Oral-facial-digital syndrome type VI: is C5orf42 really the major gene?

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Abstract

Oral-facial-digital type VI syndrome (OFDVI) is a rare phenotype of Joubert syndrome (JS). Recently, C5orf42 was suggested as the major OFDVI gene, being mutated in 9 of 11 families (82 %). We sequenced C5orf42 in 313 JS probands and identified mutations in 28 (8.9 %), most with a phenotype of pure JS. Only 2 out of 17 OFDVI patients (11.7 %) were mutated. A comparison of mutated vs. non-mutated OFDVI patients showed that preaxial and mesoaxial polydactyly, hypothalamic hamartoma and other congenital defects may predict C5orf42 mutations, while tongue hamartomas are more common in negative patients.

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Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

Enza Maria Valente, Clare Logan, Soumaya Mougou-Zerelli … (2010)

Joubert syndrome (JBTS), related disorders (JSRD) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and JBTS2 loci are allelic and due to mutations in TMEM216, encoding an uncharacterized tetraspan transmembrane protein. JBTS2 patients displayed frequent nephronophthisis and polydactytly, and two cases conformed to the Oro-Facio-Digital type VI phenotype, whereas skeletal dysplasia was common in MKS fetuses. A single p.R73L mutation was identified in all patients of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in patient fibroblasts or following siRNA knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 complexed with Meckelin, encoded by a gene also mutated in JSRD and MKS. Abrogation of tmem216 expression in zebrafish led to gastrulation defects that overlap with other ciliary morphants. The data implicate a new family of proteins in the ciliopathies, and further support allelism between ciliopathy disorders.

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OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin.

Karlien L.M. Coene, Ronald Roepman, Dan Doherty … (2009)

We ascertained a multi-generation Malaysian family with Joubert syndrome (JS). The presence of asymptomatic obligate carrier females suggested an X-linked recessive inheritance pattern. Affected males presented with mental retardation accompanied by postaxial polydactyly and retinitis pigmentosa. Brain MRIs showed the presence of a "molar tooth sign," which classifies this syndrome as classic JS with retinal involvement. Linkage analysis showed linkage to Xpter-Xp22.2 and a maximum LOD score of 2.06 for marker DXS8022. Mutation analysis revealed a frameshift mutation, p.K948NfsX8, in exon 21 of OFD1. In an isolated male with JS, a second frameshift mutation, p.E923KfsX3, in the same exon was identified. OFD1 has previously been associated with oral-facial-digital type 1 (OFD1) syndrome, a male-lethal X-linked dominant condition, and with X-linked recessive Simpson-Golabi-Behmel syndrome type 2 (SGBS2). In a yeast two-hybrid screen of a retinal cDNA library, we identified OFD1 as an interacting partner of the LCA5-encoded ciliary protein lebercilin. We show that X-linked recessive mutations in OFD1 reduce, but do not eliminate, the interaction with lebercilin, whereas X-linked dominant OFD1 mutations completely abolish binding to lebercilin. In addition, recessive mutations in OFD1 did not affect the pericentriolar localization of the recombinant protein in hTERT-RPE1 cells, whereas this localization was lost for dominant mutations. These findings offer a molecular explanation for the phenotypic spectrum observed for OFD1 mutations; this spectrum now includes OFD1 syndrome, SGBS2, and JS.

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Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome.

Laurence Faivre, Marie Gonzales, John Dean … (2013)

Oral-facial-digital syndrome type VI (OFD VI) is characterized by the association of malformations of the face, oral cavity and extremities, distinguished from the 12 other OFD syndromes by cerebellar and metacarpal abnormalities. Cerebellar malformations in OFD VI have been described as a molar tooth sign (MTS), thus, including OFD VI among the "Joubert syndrome related disorders" (JSRD). OFD VI diagnostic criteria have recently been suggested: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of hands or feet; 3) hypothalamic hamartoma. In order to further delineate this rare entity, we present the neurological and radiological data of 6 additional OFD VI patients. All patients presented oral malformations, facial dysmorphism and distal abnormalities including frequent polydactyly (66%), as well as neurological symptoms with moderate to severe mental retardation. Contrary to historically reported patients, mesoaxial polydactyly did not appear to be a predominant clinical feature in OFD VI. Sequencing analyzes of the 14 genes implicated in JSRD up to 2011 revealed only an OFD1 frameshift mutation in one female OFD VI patient, strengthening the link between these two oral-facial-digital syndromes and JSRD. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

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Author and article information

Contributors

Marta Romani: m.romani@css-mendel.it

Enza Maria Valente: +39 06 4416 0537 , e.valente@css-mendel.it

Journal

Journal ID (nlm-ta): Hum Genet

Journal ID (iso-abbrev): Hum. Genet

Title: Human Genetics

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0340-6717

ISSN (Electronic): 1432-1203

Publication date (Electronic): 19 November 2014

Publication date PMC-release: 19 November 2014

Publication date (Print): 2015

Volume: 134

Pages: 123-126

Affiliations

[ ]Lab. Mendel, IRCCS Casa Sollievo della Sofferenza, Viale Regina Margherita 261, 00198 Rome, Italy

[ ]Department of Biological and Environmental Science, University of Messina, Messina, Italy

[ ]Section of Pediatric Neuroradiology, Division of Pediatric Radiology, The Johns Hopkins School of Medicine, Baltimore, MD USA

[ ]Pediatric Neuropsychiatric Division, Spedali Civili, Brescia, Italy

[ ]Unit of Pediatrics and Medical Genetics, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy

[ ]Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children’s Research Hospital, Rome, Italy

[ ]Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco Italy

[ ]Intergen Genetic Diagnosis, Research and Education Center, Ankara, Turkey

[ ]Section of Neuroscience, Department of Medicine and Surgery, University of Salerno, Salerno, Italy

[ ]Developmental Neurology Division, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy

[ ]Department of Pediatrics I and Division of Human Genetics, Innsbruck Medical University, Innsbruck, Austria

[ ]Preconceptional and Prenatal Physiopathology, Galliera Hospital, Genoa, Italy

[ ]Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University of Padova, Padua, Italy

[ ]Department of Molecular Genetics, Hospital Sant Joan de Déu, Barcelona, Spain

[ ]Service de Génétique Médicale, CHU Hôpital Sud, Rennes, France

[ ]Department of Neuroradiology, Spedali Civili, Brescia, Italy

[ ]Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain

[ ]Pediatric Neuropsychiatry Unit, IRCCS Istituto di Scienze Neurologiche, Bologna, Italy

[ ]Unit of Child Neurology and Psychiatry, Centre of Child Neuro-ophthalmology, C. Mondino National Neurological Institute, Pavia, Italy

[ ]Department of Neurological Sciences and Movement-Neurology (Child Neurology), University of Verona, Verona, Italy

[ ]Emek Medical Center, Genetic Institute, Afula, Israel

[ ]Department of Pediatrics, Genetic Counselling Service, Regional Hospital of Bolzano, Bolzano, Italy

[ ]Department of Pediatric Neurology, University Children’s Hospital, Bern, Switzerland

[ ]Division of Pediatric Neurology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia

[ ]Department of Child Neurology, VU University Medical Center and Neuroscience Campus Amsterdam, Amsterdam, The Netherlands

[ ]Department of Child Neurology, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy

[ ]Department of Pediatric Neurology, University Children’s Hospital, Zurich, Switzerland

[ ]Neurogenetics Unit, CSS-Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy

Article

Publisher ID: 1508

DOI: 10.1007/s00439-014-1508-3

PMC ID: 4282684

PubMed ID: 25407461

SO-VID: c4d8e79a-0f13-43fe-acfd-f29a8ad53759

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

History

Date received : 30 July 2014

Date accepted : 1 November 2014

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Oral-facial-digital syndrome type VI: is C5orf42 really the major gene?

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Most cited references 3

Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin.

Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome.

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