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

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...

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Published in:	American journal of human genetics Vol. 105; no. 5; pp. 907 - 920
Main Authors:	Ansar, Muhammad, Chung, Hyung-lok, Al-Otaibi, Ali, Elagabani, Mohammad Nael, Ravenscroft, Thomas A., Paracha, Sohail A., Scholz, Ralf, Abdel Magid, Tayseer, Sarwar, Muhammad T., Shah, Sayyed Fahim, Qaisar, Azhar Ali, Makrythanasis, Periklis, Marcogliese, Paul C., Kamsteeg, Erik-Jan, Falconnet, Emilie, Ranza, Emmanuelle, Santoni, Federico A., Aldhalaan, Hesham, Al-Asmari, Ali, Faqeih, Eissa Ali, Ahmed, Jawad, Kornau, Hans-Christian, Bellen, Hugo J., Antonarakis, Stylianos E.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 07-11-2019 Elsevier
Subjects:	Adult Alleles Animals autosomal recessive axon guidance BRAG2 Child dendritic spines Dendritic Spines - genetics Developmental Disabilities - genetics Drosophila Drosophila - genetics Dwarfism - genetics Female Guanine Nucleotide Exchange Factors - genetics Humans Intellectual Disability - genetics Male Mice Mutation - genetics Saudi Arabia schizo, mice Synapses - genetics Young Adult Saudi Arabia BRAG2 schizo, mice axon guidance dendritic spines Drosophila autosomal recessive
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Summary:	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 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 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work
ISSN:	0002-9297 1537-6605
DOI:	10.1016/j.ajhg.2019.09.013