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

Abstract

We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). In a Pakistani family, the IQSEC1 segregating 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 factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2 nd 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 Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis.

Genome-Wide Association Study of Motor Coordination

“…Recessive, rare mutations in IQSEC1 are associated with intellectual developmental disorder with short stature and behavioral abnormalities (OMIM #618687). Ansar et al (2019) recently reported the first case of bi-allelic pathogenic variants in IQSEC1 . Functional studies suggested that the pathogenic IQSEC1 variants resulted in defects in axon guidance and dendritic projection processes.…”

Identification of Novel lncRNAs Differentially Expressed in Placentas of Chinese Ningqiang Pony and Yili Horse Breeds

“…LGR6 (luteinizing hormone receptor 6) is expressed in embryonic hair follicles, and acts as a marker in the most primitive epidermal stem cells [54]. A mutation in IQSEC1 can cause intellectual disability, developmental delay, and short stature [55]. KCNA5 (potassium voltage-gated channel subfamily A member 5) genes, associated with pulmonary arterial hypertension (PAH) [56], may affect the motion of the horse.…”

The small GTPase Arf6 is dysregulated in a mouse model for fragile X syndrome

“…Targeted depletion of IQSEC1 after P21 resulted in smaller NMDA/AMPA current ratios at Schaffer collateral synapses (Elagabani et al., 2016) and the same change has been observed in Fmr1 KO mice (Aloisi et al., 2017). In addition, targeted depletion of IQSEC1 throughout development in projection neurons of the cortex resulted in an increased density of dendritic spines and in a higher fraction of spines with small heads (Ansar et al., 2019), similar to the morphological abnormalities of dendritic spines observed in FXS patients and in Fmr1 KO mice (Irwin et al., 2001, 2002). These results collectively support a developmental stage‐dependent loss of IQSEC1 and IQSEC2 recruitment in Fmr1 KO mice.…”

“…The density and morphology of spines in neuronal cultures were shown to depend on the dosage of Iqsec2 (Hinze et al., 2017). In addition, we recently found an increased frequency of immature spines upon targeted depletion of IQSEC1 in cortical projection neurons of mice (Ansar et al., 2019). Finally, variants in the X‐chromosomal human gene IQSEC2 (Kalscheuer et al., 2015; Shoubridge et al., 2010, 2019; Zerem et al., 2016) and biallelic variants in IQSEC1 (Ansar et al., 2019) and IQSEC3 (Monies et al., 2019) were identified in individuals and families with ID, developmental delay and in some cases with seizures, aggressive, and autistic behaviors.…”