Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature

2019
We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotoniain which homozygous non-synonymous variants were identified in IQSEC1(GenBank: NM_001134382.3 ). In a Pakistani family, the IQSEC1segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1-3 encode guanine nucleotide exchange factorsfor the small GTPaseARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptortrafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth coneguidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1deletion in cortical neurons exhibited an increased density of dendritic spineswith an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidanceand dendritic projection defects as well as dendritic spine dysgenesismay underlie disease pathogenesis.
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