Establishing an objective clinical spectrum, genotype-phenotype correlations, and as a modifier in the Ellis-van Creveld syndrome: The first systematic review of and -associated conditions.

Purpose: Ellis-van Creveld (EVC) syndrome is an autosomal recessive skeletal ciliopathy that was first identified in the Old Order Amish. Since its discovery, two causal genes have been identified, and , showing that several cases were misdiagnosed and were, in fact, other entities. Nevertheless, there has not been any adequate phenotypic characterization of molecularly defined EVC syndrome so far.

Methods: We performed a systematic review of case reports of EVC syndrome with molecular confirmation of pathogenic variants in or . Demographic, genetic, and clinical information of patients was assessed.

Results: We reviewed 725 papers and obtained 54 case reports/series that met the inclusion criteria, with a total subject sample of 310. Of these, 190 had biallelic variants, whereas 28 were affected heterozygotes. Our analysis revealed new phenotypes that have not been classically linked to the syndrome and others that have been linked but are very rare. Monoallelic symptomatic forms had less expressivity, and biallelic cases were milder if associated with and/or missense variants. Finally, we identified , a gene whose coding region partially overlaps with , as a potential genetic modifier of the severity of the EVC syndrome.

Conclusion: We provided the first objective clinical characterization of molecularly defined EVC syndrome and identified the first associated genetic modifier, , which had not been implicated in human disease before.