of neurodevelopmental disorders.

Automated summary

In this study, the genetic deficits in two siblings affected with ID and ASD were investigated. A microdeletion at 22q13.3 resulting in the haploinsufficiency of SHANK3 and several nearby genes was found in the younger sister, leading to the diagnosis of Phelan-McDermid syndrome. Whole-genome sequencing analysis in the family identified several rare, likely pathogenic variants in seven genes implicated in neurodevelopmental disorders in the elder brother. These variants have only moderate clinical effects and were transmitted from unaffected parents. The results suggest that the combination of multiple genes with moderate effects is part of the genetic mechanism of neurodevelopmental disorders.