IQCE – Postaxial Polydactyly

IQCE has emerged as an important gene in the etiology of postaxial polydactyly, with evidence supporting an autosomal recessive inheritance. Multiple studies have identified loss‑of‑function variants in IQCE that disrupt the function of primary cilia and the Hedgehog signaling pathway, which is critical for limb patterning. The clinical presentations include postaxial polydactyly along with syndactyly, brachydactyly, and hypoplastic teeth, underscoring a syndromic overlap that aids in diagnostic decision‑making (PMID:37323200).

A detailed case report documented a 3‑year‑old female patient with predominantly postaxial polydactyly features who was found to harbor a homozygous variant, c.895_904del (p.Val301SerfsTer8), in IQCE. This study also identified a novel large deletion covering exons 2‑18 of IQCE, confirming the loss‑of‑function mechanism. The findings from this case were supported by segregation analysis within the family, thereby strengthening the gene‑disease association (PMID:37323200).

Evidence from multi‑patient investigations further substantiates the role of IQCE in postaxial polydactyly. In one study involving three independent families, the recurrent c.895_904del (p.Val301SerfsTer8) variant was observed without a common haplotype, indicating a recurrent mutational event. This work not only confirmed autosomal recessive inheritance but also provided robust segregation data across affected relatives (PMID:31549751).

From a genetic evidence standpoint, the identification of the recurrent homozygous c.895_904del (p.Val301SerfsTer8) variant across four probands in independent studies, along with supportive segregation data, underscores a strong gene‑disease relationship. Additional variants, including missense and splice site mutations, were reported; however, the c.895_904del variant remains the exemplar for this association. This collective evidence supports the ClinGen rating of a strong association for IQCE with postaxial polydactyly (PMID:37323200, PMID:31549751).

Functional studies have provided crucial insights into the pathogenicity of IQCE variants. A homozygous splice acceptor variant, c.395-1G>A, was shown to result in a -1 frameshift and a premature termination (p.Gly132ValfsTer22) in a consanguineous family, effectively linking the loss‑of‑function mechanism to the limb developmental anomalies observed. Zebrafish models further demonstrated ciliary defects and aberrant Hedgehog signaling, activities that are concordant with the human phenotype (PMID:28488682).

In summary, the integration of genetic and functional evidence confirms the role of IQCE in autosomal recessive postaxial polydactyly. The recurrent c.895_904del (p.Val301SerfsTer8) variant, along with complementary evidence from large deletions and splice variants, provides a robust framework for clinical diagnosis. Key take‑home message: Detailed molecular characterization of IQCE variants is essential for accurate diagnosis and informs tailored management strategies in patients with postaxial polydactyly.

References

• Molecular Syndromology • 2023 • Identification of a Novel IQCE Large Deletion through Copy Number Variant Analysis from Whole‑Exome Sequencing Data of a Patient with Postaxial Polydactyly Type A7 PMID:37323200
• Human Mutation • 2020 • Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish PMID:31549751
• European Journal of Human Genetics • 2017 • Exome sequencing revealed a splice site variant in the IQCE gene underlying post‑axial polydactyly type A restricted to lower limb PMID:28488682

Evidence Based Scoring (AI generated)