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

Abstract

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.

Autism-related KLHL17 and SYNPO act in concert to control activity-dependent dendritic spine enlargement and the spine apparatus

“…Deletion of both alleles did not further exacerbate the phenotype. These results reveal that Klhl17 haploinsufficiency impairs activity-dependent dendritic spine enlargement, consistent with genetic features of patients in which only 1 allele of the Klhl17 gene is mutated or deleted [2,14,26].…”

“…Among the various ASD-associated genes, Kelch-like protein 17 (KLHL17), also known as actinfilin [11,12], has been shown to contribute to dendritic spine enlargement during development [13]. Klhl17 +/mice exhibit social deficits and hyperactive locomotion [13], echoing genetic evidence from patients that Klhl17 deficiency is associated with ASD [2,14]. Since KLHL17 controls dendritic spine enlargement, this protein may serve as a model to explore how morphological plasticity is relevant to ASD etiology.…”

Genome-wide CNV analysis uncovers novel pathogenic regions in cohort of five multiplex families with neurodevelopmental disorders

“…Neurodevelopmental disorders have variable phenotype expression and heterogenetic pathways which make it challenging for clinicians and geneticists to diagnose. With advent of modern technology involving CMA and genome-wide CNV analysis, Cytoscan HD array is considered as first-tier test for diagnosis of neurodevelopmental disorders with more than 99% accuracy [ 44 ]. Despite these facts, a large number of neurodevelopmental and neuropsychiatric families genetic outlook is missing.…”

A Genome-Wide Association Study of Dementia Using the Electronic Medical Record

“…Among the genes identified using a relaxed p-value threshold, two genes were confirmed related to brain development and neurodevelopment. In a genetic study involving intellectual disability, autism and psychosis, ATP10A was identified as a gene that may affect neurodevelopmental disorders [22]. Therefore, we investigated these genes to explore their association with dementia.…”