IQSEC2 – Intellectual Disability

IQSEC2, encoding an Arf-specific guanine nucleotide exchange factor, is an X-linked gene that escapes X-inactivation and whose haploinsufficiency or mutant alleles cause intellectual disability ([PMID:25858702]). A de novo 0.4 Mb microdeletion encompassing IQSEC2 was identified in a female patient with severe intellectual disability and autistic features, despite skewed X-inactivation, implicating heterozygous loss of IQSEC2 in the phenotype ([PMID:25858702]).

Subsequent case reports described a truncating variant c.2679_2680insA (p.Asp894ArgfsTer10) segregating with moderate to severe intellectual disability and epilepsy in affected sisters, with gonadal mosaicism in a parent ([PMID:28295038]). Frameshift variants such as c.4164dupC (p.Ile1389HisfsTer218) and missense changes in the Sec7 and IQ domains have been documented in sporadic and familial cases, including male and female probands, demonstrating variable expressivity tied to escape from X-inactivation ([PMID:31490346]; [PMID:31829726]; [PMID:32564198]).

Large-scale studies have reinforced the association: Medline and cohort analyses identified 48 patients with IQSEC2 variants, 18 of whom presented with intellectual disability and epilepsy, including both inherited and de novo loss-of-function alleles ([PMID:27665735]). Targeted sequencing in XLID and neurodevelopmental panels further reported pathogenic IQSEC2 variants in ~9 % of positive exome findings among patients with seizures ([PMID:24306141]; [PMID:33486335]).

IQSEC2 variant spectrum spans nonsense, frameshift, splice-site, intragenic duplications, and missense mutations clustering in functional domains. A recurrent de novo frameshift, c.2679_2680insA (p.Asp894ArgfsTer10), exemplifies a loss-of-function mechanism. Missense variants such as p.Ala789Val in the Sec7 domain impair catalytic exchange activity ([PMID:26793055]).

Functional assays of patient-derived or recombinant IQSEC2 mutations demonstrate reduced GEF activity for Arf1/Arf6, impaired AMPA receptor removal, and altered synaptic transmission. Subtle defects in GTP binding capacity were observed for mutations in IQ-like and Sec7 domains, establishing a haploinsufficiency mechanism ([PMID:21686261]; [PMID:22915114]).

Mouse models bearing the A350V mutation exhibit constitutive Arf6 activation, decreased surface GluA2 AMPA receptors, hippocampal synaptic deficits, and behavioral abnormalities mirroring human intellectual disability and autism spectrum features ([PMID:30842726]). Bidirectional regulation studies reveal that BRAG1/IQSEC2 is essential for both maintenance and activity-dependent modulation of synaptic strength, linking reduced GEF activity to cognitive dysfunction ([PMID:27009485]).

Collectively, the genetic and functional evidence fulfills criteria for a Definitive gene–disease relationship. IQSEC2 should be included in diagnostic panels for intellectual disability and epilepsy. Key Take-home: Loss-of-function and perturbation of IQSEC2 GEF activity cause intellectual disability through synaptic dysregulation, with clear utility for molecular diagnosis and potential therapeutic targeting.

References

• European journal of medical genetics • 2015 • Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features. PMID:25858702
• European journal of human genetics : EJHG • 2017 • Gonadal mosaicism of a novel IQSEC2 variant causing female limited intellectual disability and epilepsy. PMID:28295038
• Epilepsia • 2016 • The molecular and phenotypic spectrum of IQSEC2-related epilepsy. PMID:27665735
• Small GTPases • 2010 • Subtle functional defects in the Arf-specific guanine nucleotide exchange factor IQSEC2 cause non-syndromic X-linked intellectual disability. PMID:21686261
• The Journal of neuroscience : the official journal of the Society for Neuroscience • 2012 • Arf6-GEF BRAG1 regulates JNK-mediated synaptic removal of GluA1-containing AMPA receptors: a new mechanism for nonsyndromic X-linked mental disorder. PMID:22915114
• Nature communications • 2016 • Bidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression. PMID:27009485
• Frontiers in molecular neuroscience • 2019 • An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors. PMID:30842726

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