Multi-Level Genomic and Computational Analyses Identify a Novel IFT122 Variant Associated With Cranioectodermal...

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Cranioectodermal dysplasia (CED) is a rare ciliopathy with variable phenotypes, often overlapping with Robinow syndrome.
• Diagnosing CED is challenging due to phenotypic heterogeneity and complex genetic factors in consanguineous families.

Purpose of the Study:

• To elucidate the genetic basis of a complex syndromic presentation in a consanguineous Saudi family with features of CED and Robinow syndrome.
• To utilize an integrated approach combining phenotypic, genomic, and computational analyses.

Main Methods:

• Whole exome sequencing in affected siblings.
• Sanger sequencing for segregation analysis.
• In silico pathogenicity prediction, 3D protein modeling, protein-protein interaction, and molecular docking analyses.

Main Results:

• A homozygous IFT122 (c.94G>A; p.Gly32Arg) variant was identified as the cause of CED1.
• Segregation analysis confirmed the IFT122 variant's inheritance pattern and excluded a DVL3 variant.
• Computational analyses predicted deleterious effects of the IFT122 variant, impacting protein structure, stability, and intraflagellar transport complex interactions.

Conclusions:

• A novel homozygous IFT122 variant is identified as the molecular cause of CED1.
• This expands the known genetic spectrum of IFT122-related ciliopathies.
• Integrated analyses are crucial for diagnosing complex genetic disorders in consanguineous populations.