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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.

SUBMITTER: Piceci-Sparascio F

PROVIDER: S-EPMC10133340 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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

Piceci-Sparascio Francesca F Micale Lucia L Torres Barbara B Guida Valentina V Consoli Federica F Torrente Isabella I Onori Annamaria A Frustaci Emanuela E D'Asdia Maria Cecilia MC Petrizzelli Francesco F Bernardini Laura L Mancini Cecilia C Soli Fiorenza F Cocciadiferro Dario D Guadagnolo Daniele D Mastromoro Gioia G Putotto Carolina C Fontana Franco F Brunetti-Pierri Nicola N Novelli Antonio A Pizzuti Antonio A Marino Bruno B Digilio Maria Cristina MC Mazza Tommaso T Dallapiccola Bruno B Ruiz-Perez Victor Luis VL Tartaglia Marco M Castori Marco M De Luca Alessandro A

European journal of human genetics : EJHG 20230104 4

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 ...[more]

PMID: 36599940

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Project description:BackgroundEllis-van Creveld is a dwarfing syndrome transmitted as an autosomal recessive trait. The constant features of the condition include acromelic-micromelic dwarfism, ectodermal dysplasia involving the nails, teeth and gums, postaxial polydactyly of the hands and congenital heart disease. Congenital heart disease affects 50-60 % of all patients and nearly 50 % of patients die by 18 months of age from cardiopulmonary complications. This study is intended to characterise the orthopaedic manifestations of Ellis-van Creveld based on the authors' unique opportunity to interview and examine the largest group of patients to date in the literature.MethodsDetailed interviews, physical examinations and/or radiographs were available on 71 cases of Ellis-van Creveld syndrome. Data were collected from physical examinations, radiographs, computed tomography (CT) reconstruction and magnetic resonance imaging (MRI) of the knee. Pathoanatomy of the knee was reinforced by the direct surgical observation of 25 limbs surgically managed during adolescence and puberty.ResultsA number of interesting clinical and radiographic abnormalities were noted in the upper extremities and lower extremities, but by far the most significant orthopaedic finding was a severe and relentlessly progressive valgus deformity of the knee. Although many patients had difficulties making a "fist" with the hand, no patient reported any functional disability. The severe valgus deformity of the knee is the result of a combination of profound contractures of the iliotibial band, lateral quadriceps, lateral hamstrings and lateral collateral ligament, leading to lateral patellar subluxation and dislocation. The lateral portion of the upper tibial plateau presents with cupping and progressive depression of the lateral plateau, along with severe valgus angulation of the proximal tibia and fibula. A proximal medial tibial exostosis is seen in nearly all cases.ConclusionThis is the largest group of Ellis-van Creveld syndrome patients identified in the literature. An understanding of the orthopaedic pathoanatomy of the knee deformity is critical to determining the appropriate surgical management. This paper characterises the orthopaedic manifestations of Ellis-van Creveld syndrome and especially identifies the pathoanatomy of the severe and progressive valgus knee deformity.Level of evidenceLevel II.

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

Publications

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

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