Limb disorders

Gene: IQCE

Green List (high evidence)

Four families reported with bi-allelic variants in this gene. The c.895_904del (p.Val301Serfs*8) was found in three of the families without sharing a common haplotype, suggesting a recurrent mechanism. RNA expression analysis on patients’ fibroblasts showed that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog‐signaling pathway, and zebrafish experiments demonstrated a full spectrum of phenotypes linked to defective cilia: Body curvature, kidney cysts, left–right asymmetry, misdirected cilia in the pronephric duct, and retinal defects. Suggest adding to ciliopathy panel(s).

Created: 1 May 2020, 10:16 a.m. | Last Modified: 1 May 2020, 10:16 a.m.

Panel Version: 2.5

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Postaxial polydactyly

Publications

• 31549751
• 28488682

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

Green List (high evidence)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 5 Mar 2022, 8:17 p.m. | Last Modified: 5 Mar 2022, 8:17 p.m.

Panel Version: 2.67

Comment on list classification: Promoting from red to amber, but with recommendation of promoting to green following GMS review. 4 cases now reported.

Created: 18 Jan 2021, 3:55 p.m. | Last Modified: 18 Jan 2021, 3:55 p.m.

Panel Version: 2.22

PMID: 28488682 Umair et al 2017 report a large consanguineous family of Pakistani origin segregating post-axial polydactyly type A in the feet. A homozygous splice acceptor site variant (c.395-1G>A) was identified by WES in the IQCE gene, which completely co-segregated with the phenotype in the family. They report that the Iqce knockout mouse (MGI:1921489) shows various types of skeletal deformities including pre-axial polydactyly, digit abnormalities, and short and long tibia.

PMID: 31549751 - Estrada-Cuzcano et al 2019 - report 3 families with biallelic pathogenic variations in IQCE identified by WES. The same variant c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. In one family this variant as compound heterozygous with another IQCE variant p.Glu451Argfs*15. These families with post-axial polydactyly were initially recruited as syndromic ciliopathies and two have additional pathogenic variations in other genes (TULP1 and ATP6V1B1) explaining their apparent syndromic phenotype. Functional studies based on the patient's cells or zebrafish (Danio rerio) assays confirm the ciliary role of IQCE.

Created: 18 Jan 2021, 3:54 p.m. | Last Modified: 18 Jan 2021, 3:54 p.m.

Panel Version: 2.21

Genomics England clinical team notes - Agree with red rating. Single paper found splice site variant segregating with postaxial polydactyly in a single family

Created: 9 Sep 2018, 6:19 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Polydactyly, postaxial, type A7 OMIM:617642; polydactyly, postaxial, type a7 MONDO:0060550

Publications

• 28488682
• 31549751

Red List (low evidence)

PMID: 20610440 Single publication of homozygous splice-site mutation in large consanguineous family identified by whole exome analysis. Segregating with condition in that family.

Knockout mouse has limb phenotype (information from publication above) including polydactyly, digital anomalies and short/long lower limb

No further publications found

Created: 24 Apr 2018, 11:32 a.m.

Phenotypes
617642 POLYDACTYLY, POSTAXIAL, TYPE A7; PAPA7

Publications

• PMID: 20610440

Comment on list classification: No other evidence found.

Created: 9 Apr 2018, 2:16 p.m.

Comment on publications: PMID: 28488682 one family report.

Created: 9 Apr 2018, 1:09 p.m.