Whole-Exome Sequencing for Identifying Genetic Causes of Intellectual Developmental Disorders

Abstract

Background Intellectual developmental disorders (IDD) generally refers to the persistent impairment of cognitive activities and mental retardation caused by physical damage to the brain or incomplete brain development. We aimed to explore its genetic causes. Methods In this study, 21 IDD patients were recruited. The Gesell developmental scales (GDS) and Wechsler intelligence scale for children (WISC) were used to assess the impaired level of intellectual development for all probands. A superconducting MRI scanner (Philips AcsNT 3.0 T Philips, Best, The Netherlands) was used to perform a plain MRI scan of the skull on the probands. The whole-exome sequencing was carried out using next-generation sequencing in all probands and their families. Results Eight had seizures and four had typical characteristics of autism. Pregnancy and delivery were uneventful except for three patients. Moderate IDD (52.4%) accounted for the majority. The abnormal MRI results included ventriculomegaly, pachygyria, broadening external cerebral space, abnormal signal change and agenesis of corpus callosum. Eleven variants were identified, including the variant in CREBBP, MECP2, HCFC1, ATRX, RAB39B, CLCN4, DYRK1A and CASK genes. The function areas result of gene-positive group were compared to that of gene-negative group. Not significant (p>0.05) items were revealed after this analysis. Conclusion Eleven variants were identified, including the variant in CREBBP, MECP2, HCFC1, ATRX, RAB39B, CLCN4, DYRK1A and CASK genes. The function areas result of gene-positive group were not significantly different from the gene-negative group.

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

“…In Table 1 , Group A also includes seven families that we previously reported on with loss or reduced function [ 5 ]. It also includes data from 23 families whose variant was recurrent with one in our cohort, for whom only limited data was available in public databases (ClinVar, DECIPHER, LOVD) as of the 25th May 2022, or from publications from other groups [ 7 , 8 , 11 , 31 ]. We included these families as further evidence of the pathogenicity of these recurrent variants.…”

“…This study thus brings the total number of individuals with (likely) pathogenic variants in CLCN4 to a total of 122: 58 males and 64 females. For 20 of the females, parental studies demonstrated the variant to be de novo , while the other 44 females were identified as being heterozygous for a CLCN4 variant only after a relative (usually a son, but on two occasions a daughter) was identified in their family to have CLCN4 -related condition [ 1 , 2 , 5 , 7 , 11 , 31 ]. The clinical features of this expanded cohort are summarized in Table 2 .…”

“…Other common clinical features included epilepsy, subtle white matter changes on neuroimaging, autism spectrum disorder, challenging behaviors, and mental health complications including bipolar disorder, depression, and anxiety. More recently, an additional six males with CLCN4-related neurodevelopmental condition were reported confirming the core feature of ID and common comorbidities of epilepsy and challenging behaviors [2,6,7]. Xu et al, reported on a female with ID, autistic features and brain abnormalities, with a maternally inherited CLCN4 missense variant where the mother had mild ID [8].…”

Decoding the Neurodevelopment and Seizure Puzzle: A Pediatric Case of DYRK1A Gene Mutation and Autosomal Dominant Mental Retardation Type 7

“…Whole Exome Sequencing emerged as a pivotal tool in diagnosing rare genetic disorders, including DYRK1A mutations. This technique offers a comprehensive view of genetic variants, aiding clinicians in unraveling complex cases [ 7 ]. Hence, the patient presented in this case was diagnosed based on Whole Exome Sequencing.…”

On Gesell Evaluation System for Disabled Children in Minority Areas

“…Limited by regional economy, health and culture, and other factors, minority areas have always lagged behind other areas. It is difficult for them to effectively utilize existing child health resources, especially ethnic minorities in remote border areas, so health level of children is far below the national average [ 1 ].…”