A novel splicing mutation in the IQSEC2 gene that modulates the phenotype severity in a family with intellectual disability

Abstract

The IQSEC2 gene is located on chromosome Xp11.22 and encodes a guanine nucleotide exchange factor for the ADPribosylation factor family of small GTPases. This gene is known to have a significant role in cytoskeletal organization, dendritic spine morphology and synaptic organization. Variants in IQSEC2 cause moderate to severe intellectual disability in males and a variable phenotype in females because this gene escapes from X-chromosome inactivation. Here we report on the first splicing variant in IQSEC2 (g.88032_88033del; NG_021296.1) that co-segregates in a family diagnosed with an X-linked form of ID. In a percentage of the cells, the variant activates an intraexonic splice acceptor site that abolishes 26 amino acids from the highly conserved PH domain of IQSEC2 and creates a premature stop codon 36 amino acids later in exon 13. Interestingly, the percentage of aberrant splicing seems to correlate with the severity of the disease in each patient. The impact of this variant in the target tissue is unknown, but we can hypothesize that these differences may be related to the amount of abnormal IQSEC2 transcript. To our knowledge, we are reporting a novel mechanism of IQSEC2 involvement in ID. Variants that affect splicing are related to many genetic diseases and the understanding of their role in disease expands potential opportunities for gene therapy. Modulation of aberrant splicing transcripts can become a potent therapeutic approach for many of these diseases.

IQSEC2-related encephalopathy in males and females: a comparative study including 37 novel patients

“…Splice-site variants also seem to be better tolerated in females than in males, as exemplified by the splice-site variant reported by Madrigal and collaborators. 30 This is further indicated by the occurrence of males with splice-site variants inherited from unaffected mothers in our series.…”

“…11 Although a de novo translocation interrupting IQSEC2 had been described earlier in a female patient, 20 the recognition that IQSEC2 encephalopathy also affects females came from the further identification of de novo IQSEC2 variants in females with epileptic encephalopathy or ID. 1,21–29 Recently, two families with affected males and females, 18,30 and one family with affected females only, probably as the result of paternal gonadal mosaicism, 31 were also described.…”

Deep phenotyping of 14 new patients with IQSEC2 variants, including monozygotic twins of discordant phenotype

“…The fact that the mother of patient 5 (with normal intelligence) had a normal X inactivation pattern does not exclude pathogenicity of his variant because inheritance of the IQSEC2 missense variant from a non‐epileptic, normal intelligence female has been reported . as has inheritance from females with only mild learning difficulties . The variants of patients 1 and 5 have not been previously reported, and there does remain some uncertainty as to their pathogenicity.…”

“…13 as has inheritance from females with only mild learning difficulties. [16][17][18][19] The variants of patients 1 and 5 have not been previously reported, and there does remain some uncertainty as to their pathogenicity. However, many IQSEC2 missense variants in regions not known to be functional have been described in patients with intellectual disability, with or without epilepsy.…”

IQSEC2mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy

“…For example, there are two variants in males presenting with severe ID but no seizures (Rauch et al., ; Tran Mau‐Them et al., ; Tzschach et al., ). Similarly, a splice‐site variant in the PH domain presents with moderate to severe ID in males and mild ID in carrier females, with no history of seizures (Madrigal et al., ). The variant activates an exonic splice acceptor site, producing a deletion spanning 70 nucleotides in exon 12.…”