Novel IQCE variations confirm its role in postaxial polydactyly and cause ciliary defect phenotype in zebrafish

Hum Mutat. 2020 Jan;41(1):240-254. doi: 10.1002/humu.23924. Epub 2019 Oct 17.

Abstract

Polydactyly is one of the most frequent inherited defects of the limbs characterized by supernumerary digits and high-genetic heterogeneity. Among the many genes involved, either in isolated or syndromic forms, eight have been implicated in postaxial polydactyly (PAP). Among those, IQCE has been recently identified in a single consanguineous family. Using whole-exome sequencing in patients with uncharacterized ciliopathies, including PAP, we identified three families with biallelic pathogenic variations in IQCE. Interestingly, the c.895_904del (p.Val301Serfs*8) was found in all families without sharing a common haplotype, suggesting a recurrent mechanism. Moreover, in two families, the systemic phenotype could be explained by additional pathogenic variants in known genes (TULP1, ATP6V1B1). RNA expression analysis on patients' fibroblasts confirms that the dysfunction of IQCE leads to the dysregulation of genes associated with the hedgehog-signaling pathway, and zebrafish experiments demonstrate 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. In conclusion, we identified three additional families confirming IQCE as a nonsyndromic PAP gene. Our data emphasize the importance of taking into account the complete set of variations of each individual, as each clinical presentation could finally be explained by multiple genes.

Keywords: IQCE; RNA-seq; cilia; hedgehog signaling; polydactyly; zebrafish.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ciliopathies / diagnosis*
  • Ciliopathies / genetics*
  • Consanguinity
  • Fingers / abnormalities*
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Genetic Association Studies / methods
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Homozygote
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Pedigree
  • Phenotype*
  • Polydactyly / diagnosis*
  • Polydactyly / genetics*
  • Signal Transduction
  • Toes / abnormalities*
  • Transcriptome
  • Whole Exome Sequencing
  • Zebrafish

Substances

  • IQCE protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins

Supplementary concepts

  • Polydactyly, Postaxial