Gonadal mosaicism of a novel IQSEC2 variant causing female limited intellectual disability and epilepsy

Abstract

We report a family with four girls with moderate to severe intellectual disability and epilepsy. Two girls showed regression in adolescence and died of presumed sudden unexpected death in epilepsy at 16 and 22 years. Whole exome sequencing identified a truncating pathogenic variant in IQSEC2 at NM_001111125.2: c.2679_2680insA, p.(D894fs*10), a recently identified cause of epileptic encephalopathy in females (MIM 300522). The IQSEC2 variant was identified in both surviving affected sisters but in neither parent. We describe the phenotypic spectrum associated with IQSEC2 variants, highlighting how IQSEC2 is adding to a growing list of X-linked genes that have a female-specific phenotype typically associated with de novo mutations. This report illustrates the need for careful review of all whole exome data, incorporating all possible modes of inheritance including that suggested by the family history.

Figure 1

Identification of a c.2679_2680insA (NM_001111125.2) variant resulting in p.(D894fs*10) (NP_001104595) in IQSEC2. (a) Pedigree of family. Facial photos of II-2 and II-5 shown above the pedigree. Open symbols represent unaffected individuals, filled grey circle represents a female of borderline intellect to mild intellectual disability with ASD, while filled black circles represent females with moderate intellectual disability and epilepsy. Normal (N) and mutant (M) alleles shown for individuals tested. (b) DNA sequence electropherograms for the chrX:g.53276220_53276221insT (GRCh37/hg19 assembly); c.2679_2680insA mutation in exon 8 of 15 of IQSEC2. (c) Predicted impact of the novel variants in IQSEC2. The exon-intron structure of the longest isoform of IQSEC2 gene [NM_0011111125.2] with 15 exons, the ATG, open reading frame and stop codon positions in black and 5' and 3' untranslated regions in light grey. The predicted protein structure (NP_001104595) with known functional domains highlighted; coiled-coiled (CC, red), IQ-like (orange), Sec 7 enzyme domain (Sec 7, green), PH domain (purple) and the PDZ binding motif (blue), corresponding amino acids listed below each domain. The variant c.2679_2680insA causes a frame-shift at the site of insertion with the premature stop codon 29 nucleotides subsequent of the insertion, 41 nucleotides from the exon 8 and 9 junction. This transcript may escape nonsense mediated decay. In addition to a 9 amino acid nonsense peptide encoded prior to the PTC, the C-terminally truncated protein would lack a portion of the Sec7 domain, the PH domain and the PDZ binding domain.