Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1 and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a non-canonical splice-site in-frame change (c.1316-7A>G) in the daughter. cDNA sequencing, immunoblot and immunofluorescence experiments using patient-derived fibroblasts and Evc-/- mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316-7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as "common atrium/AVCD with postaxial polydactyly" is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome. This article is protected by copyright. All rights reserved.

Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical splice-site in-frame change (c.1316–7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patient-derived fibroblasts and Evc–/– mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316–7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as “common atrium/AVCD with postaxial polydactyly” is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome.

Common atrium/atrioventricular canal defect and postaxial polydactyly: a mild clinical subtype of Ellis-van Creveld syndrome caused by hypomorphic mutations in the EVC gene / Piceci-Sparascio, F.; Palencia-Campos, A.; Soto-Bielicka, P.; D'Anzi, A.; Guida, V.; Rosati, J.; Caparros-Martin, J. A.; Torrente, I.; D'Asdia, M. C.; Versacci, P.; Briuglia, S.; Lapunzina, P.; Tartaglia, M.; Marino, B.; Digilio, M. C.; Ruiz-Perez, V. L.; De Luca, A.. - In: HUMAN MUTATION. - ISSN 1059-7794. - 41:12(2020), pp. 2087-2093. [10.1002/humu.24112]

Common atrium/atrioventricular canal defect and postaxial polydactyly: a mild clinical subtype of Ellis-van Creveld syndrome caused by hypomorphic mutations in the EVC gene

Piceci-Sparascio F.;D'Anzi A.;Rosati J.;Versacci P.;Marino B.;
2020

Abstract

Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical splice-site in-frame change (c.1316–7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patient-derived fibroblasts and Evc–/– mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316–7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as “common atrium/AVCD with postaxial polydactyly” is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome.
2020
Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1 and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a non-canonical splice-site in-frame change (c.1316-7A>G) in the daughter. cDNA sequencing, immunoblot and immunofluorescence experiments using patient-derived fibroblasts and Evc-/- mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316-7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as "common atrium/AVCD with postaxial polydactyly" is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome. This article is protected by copyright. All rights reserved.
atrioventricular canal defect; Ellis-van Creveld syndrome; EVC; hypomorphic mutation; postaxial polydactyly; Weyers acrodental dysostosis
01 Pubblicazione su rivista::01a Articolo in rivista
Common atrium/atrioventricular canal defect and postaxial polydactyly: a mild clinical subtype of Ellis-van Creveld syndrome caused by hypomorphic mutations in the EVC gene / Piceci-Sparascio, F.; Palencia-Campos, A.; Soto-Bielicka, P.; D'Anzi, A.; Guida, V.; Rosati, J.; Caparros-Martin, J. A.; Torrente, I.; D'Asdia, M. C.; Versacci, P.; Briuglia, S.; Lapunzina, P.; Tartaglia, M.; Marino, B.; Digilio, M. C.; Ruiz-Perez, V. L.; De Luca, A.. - In: HUMAN MUTATION. - ISSN 1059-7794. - 41:12(2020), pp. 2087-2093. [10.1002/humu.24112]
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