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...

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Published in:European journal of human genetics : EJHG 2023-04, Vol.31 (4), p.479-484
Main Authors: Piceci-Sparascio, Francesca, Micale, Lucia, Torres, Barbara, Guida, Valentina, Consoli, Federica, Torrente, Isabella, Onori, Annamaria, Frustaci, Emanuela, D'Asdia, Maria Cecilia, Petrizzelli, Francesco, Bernardini, Laura, Mancini, Cecilia, Soli, Fiorenza, Cocciadiferro, Dario, Guadagnolo, Daniele, Mastromoro, Gioia, Putotto, Carolina, Fontana, Franco, Brunetti-Pierri, Nicola, Novelli, Antonio, Pizzuti, Antonio, Marino, Bruno, Digilio, Maria Cristina, Mazza, Tommaso, Dallapiccola, Bruno, Ruiz-Perez, Victor Luis, Tartaglia, Marco, Castori, Marco, De Luca, Alessandro
Format: Article
Language:English
Subjects:
Brief Communication
Ciliopathies - diagnosis
Ciliopathies - genetics
Cytoplasmic Dyneins - genetics
Dystrophy
Ellis-van Creveld syndrome
Ellis-Van Creveld Syndrome - diagnosis
Ellis-Van Creveld Syndrome - genetics
Genetics
Heterozygotes
Hospitals
Humans
Majewski syndrome
Mutation
Pediatrics
Phenotypes
Polydactyly
Polydactyly - genetics
Thorax
Twins
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Summary: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.
ISSN:1018-4813
1476-5438
DOI:10.1038/s41431-022-01276-7