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Intellectual disability

Gene: IQSEC1

Amber List (moderate evidence)

IQSEC1 (IQ motif and Sec7 domain 1)
EnsemblGeneIds (GRCh38): ENSG00000144711
EnsemblGeneIds (GRCh37): ENSG00000144711
OMIM: 610166, Gene2Phenotype
IQSEC1 is in 1 panel

3 reviews

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Five individuals from two unrelated families plus functional data from two model organisms. We have rated this gene Green.
Created: 8 Feb 2020, 7:14 a.m. | Last Modified: 8 Feb 2020, 7:14 a.m.
Panel Version: 3.0

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual developmental disorder with short stature and behavioral abnormalities, MIM# 618687

Publications

Variants in this GENE are reported as part of current diagnostic practice

Catherine Snow (Genomics England)

I don't know

Comment on list classification: Expert review by Konstantinos Varvagiannis on IQSEC1 following a publication by Ansar et al. (2019 - PMID: 31607425) who reported on 5 individuals with biallelic IQSEC1 variants.

IQSEC1 is not in OMIM or Gene2Phenotype. There are <3 individuals/variants/families where ID is reported. Therefore classify IQSEC1 as Amber until more evidence is available.
Created: 26 Nov 2019, 3:34 p.m. | Last Modified: 26 Nov 2019, 3:34 p.m.
Panel Version: 2.1119

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

Konstantinos Varvagiannis (Other)

I don't know

Ansar et al. (2019 - PMID: 31607425) reported on 5 individuals with biallelic IQSEC1 variants.

Common features included hypotonia, DD, speech impairment, severe ID, behavioral problems as well as short stature. Early-onset seizures were observed in 3 sibs (for whom there was also a paternal family history of seizures).

These subjects belonging to 2 consanguineous families from Pakistan and S. Arabia were found to harbor homozygous missense variants private to each family (Fam1: NM_001134382.2:c.1028C>T or p.Thr354Met following SNP genotyping of several members and exome of the proband | Fam2: c.962G>A or p.Arg321Gln following exome in 2 affected members). Sanger confirmation and study of parents (+/- sibs) were compatible.

The homozygous variant was the only candidate in the 1st family (also following exclusion of other causes of ID/short stature), and most likely/compatible with the patient's phenotype in the 2nd.

As the authors note, IQSEC1-3 encode guanine exchange factors (GEFs) for the ARF family of GTPases. IQSEC2 is a known XLID gene, while biallelic IQSEC3 mutations in ID have been recently reported (PMID: 31130284), all presenting phenotypic similarities (ID, short stature, speech defect).

Previous studies cited had shown that IQSEC1 & 2 are concentrated at the postsynaptic density of glutamatergic synapses in mammalian brain, playing a role in actin-dependent processes incl. AMPA receptor trafficing at synapses (all refs in article).

Drosophila model: The ortholog of IQSEC1, 2 and 3 is schizo and the phenotype associated with its loss is a growth cone guidance defect through dysregulation of the Slit-Robo pathway (all refs in article). The authors studied overexpression of either reference IQSEC1 cDNA or variant cDNAs in wt flies, the former only being toxic/lethal. Loss of schizo was also embryonically lethal but was partially rescued by expression of reference IQSEC1 cDNA. Expression of cDNA for the 2 variants did not rescue lethality. As a result LoF appears to be the underlying effect of both variants. The authors provided evidence that schizo is localized in glia and neurons at various stages of development and is important for proper axon guidance in both CNS and PNS. In Drosophila, schizo is also localized in photoreceptors and RNAi-mediated knockdown resulted in severely impaired sight (also observed in 1 patient).

Mouse model: Through generation of Iqsec1-floxed mice, it was demonstrated that targeted depletion of Iqsec1 in the cortex resulted in increased density/immature morphology of dendritic spines.

IQSEC1 is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in gene panels for ID.

As a result, this gene could be considered for inclusion in the ID panel as probably as amber (2 families/variants).
Sources: Literature
Created: 11 Nov 2019, 3:17 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Central hypotonia
  • Global developmental delay
  • Intellectual disability
  • Behavioral abnormality
  • Short stature
OMIM
610166
Clinvar variants
Variants in IQSEC1
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

26 Nov 2019, Gel status: 2

Entity classified by Genomics England curator

Catherine Snow (Genomics England)

Gene: iqsec1 has been classified as Amber List (Moderate Evidence).

11 Nov 2019, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: IQSEC1 was added gene: IQSEC1 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: IQSEC1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IQSEC1 were set to 31607425 Phenotypes for gene: IQSEC1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature Penetrance for gene: IQSEC1 were set to Complete Review for gene: IQSEC1 was set to AMBER