Genome-wide investigation of an ID cohort reveals de novo 3′UTR variants affecting gene expression

Abstract

Intellectual disability (ID) is a severe neurodevelopmental disorder with genetically heterogeneous causes. Large-scale sequencing has led to the identification of many gene-disrupting mutations; however, a substantial proportion of cases lack a molecular diagnosis. As such, there remains much to uncover for a complete understanding of the genetic underpinnings of ID. Genetic variants present in non-coding regions of the genome have been highlighted as potential contributors to neurodevelopmental disorders given their role in regulating gene expression. Nevertheless the functional characterization of non-coding variants remains challenging. We describe the identification and characterization of de novo non-coding variation in 3′UTR regulatory regions within an ID cohort of 50 patients. This cohort was previously screened for structural and coding pathogenic variants via CNV, whole exome and whole genome analysis. We identified 44 high-confidence single nucleotide non-coding variants within the 3′UTR regions of these 50 genomes. Four of these variants were located within predicted miRNA binding sites and were thus hypothesised to have regulatory consequences. Functional testing showed that two of the variants interfered with miRNA-mediated regulation of their target genes, AMD1 and FAIM. Both these variants were found in the same individual and their functional consequences may point to a potential role for such variants in intellectual disability.Electronic supplementary materialThe online version of this article (10.1007/s00439-018-1925-9) contains supplementary material, which is available to authorized users.

FAIM: An Antagonist of Fas-Killing and Beyond

“…Large-scale sequencing has led to the identification of more than 700 candidate genes involved in ID, reflecting the complexity of the molecular mechanism involved [50]. It has been hypothesised that de novo variation in the three prime untranslated region (3′-UTR) might contribute to ID pathogenesis [51]. Studies have discovered 44 single nucleotide non-coding variants within the 3′UTR of 50 severe ID patient genomes with high-confidence, with 3′UTR of faim being one of the non-coding variants.…”

Pathogenic variants in CDC45 on the remaining allele in patients with a chromosome 22q11.2 deletion result in a novel autosomal recessive condition

“…For instance, variants in 3' UTR have been reported as a cause of intellectual disability and congenital myasthenic syndrome. 17,18 Although functional studies are needed to confirm its pathogenicity we report this variant because of the coexistence with atypical clinical findings in our patient. Additional evidence for the pathogenicity of the abovementioned variants is their lack in the control group of patients without atypical features.…”

Interpreting the impact of noncoding structural variation in neurodevelopmental disorders

“…Variation in the promoter as well as the 3'UTR of developmental genes has been linked to NDDs 32,33 . For example, several studies leveraged exome sequencing data to identify noncoding SNVs with a putative regulatory effect in 3'UTRs in patients with ASD, ID, and specific language impairment 34,35 .…”