Complex Diagnostics of Non-Specific Intellectual Developmental Disorder

Abstract

Intellectual development disorder (IDD) is characterized by a general deficit in intellectual and adaptive functioning. In recent years, there has been a growing interest in studying the genetic structure of IDD. Of particular difficulty are patients with non-specific IDD, for whom it is impossible to establish a clinical diagnosis without complex genetic diagnostics. We examined 198 patients with non-specific IDD from 171 families using whole-exome sequencing and chromosome microarray analysis. Hereditary forms of IDD account for at least 35.7% of non-specific IDD, of which 26.9% are monogenic forms. Variants in the genes associated with the BAF (SWI/SNF) complex were the most frequently identified. We were unable to identify phenotypic features that would allow differential diagnosis of monogenic and microstructural chromosomal rearrangements in non-specific IDD at the stage of clinical examination, but due to its higher efficiency, exome sequencing should be the diagnostic method of the highest priority study after the standard examination of patients with NIDD in Russia.

Clinical Case of Mild Tatton–Brown–Rahman Syndrome Caused by a Nonsense Variant in DNMT3A Gene

“…Whole-exome sequencing revealed a previously reported [ 12 ] variant in exon 12 in the DNMT3A gene (hg19—chr2:25468920G>T) in a heterozygous state. This variant is absent in the gnomAD database and leads to the formation of a premature stop codon—c.1443C>A (p.Tyr481Ter).…”

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

“…Amino acid residue 130 of PTEN is a site of frequent somatic mutation in cancers of the breast 47 , thyroid 48 , head and neck 49 , and endometrium 50 . p.Arg130Gln, p.Arg130*, and p.Arg335X have been reported in patients with autism-macrocephaly syndrome [51][52][53][54][55][56][57][58] . Notably, these neurosurgically-treated PTEN-mutated probands had no previous diagnosis of PHTS, autismmacrocephaly syndrome, or other cancers before WES.…”

Genome-Wide Sequencing Modalities for Children with Unexplained Global Developmental Delay and Intellectual Disabilities—A Narrative Review

“…The top 10 most prevalent DNV among GDD/ID are listed in Table 1 [ 2 ]. Most of the GDD/ID genes discovered were de novo variants (DNV) [ 2 , 8 , 13 , 14 ]. Deletions were more common than duplications, resulting in frameshift, stop-gained, alternative-splice-site, or missense mutations.…”

“…Overall, the diagnostic yield of molecular modalities is positively correlated with the number of dysmorphic features or MCA that are present [ 8 ]. The more profoundly the IQ of an individual is affected, the more likely the ID is to have a genetic etiology.…”

“…Recently, high-throughput sequencing, such as ES or GS, has allowed for rapid, in-depth analysis of the human genome. New evidence is showing support for MPS to replace CMA as the first-tier test for unexplained autistic spectrum disorder, GDD/ID, and MCA [ 6 , 7 , 8 , 9 ]. ACMG has also published an updated guideline to recommend ES and GS as the first-tier genetic evaluation for patients with ID [ 10 ].…”