Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders.

Travaglini L, Brancati F, Silhavy J, Iannicelli M, Nickerson E, Elkhartoufi N, Scott E, Spencer E, Gabriel S, Thomas S, Ben-Zeev B, Bertini E, Boltshauser E, Chaouch M, Cilio MR, de Jong MM, Kayserili H, Ogur G, Poretti A, Signorini S, Uziel G, Zaki MS, Johnson C, Attié-Bitach T, Gleeson JG, Valente EM, Ali Pacha L, Zankl A, Leventer R, Grattan-Smith P, Janecke A, Koch J, Freilinger M, D'Hooghe M, Sznajer Y, Vilain C, Van Coster R, Demerleir L, Dias K, Moco C, Moreira A, Ae Kim C, Maegawa G, Dakovic I, Loncarevic D, Mejaski-Bosnjak V, Petkovic D, Abdel-Salam GM, Abdel-Aleem A, Marti I, Pinard JM, Quijano-Roy S, Sigaudy S, de Lonlay P, Romano S, Verloes A, Touraine R, Koenig M, Dollfus H, Flori E, Fradin M, Lagier-Tourenne C, Messer J, Collignon P, Penzien JM, Bussmann C, Merkenschlager A, Philippi H, Kurlemann G, Grundmann K, Dacou-Voutetakis C, Kitsiou Tzeli S, Pons R, Jerney J, Halldorsson S, Johannsdottir J, Ludvigsson P, Phadke SR, Girisha KM, Doshi H, Udani V, Kaul M, Stuart B, Magee A, Spiegel R, Shalev S, Mandel H, Lev D, Michelson M, Idit M, Ben-Zeev B, Gershoni-Baruch R, Ficcadenti A, Fischetto R, Gentile M, Della Monica M, Pezzani M, Graziano C, Seri M, Benedicenti F, Stanzial F, Borgatti R, Romaniello R, Accorsi P, Battaglia S, Fazzi E, Giordano L, Pinelli L, Boccone L, Barone R, Sorge G, Briatore E, Bigoni S, Ferlini A, Donati MA, Biancheri R, Caridi G, Divizia MT, Faravelli F, Ghiggeri G, Mirabelli M, Pessagno A, Rossi A, Uliana V, Amorini M, Briguglio M, Briuglia S, Salpietro CD, Tortorella G, Adami A, Bonati MT, Castorina P, D'Arrigo S, Lalatta F, Marra G, Moroni I, Pantaleoni C, Riva D, Scelsa B, Spaccini L, Del Giudice E, Ludwig K, Permunian A, Suppiej A, Macaluso C, Pichiecchio A, Battini R, Di Giacomo M, Priolo M, Timpani P, Pagani G, Di Sabato ML, Emma F, Leuzzi V, Mancini F, Majore S, Micalizzi A, Parisi P, Romani M, Stringini G, Zanni G, Ulgheri L, Pollazzon M, Renieri A, Belligni E, Grosso E, Pieri I, Silengo M, Devescovi R, Greco D, Romano C, Cazzagon M, Simonati A, Al-Tawari AA, Bastaki L, Mégarbané A, Sabolic Avramovska V, Said E, Stromme P, Koul R, Rajab A, Azam M, Barbot C, Salih MA, Tabarki B, Jocic-Jakubi B, Martorell Sampol L, Rodriguez B, Pascual-Castroviejo I, Gener B, Puschmann A, Starck L, Capone A, Lemke J, Fluss J, Niedrist D, Hennekam RC, Wolf N, Gouider-Khouja N, Kraoua I, Ceylaner S, Teber S, Akgul M, Anlar B, Comu S, Kayserili H, Yüksel A, Akcakus M, Caglayan AO, Aldemir O, Al Gazali L, Sztriha L, Nicholl D, Woods CG, Bennett C, Hurst J, Sheridan E, Barnicoat A, Hemingway C, Lees M, Wakeling E, Blair E, Bernes S, Sanchez H, Clark AE, DeMarco E, Donahue C, Sherr E, Hahn J, Sanger TD, Gallager TE, Daugherty C, Krishnamoorthy KS, Sarco D, Walsh CA, McKanna T, Milisa J, Chung WK, De Vivo DC, Raynes H, Schubert R, Seward A, Brooks DG, Goldstein A, Caldwell J, Finsecke E, Maria BL, Holden K, Cruse RP, Karaca E, Swoboda KJ, Viskochil D, Dobyns WB.

Source : Eur J Hum Genet

2013 Oct 1

Pmid : 23386033

Abstract

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

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