title: Molecular genetic analysis of 30 families with Joubert syndrome.
abstract: Joubert syndrome (JS) is rare recessive disorders characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles, and a deep interpeduncular fossa which is defined by neuroimaging and is termed the 'molar tooth sign'. JS is genetically highly heterogeneous, with at least 29 disease genes being involved. To further understand the genetic causes of JS, we performed whole-exome sequencing in 24 newly recruited JS families. Together with six previously reported families, we identified causative mutations in 25 out of 30 (24 + 6) families (83.3%). We identified eight mutated genes in 27 (21 + 6) Japanese families, TMEM67 (7/27, 25.9%) and CEP290 (6/27, 22.2%) were the most commonly mutated. Interestingly, 9 of 12 CEP290 disease alleles were c.6012-12T>A (75.0%), an allele that has not been reported in non-Japanese populations. Therefore c.6012-12T>A is a common allele in the Japanese population. Importantly, one Japanese and one Omani families carried compound biallelic mutations in two distinct genes (TMEM67/RPGRIP1L and TMEM138/BBS1, respectively). BBS1 is the causative gene in Bardet-Biedl syndrome. These concomitant mutations led to severe and/or complex clinical features in the patients, suggesting combined effects of different mutant genes.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.|Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tsurusaki
authors.affiliation: Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Okamoto
authors.affiliation: Department of Genetics, Sultan Qaboos University Hospital, Muscat, Oman.
authors.forename: A
authors.initials: A
authors.lastname: Alkindy
authors.affiliation: Yokohama City University Medical Center, Children's Medical Center, Yokohama, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Inaba
authors.affiliation: Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Pediatrics, Graduate school of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Muramatsu
authors.affiliation: Kumamoto City Child Development Support Center, Kumamoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Ieda
authors.affiliation: Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Saitoh
authors.affiliation: Division of Child Neurology, Okinawa Prefectural Southern Medical Center & Children's Medical Center, Okinawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hiyane
authors.affiliation: Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Suzumura
authors.affiliation: Department of Child and Adolescent Psychiatry, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yagyu
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shiraishi
authors.affiliation: Department of Pediatrics, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Division of Rehabilitation, Nagano Children's Hospital, Nagano, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Fueki
authors.affiliation: Department of Pediatric Rehabilitation, Hokkaido Medical Center for Child Health and Rehabilitation, Hokkaido, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Habata
authors.affiliation: Nire-no-kai Children's Clinic, Hokkaido, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Ueda
authors.affiliation: Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Komatsu
authors.affiliation: Department of Pediatrics, Kyorin University School of Medicine, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yan
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Shimoda
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shitara
authors.affiliation: Department of Pediatrics, Central Hospital, Aichi Human Service Center, Aichi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Mizuno
authors.affiliation: Department of Neonatology, Gunma Children's Medical Center, Gunma, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ichinomiya
authors.affiliation: Division of Medical Genetics, Gunma Children's Medical Center, Gunma, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sameshima
authors.affiliation: Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuyusaki
authors.affiliation: Division of Medical Genetics, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kurosawa
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Pediatric Neurology, Miyagi Children's Hospital, Sendai, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Haginoya
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.|Academic Renal Unit, School of Clinical Science, University of Bristol, Bristol, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Yoshizawa
authors.affiliation: Department of Nephrology, Chiba Children's Hospital, Chiba, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hisano
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.|Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Obstetrics and Gynecology, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Matsumoto
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D000951:Antigens, Neoplasm / Q000235:genetics*; D018797:Cell Cycle Proteins; D002531:Cerebellum / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000503:physiopathology; D003598:Cytoskeletal Proteins; D005124:Eye Abnormalities / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan / Q000453:epidemiology; D052177:Kidney Diseases, Cystic / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009850:Oman / Q000453:epidemiology; D010375:Pedigree; D012160:Retina / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000503:physiopathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000951:Antigens, Neoplasm; C464790:Bbs1 protein, human; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C532826:RPGRIP1L protein, human; C468846:TMEM67 protein, human
keywords: Japanese; Joubert syndrome; Whole-exome sequencing; concomitant mutations