Comorbidities associated with genetic abnormalities in children with intellectual disability

Abstract

Intellectual disability (ID) has emerged as the commonest manifestation of underlying genomic abnormalities. Given that molecular genetic tests for diagnosis of ID usually require high costs and yield relatively low diagnostic rates, identification of additional phenotypes or comorbidities may increase the genetic diagnostic yield and are valuable clues for pediatricians in general practice. Here, we enrolled consecutively 61 children with unexplained moderate or severe ID and performed chromosomal microarray (CMA) and sequential whole-exome sequencing (WES) analysis on them. We identified 13 copy number variants in 12 probands and 24 variants in 25 probands, and the total diagnostic rate was 60.7%. The genetic abnormalities were commonly found in ID patients with movement disorder (100%) or with autistic spectrum disorder (ASD) (93.3%). Univariate analysis showed that ASD was the significant risk factor of genetic abnormality (P = 0.003; OR 14, 95% CI 1.7–115.4). At least 14 ID-ASD associated genes were identified, and the majority of ID-ASD associated genes (85.7%) were found to be expressed in the cerebellum based on database analysis. In conclusion, genetic testing on ID children, particularly in those with ASD is highly recommended. ID and ASD may share common cerebellar pathophysiology.

Novel Variations in the KDM5C Gene Causing X-Linked Intellectual Disability

“…From our previously reported cohort of 61 patients with ID, we identified 2 unrelated families with patients with XLID, harboring 2 novel KDMC variations, p.Q745E, and p.E1131Afs. 17 The previous cohort included patients with ID with unexplained etiology. ID was defined by a performance score at least 2 SDs below the mean for an appropriate test, including the Bayley Scales of Infant Development (BSID-III) or Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV).…”

“…ID was defined by a performance score at least 2 SDs below the mean for an appropriate test, including the Bayley Scales of Infant Development (BSID-III) or Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV). 17 All medical records and laboratory results, especially MR neuroimages and metabolic disorder surveys, were reviewed. 17 Patients with ID with any possible known etiology were excluded.…”

“… 17 All medical records and laboratory results, especially MR neuroimages and metabolic disorder surveys, were reviewed. 17 Patients with ID with any possible known etiology were excluded. 17 …”

“…We subjected the enriched fragmental DNAs to sequencing by using the nextseq500 high-output sequencing system (Illumina) to produce 2 × 150 bp paired-end sequencing raw data. 17 Paired sequence reads were aligned to the human reference genome (hg 19) using Burrows-Wheeler Aligner (BWA version 0.7.8), and then, variants were called using SAMtools, which were provided by Partek Flow (Partek Inc.). Rare variants were filtered according to the related records from genomic sequences databases including 1000 Genomes Project, ExAC, dbSNP, and gnomAD, and the allele frequency of rare variant also was checked with the information from Taiwan Biobank to pick up meaningful variant.…”

“… 12 , 16 Here, we present 2 unrelated families with patients with XLID, harboring 2 novel KDMC variations, p.Q745E and p.E1131Afs. 17 Phenotypes, clinical manifestations, and neurologic developmental courses of them were provided. In addition, the pathogenicity of these 2 novel variations was confirmed by in vitro functional assays.…”