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


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.

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

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. All variants have been added to the Leiden Open Variation Database (LOVD,


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We would like to express our gratitude to the patients who made this study possible.


This study was supported by funding from the Italian Ministry of Health (RC‐2020 and RC-2021, to ADL; RC-2018-2021 to LM and MC; 5 × 1000, to MT and TM), and the Sapienza University of Rome research grants “avvio alla ricerca 2019 (AR11916B7A1835AC)” and “avvio alla ricerca 2021 (AR12117A86EA0740)” to FP-S.

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Authors and Affiliations



Conceptualization: FP-S, BM, MT, ADL; Formal analysis: MCD, FP, LB, TM; Funding acquisition: FP-S, LM, TM, MT, MC, ADL; Investigation: FP-S, LM, BT, VG, FC, IT, AO, EF, MCD, FP, LB, CM, DC, ADL; Project administration: FP-S, ADL; Resources: FS, DG, GM, CP, FF, NB-P, AN, AP, BM, MCD, BD, VLR-P, MC; Supervision: TM, MC, ADL; Visualization: FP-S, LM, LB, MCD, TM, ADL; Writing – original draft: FP-S, LM; Writing – review & editing: TM, BD, VLR-P, MT, MC, ADL.

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Correspondence to Alessandro De Luca.

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The authors declare no competing interests.

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The study was performed in accordance with the principles set out in the 1984 Declaration of Helsinki and subsequent versions and was approved by the local institutional review board (no. 13/CE 2021). All patients signed an informed consent for the scientific use of clinical and genetic data. Written informed consent for publication of images was obtained.

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Piceci-Sparascio, F., Micale, L., Torres, B. et al. Clinical variability in DYNC2H1-related skeletal ciliopathies includes Ellis-van Creveld syndrome. Eur J Hum Genet (2023).

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