Multi-Level Genomic and Computational Analyses Identify a Novel IFT122 Variant Associated With Cranioectodermal Dysplasia 1 in a Consanguineous Saudi Family.

BACKGROUND: Cranioectodermal dysplasia (CED) is a rare autosomal recessive ciliopathy characterized by craniofacial, skeletal, and ectodermal anomalies. Significant phenotypic heterogeneity often results in clinical overlap with other skeletal dysplasias, including Robinow syndrome. In consanguineous populations, the presence of multiple rare variants can further complicate the molecular diagnosis. This study aimed to clarify the genetic basis of a complex syndromic presentation in a consanguineous Saudi family exhibiting features suggestive of both disorders using an integrated phenotypic, genomic, and computational approach.

METHODS: Exome sequencing was performed on two affected siblings, followed by Sanger sequencing for the familial segregation analysis. Detailed phenotypic evaluation was combined with structural and bioinformatics analyses, including in silico pathogenicity prediction tools, three-dimensional protein modeling, protein-protein interaction analysis, and molecular docking to assess the structural and functional impact of candidate variants.

RESULTS: Exome sequencing identified a homozygous missense variant in IFT122 gene (c.94G > A; p.Gly32Arg), associated with cranioectodermal dysplasia 1, and a heterozygous frameshift variant in DVL3 gene (c.1949_1950del; p.His650Profs*60), associated with Robinow syndrome. Segregation analysis excluded the DVL3 variant as the primary cause, while the IFT122 variant segregated with the phenotype in an autosomal recessive manner. Computational analyses demonstrated that the p.Gly32Arg substitution affects a highly conserved residue and is consistently predicted to be deleterious. Structural modeling revealed the disruption of local hydrogen bonding, increased solvent accessibility, and reduced protein stability. Protein-protein interaction and molecular docking analyses further indicated altered interactions with key IFT-A components, including TTC21B, IFT140, TULP3, and IFT43, suggesting impaired intraflagellar transport complex integrity and ciliary protein trafficking.

CONCLUSION: This study identifies a novel homozygous IFT122 (c.94G > A; p.Gly32Arg) variant underlying CED1, thereby expanding the molecular spectrum of IFT122-related ciliopathies. These findings emphasize the value of integrating phenotypic, genomic, segregation, and structural analyses to resolve diagnostically challenging cases, particularly in consanguineous populations. Further functional studies are warranted to confirm this molecular mechanism.