Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions
Purpose: Ellis-van Creveld (EVC) syndrome is an autosomal recessive skeletal ciliopathy that was first identified in the Old Order Amish. Since its discovery, two causal genes have been identified, EVC and EVC2, showing that several cases were misdiagnosed and were, in fact, other entities. Neverthe...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-01-01
|
| Series: | Genetics in Medicine Open |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2949774423007902 |
| _version_ | 1797341917095133184 |
|---|---|
| author | Jorge Diogo Da Silva Ana Rita Soares Ana Maria Fortuna Nataliya Tkachenko |
| author_facet | Jorge Diogo Da Silva Ana Rita Soares Ana Maria Fortuna Nataliya Tkachenko |
| author_sort | Jorge Diogo Da Silva |
| collection | DOAJ |
| description | Purpose: Ellis-van Creveld (EVC) syndrome is an autosomal recessive skeletal ciliopathy that was first identified in the Old Order Amish. Since its discovery, two causal genes have been identified, EVC and EVC2, showing that several cases were misdiagnosed and were, in fact, other entities. Nevertheless, there has not been any adequate phenotypic characterization of molecularly defined EVC syndrome so far. Methods: We performed a systematic review of case reports of EVC syndrome with molecular confirmation of pathogenic variants in EVC or EVC2. Demographic, genetic, and clinical information of patients was assessed. Results: We reviewed 725 papers and obtained 54 case reports/series that met the inclusion criteria, with a total subject sample of 310. Of these, 190 had biallelic variants, whereas 28 were affected heterozygotes. Our analysis revealed new phenotypes that have not been classically linked to the syndrome and others that have been linked but are very rare. Monoallelic symptomatic forms had less expressivity, and biallelic cases were milder if associated with EVC and/or missense variants. Finally, we identified CRMP1, a gene whose coding region partially overlaps with EVC, as a potential genetic modifier of the severity of the EVC syndrome. Conclusion: We provided the first objective clinical characterization of molecularly defined EVC syndrome and identified the first associated genetic modifier, CRMP1, which had not been implicated in human disease before. |
| first_indexed | 2024-03-08T10:25:53Z |
| format | Article |
| id | doaj.art-ab20495f31eb49149c71d2a2b6b396f8 |
| institution | Directory Open Access Journal |
| issn | 2949-7744 |
| language | English |
| last_indexed | 2024-03-08T10:25:53Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Genetics in Medicine Open |
| spelling | doaj.art-ab20495f31eb49149c71d2a2b6b396f82024-01-27T07:12:06ZengElsevierGenetics in Medicine Open2949-77442023-01-0111100781Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditionsJorge Diogo Da Silva0Ana Rita Soares1Ana Maria Fortuna2Nataliya Tkachenko3Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário de Santo António, Porto, Portugal; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B’s – PT Government Associate Laboratory, Braga/Guimarães, Portugal; Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute, Porto University, Porto, Portugal; Correspondence and requests for materials should be addressed to Jorge Diogo Da Silva, Centro Hospitalar Universitário de Santo António, E. P. E., Centro de Genética Médica Doutor Jacinto Magalhães, Praça Pedro Nunes, 88, 4099-028 Porto, PortugalCentro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário de Santo António, Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute, Porto University, Porto, PortugalCentro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário de Santo António, Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute, Porto University, Porto, PortugalCentro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar Universitário de Santo António, Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Biomedical Sciences Institute, Porto University, Porto, PortugalPurpose: Ellis-van Creveld (EVC) syndrome is an autosomal recessive skeletal ciliopathy that was first identified in the Old Order Amish. Since its discovery, two causal genes have been identified, EVC and EVC2, showing that several cases were misdiagnosed and were, in fact, other entities. Nevertheless, there has not been any adequate phenotypic characterization of molecularly defined EVC syndrome so far. Methods: We performed a systematic review of case reports of EVC syndrome with molecular confirmation of pathogenic variants in EVC or EVC2. Demographic, genetic, and clinical information of patients was assessed. Results: We reviewed 725 papers and obtained 54 case reports/series that met the inclusion criteria, with a total subject sample of 310. Of these, 190 had biallelic variants, whereas 28 were affected heterozygotes. Our analysis revealed new phenotypes that have not been classically linked to the syndrome and others that have been linked but are very rare. Monoallelic symptomatic forms had less expressivity, and biallelic cases were milder if associated with EVC and/or missense variants. Finally, we identified CRMP1, a gene whose coding region partially overlaps with EVC, as a potential genetic modifier of the severity of the EVC syndrome. Conclusion: We provided the first objective clinical characterization of molecularly defined EVC syndrome and identified the first associated genetic modifier, CRMP1, which had not been implicated in human disease before.http://www.sciencedirect.com/science/article/pii/S2949774423007902CRMP1Ellis-van CreveldEVCEVC2Skeletal ciliopathy |
| spellingShingle | Jorge Diogo Da Silva Ana Rita Soares Ana Maria Fortuna Nataliya Tkachenko Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions Genetics in Medicine Open CRMP1 Ellis-van Creveld EVC EVC2 Skeletal ciliopathy |
| title | Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions |
| title_full | Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions |
| title_fullStr | Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions |
| title_full_unstemmed | Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions |
| title_short | Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions |
| title_sort | establishing an objective clinical spectrum genotype phenotype correlations and crmp1 as a modifier in the ellis van creveld syndrome the first systematic review of evc and evc2 associated conditions |
| topic | CRMP1 Ellis-van Creveld EVC EVC2 Skeletal ciliopathy |
| url | http://www.sciencedirect.com/science/article/pii/S2949774423007902 |
| work_keys_str_mv | AT jorgediogodasilva establishinganobjectiveclinicalspectrumgenotypephenotypecorrelationsandcrmp1asamodifierintheellisvancreveldsyndromethefirstsystematicreviewofevcandevc2associatedconditions AT anaritasoares establishinganobjectiveclinicalspectrumgenotypephenotypecorrelationsandcrmp1asamodifierintheellisvancreveldsyndromethefirstsystematicreviewofevcandevc2associatedconditions AT anamariafortuna establishinganobjectiveclinicalspectrumgenotypephenotypecorrelationsandcrmp1asamodifierintheellisvancreveldsyndromethefirstsystematicreviewofevcandevc2associatedconditions AT nataliyatkachenko establishinganobjectiveclinicalspectrumgenotypephenotypecorrelationsandcrmp1asamodifierintheellisvancreveldsyndromethefirstsystematicreviewofevcandevc2associatedconditions |