Clinical variability in DYNC2H1-related skeletal ciliopathies includes Ellis-van Creveld syndrome

Abstract

Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles.

Fig. 1. 3D structure of DYNC2H1 obtained through modeling.

Functional domains were colored in violet (stem, residues 1-1650), brown (AAA + 1, residues 1651–1875), green (AAA + 2, residues 1938–2161), beige (AAA + 3, residues 2251–2505), blue (AAA + 4, residues 2617–2863), pink (stalk, residues 2881–3169), gray (AAA + 5, residues 3244–3473) and orange (AAA + 6, residues 3690–3905). Variants were mapped on the wild-type structure and highlighted in red.