Targeted Genetic Testing Uncovers a Novel LRP4 Variant in Cenani-Lenz Syndactyly Syndrome

Cenani-Lenz syndactyly syndrome (CLSS, OMIM 212780) is a rare autosomal recessive disorder characterized by syndactyly and oligodactyly of the digits, fusion of carpal and tarsal bones, and radioulnar synostosis. Craniofacial anomalies and renal malformations have been reported in approximately half of cases, with variable expression. The condition results from homozygous or compound heterozygous mutations in the LRP4 gene. We identified a consanguineous family with four individuals affected by CLSS, comprising two brothers and their two maternal male cousins. All patients presented with bilateral complex syndactyly, characterized by absent phalanges, reduced and disorganized metacarpals, and cutaneous toe syndactyly. The 2-year-old proband had a horseshoe kidney, whereas his 6-year-old cousin presented with right renal agenesis. None of the patients exhibited growth and developmental delay, cardiac anomalies, or intellectual disability. Based on the clinical suspicion of CLSS, targeted next-generation sequencing of the LRP4 gene was performed. This analysis revealed a biallelic variant, c.3830G>T (NM_002334.3), resulting in the protein change p.Arg1277Leu, which has not been previously described. CLSS is a rare congenital disorder affecting distal limb development and is frequently associated with renal malformations and variable dysmorphic features. In this report, we describe four affected individuals carrying a novel homozygous missense variant in the LRP4 gene, thereby broadening the clinical and genetic spectrum of CLSS and highlighting the pathogenic significance of this newly identified variant.