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Am J Hum Genet. 2019 Nov 7;105(5):907-920. doi: 10.1016/j.ajhg.2019.09.013. Epub 2019 Oct 10.

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

Author information

1
Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland.
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston TX 77030, USA.
3
King Fahad Medical City, National Neuroscience Institute, 12231 Riyadh, Saudi Arabia.
4
Neuroscience Research Center (NWFZ), Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; Freie Universität Berlin, Department of Biology, Chemistry, and Pharmacy, 14195 Berlin, Germany.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
6
Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan.
7
Center for Molecular Neurobiology (ZMNH), University of Hamburg, 20251 Hamburg, Germany.
8
Department of Medicine, KMU Institute of Medical Sciences, 26000 Kohat, Pakistan.
9
Radiology department, Lady reading Hospital, 25000 Peshawar, Pakistan.
10
Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland; Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
11
Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
12
Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; Current address, Medigenome, The Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland.
13
Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland; Department of Endocrinology Diabetes and Metabolism, University hospital of Lausanne, 1011 Lausanne, Switzerland.
14
King Faisal Specialist Hospital & Research Centre, 12713 Riyadh, Saudi Arabia.
15
Medical Genetics Department, Children's Hospital, King Fahad Medical City, 12231 Riyadh, Saudi Arabia.
16
Neuroscience Research Center (NWFZ), Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany; Center for Molecular Neurobiology (ZMNH), University of Hamburg, 20251 Hamburg, Germany.
17
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Houston TX 77030, USA; Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: hbellen@bcm.edu.
18
Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland; iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland. Electronic address: stylianos.antonarakis@unige.ch.

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 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.

KEYWORDS:

BRAG2; Drosophila; autosomal recessive; axon guidance; dendritic spines; schizo, mice

PMID:
31607425
PMCID:
PMC6848997
[Available on 2020-05-07]
DOI:
10.1016/j.ajhg.2019.09.013

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