DYNC2LI1 – Ellis-van Creveld syndrome

Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondral and ectodermal dysplasia characterized by short ribs, limb shortening, ectodermal dysplasia, polydactyly, and congenital cardiopathy. While EVC and EVC2 account for the majority of EvC cases, a subset of patients remain mutation-negative in these genes despite a clinical diagnosis. Exome sequencing in a family with three affected siblings revealed compound heterozygosity for c.2T>C (p.Met1Thr) and c.662C>T (p.Thr221Ile) in DYNC2LI1, segregating with disease across all three individuals ([PMID:28857138]).

Targeted resequencing in an independent cohort identified the same missense allele (p.Thr221Ile) in compound heterozygosity with a truncating p.Val141Ter change in two siblings, and two truncating variants in a third newborn with a more severe phenotype, bringing the total to six affected individuals across three unrelated families ([PMID:28857138]). All variants were absent or extremely rare in population databases and consistent with loss of dynein-2 function. This supports autosomal recessive inheritance of EvC due to DYNC2LI1 deficiency.

Functional studies using patient fibroblasts and siRNA knockdown demonstrated that DYNC2LI1 is essential for dynein-2 complex stability, with pathogenic alleles leading to abnormal cilia length, IFT particle accumulation, and impaired Hedgehog signaling ([PMID:26077881]). These cellular phenotypes mirror the skeletal ciliopathy features observed in EvC and other dynein-2–related disorders.

Collectively, genetic and experimental concordance establish DYNC2LI1 as a bona fide EvC gene. No conflicting evidence has been reported. Additional families and rare variants have been described but do not alter the core autosomal recessive mechanism.

Key Take-home: DYNC2LI1 should be included in diagnostic gene panels for autosomal recessive Ellis-van Creveld syndrome, especially in patients lacking EVC/EVC2 mutations.

References

• Clinical genetics • 2018 • Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-van Creveld syndrome. PMID:28857138
• Nature communications • 2015 • Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome. PMID:26077881

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