Novel and recurrent EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers acrofacial dyostosis.

Ellis van Creveld syndrome and Weyers acrofacial dysostosis are allelic disorders caused by mutations in EVC or EVC2 genes. We illustrate the results of direct analysis of whole EVC and EVC2 genes' coding regions in 32 unrelated families with clinical diagnosis of Ellis van Creveld syndrome and in 2 families with Weyers acrofacial dysostosis. We identified mutations in 27/32 (84%) cases with Ellis van Creveld syndrome and 2/2 cases with Weyers acrofacial dysostosis. Of the Ellis van Creveld syndrome cases, 20/27 (74%) had a mutation in EVC and 7/27 (26%) in EVC2 genes. The two subjects with Weyers acrofacial dysostosis had a heterozygous mutation in the last exon of EVC2. In total, we detected 25 independent EVC and 11 independent EVC2 mutations. Nineteen EVC mutations (19/25, 76%) and 4 EVC2 mutations (4/11, 36%) were novel. Also one EVC2 gene mutation found in Weyers acrofacial dysostosis was novel. In 5 unrelated cases with a clinical diagnosis of Ellis van Creveld syndrome, we did not find any mutation in either EVC or EVC2 genes. Current findings expand the Ellis van Creveld syndrome and Weyers acrofacial dysostosis mutation spectra, and provide further evidence that the last exon of EVC2 gene is a hot spot for Weyers acrofacial dysostosis mutations. Accordingly, EVC2 exon 22 should be analyzed with priority by mutation screening in individuals with a suspected diagnosis of Weyers acrofacial dysostosis.

[1]  M. Digilio,et al.  Atrioventricular canal defect and associated genetic disorders: new insights into polydactyly syndromes , 2011 .

[2]  M. Digilio,et al.  Atrioventricular canal defect and postaxial polydactyly indicating phenotypic overlap of Ellis-van Creveld and Kaufman-McKusick syndromes , 1997, Pediatric Cardiology.

[3]  N. Brunetti‐Pierri,et al.  WDR35 mutation in siblings with Sensenbrenner syndrome: A ciliopathy with variable phenotype , 2012, American journal of medical genetics. Part A.

[4]  H. Weyers,et al.  Über eine korrelierte Mißbildung der Kiefer- und Extremitätenakren , 1952 .

[5]  M. Digilio,et al.  Atrioventricular canal defect without Down syndrome: a heterogeneous malformation. , 1999, American journal of medical genetics.

[6]  M. Digilio,et al.  Single atrium, atrioventricular canal/postaxial hexodactyly indicating Ellis-van Creveld syndrome , 1995, Human Genetics.

[7]  M. Digilio,et al.  Cardiac malformations in patients with oral-facial-skeletal syndromes: clinical similarities with heterotaxia. , 1999, American journal of medical genetics.

[8]  A. Guttmacher,et al.  Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus. , 1997, American journal of human genetics.

[9]  C. Phoon,et al.  Asplenia syndrome: insight into embryology through an analysis of cardiac and extracardiac anomalies. , 1994, The American journal of cardiology.

[10]  John E. Cockerham,et al.  Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene , 2008, BMC Medical Genetics.

[11]  M. Polymeropoulos,et al.  Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis , 2000, Nature Genetics.

[12]  H. Weyers.  [A correlated abnormality of the mandible and extremities (dysostosis acrofacialis)]. , 1952, Fortschritte auf dem Gebiete der Rontgenstrahlen.

[13]  J. Goodship,et al.  Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis–van Creveld syndrome patients , 2006, Human Genetics.

[14]  A. Munnich,et al.  KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes , 2011, Nature Genetics.

[15]  J. Goodship,et al.  Ellis–van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia‐mediated diminished response to hedgehog ligands , 2009, American journal of medical genetics. Part C, Seminars in medical genetics.

[16]  E. Ginns,et al.  A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. , 2002, Molecular genetics and metabolism.

[17]  J. Goodship,et al.  Long interspersed nuclear element‐1 (LINE1)‐mediated deletion of EVC, EVC2, C4orf6, and STK32B in Ellis–van Creveld syndrome with borderline intelligence , 2008, Human mutation.

[18]  L. Biesecker,et al.  Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination. , 2007, Human molecular genetics.

[19]  J. Opitz,et al.  Specific congenital heart defects in RSH/Smith-Lemli-Opitz syndrome: postulated involvement of the sonic hedgehog pathway in syndromes with postaxial polydactyly or heterotaxia. , 2003, Birth defects research. Part A, Clinical and molecular teratology.

[20]  M. Digilio,et al.  Atrioventricular Canal Defect as a Sign of Laterality Defect in Ellis-van Creveld and Polydactyly Syndromes With Ciliary and Hedgehog Signaling Dysfunction , 2012, Pediatric Cardiology.

[21]  P. Bork,et al.  Towards a structural basis of human non-synonymous single nucleotide polymorphisms. , 2000, Trends in genetics : TIG.

[22]  R. Zannolli,et al.  Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts hedgehog signaling , 2009, Human mutation.

[23]  K. Sund,et al.  Analysis of Ellis van Creveld syndrome gene products: implications for cardiovascular development and disease. , 2009, Human molecular genetics.

[24]  J. Moller,et al.  Ellis–van Creveld Syndrome and Congenital Heart Defects: Presentation of an Additional 32 Cases , 2011, Pediatric Cardiology.

[25]  A. Lin,et al.  Cardiovascular malformations in Smith-Lemli-Opitz syndrome. , 1997, American journal of medical genetics.

[26]  B. Dallapiccola,et al.  Deletions of NF1 gene and exons detected by multiplex ligation-dependent probe amplification , 2007, Journal of Medical Genetics.

[27]  J. Goodship,et al.  Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. , 2003, American journal of human genetics.

[28]  R. Ellis,et al.  A Syndrome Characterized by Ectodermal Dysplasia, Polydactyly, Chondro-Dysplasia and Congenital Morbus Cordis , 1940, Archives of disease in childhood.

[29]  S. Henikoff,et al.  Predicting deleterious amino acid substitutions. , 2001, Genome research.

[30]  E. Jabs,et al.  A novel heterozygous deletion in the EVC2 gene causes Weyers acrofacial dysostosis , 2006, Human Genetics.

[31]  C. Ponting,et al.  Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus , 2011, BMC Biology.

[32]  J. Moller,et al.  Polysplenia: A review of 146 cases , 1983, Pediatric Cardiology.

[33]  J. Goodship,et al.  Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia , 2007, Development.

[34]  L. Biesecker,et al.  Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR , 2004, Nature Genetics.

[35]  V. McKusick,et al.  DWARFISM IN THE AMISH I. THE ELLIS-VAN CREVELD SYNDROME. , 1964, Bulletin of the Johns Hopkins Hospital.

[36]  W. Ahmad,et al.  A novel missense mutation in the EVC gene underlies Ellis‐van Creveld syndrome in a Pakistani family , 2010, Pediatrics international : official journal of the Japan Pediatric Society.

[37]  R. Mostofi,et al.  Oral abnormalities in the Ellis-van Creveld syndrome: case report. , 1988, Pediatric Dentistry.