IFT122 – Cranioectodermal Dysplasia

IFT122 has been robustly associated with cranioectodermal dysplasia, a rare autosomal recessive ciliopathy marked by a range of ectodermal, craniofacial, and skeletal anomalies. Multiple independent studies have demonstrated that disruption of IFT122 function by loss‑of‑function mutations leads to impaired ciliogenesis and a spectrum of clinical manifestations, including intellectual disability, abnormal facial shape, and limb anomalies (PMID:24689072).

In one seminal case report, a novel homozygous IFT122 mutation was identified in a consanguineous family. The affected individual not only exhibited the typical craniofacial and ectodermal features of cranioectodermal dysplasia but also presented with intellectual disability and severe cutis laxa. Functional studies in patient fibroblasts confirmed reduced ciliogenesis, strongly supporting the pathogenic role of the mutation (PMID:24689072).

A second case report described a fetus with compound heterozygous variants in IFT122, who presented with aplasia/hypoplasia of the extremities and systemic edema. Although the termination of the pregnancy precluded extended phenotypic evaluation, the genetic findings and severe skeletal manifestations further underscored the significance of IFT122 disruption in the disease process (PMID:38637985).

A multi‐patient study reviewed 13 probands from 12 independent families, reinforcing an autosomal recessive inheritance pattern with segregation observed in consanguineous families. Detailed molecular analysis revealed a broad spectrum of variants ranging from missense to frameshift mutations; notably, the mutation c.3422dup (p.Asp1142fs) was among the reported variants. This study also included functional experiments, such as reduced ciliary frequency in patient fibroblasts and zebrafish knockdown models, that provided mechanistic insights into the disorder (PMID:20493458).

Additional case reports have expanded the phenotypic spectrum of IFT122-associated cranioectodermal dysplasia to include features such as abnormal facial shape, macrocephaly, and upper limb phocomelia. These observations, together with the identification of both homozygous and compound heterozygous variants, highlight the allelic heterogeneity underlying the disorder (PMID:26792575).

Functional assessment studies have corroborated the genetic findings by demonstrating compromised ciliogenesis in cellular models. In particular, rescue experiments in IFT122-deficient cells revealed that the combination of frameshift and stop-loss variants can result in partial loss-of-function, thereby recapitulating key clinical features of cranioectodermal dysplasia (PMID:33717254).

In summary, the convergence of genetic and functional evidence from multiple independent studies firmly supports a strong gene-disease association between IFT122 and cranioectodermal dysplasia. This integrated data enhances diagnostic decision-making and provides critical insights for clinical management and future therapeutic interventions.

References

• Molecular genetics & genomic medicine • 2014 • Novel IFT122 mutation associated with impaired ciliogenesis and cranioectodermal dysplasia PMID:24689072
• Congenital anomalies • 2024 • A novel variant in IFT122 associated with a severe phenotype of cranioectodermal dysplasia PMID:38637985
• American journal of human genetics • 2010 • Cranioectodermal Dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene PMID:20493458
• Experimental and therapeutic medicine • 2021 • A novel combination of biallelic IFT122 variants associated with cranioectodermal dysplasia: A case report PMID:33717254

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