X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes

Abstract

BackgroundX-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis.Methods & objectivesEnrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause.ResultsWe found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype.ConclusionsAll of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations and the challenges of interpreting the results. Further functional studies are required to confirm the cause of the syndromic phenotypes associated with ZMYM3 and SYP in this study.

Subunit-specific Regulation of N-Methyl-d-aspartate (NMDA) Receptor Trafficking by SAP102 Protein Splice Variants

“…These findings are consistent with earlier electrophysiological studies showing that SAP102 regulates glutamate receptor trafficking during synaptogenesis (8). Interestingly, mutations in the human gene encoding SAP102 are associated with X-linked intellectual dis-ability, which is often associated with dendritic spine abnormalities (45)(46)(47). Protein products of all identified SAP102 mutant alleles lack the SH3 and GK domains, which could lead to mislocalization of the truncated SAP102 protein and disruption of the downstream signaling of NMDARs.…”

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

“…For the GRIA gene family, there have been reports of a fusion transcript in GRIA2, a de novo interstitial deletion of chromosome 4q32 that contains the GRIA2 loci, missense mutations in the ligand binding and transmembrane domains of the GluA3 subunit (GRIA3), partial tandem duplication that reduced GRIA3 transcript levels, as well as frameshift in the GRIA3 gene ( Fig. 5; Supplemental Table S3) (Chiyonobu et al, 2007;Wu et al, 2007;Bonnet et al, 2009Bonnet et al, , 2012Poot et al, 2010;Tzschach et al, 2010;Hackmann et al, 2013;Philips et al, 2014). These data suggest that mutations within the GRIA gene family participate in a small subset of patients with intellectual disability; however, few cellular or mechanistic studies of these modifications have been reported.…”

Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome

“…We have also compiled the rare non-synonymous variants identified in FMR1 during large-scale studies (large panel, X-exome or wholeexome sequencing) performed on ID patients by other teams: only missense variants but no truncating variants were identified in the 3180 individuals tested. [33][34][35][36][37][38][39][40][41][42] We reanalyzed all these variants in FMR1 in the light of new public sequencing data (Exome Variant Server and the ExAC project, supposed to be free or at least not enriched in severe developmental disorders), prediction tools and functional evidence. Altogether, six previously reported variants could also be reclassified as disease-causing (pathogenic-class 5 or likely pathogenic-class 4 variants, summarized in Table 3 and in Figure 4).…”