title: Distinguishing the four genetic causes of Jouberts syndrome-related disorders.
abstract: Jouberts syndrome-related disorders are a group of recessively inherited conditions showing cerebellar vermis hypoplasia and the molar tooth sign of the midbrain-hindbrain junction. Recent analyses have suggested at least three loci, JBTS1 (9q34.3), -2 (11p11.2-q12.3), and -3 (6q23), but the phenotypic spectrum associated with each locus has not been delineated. In addition, deletions of the NPHP1 gene, usually responsible for isolated juvenile nephronophthisis, are occasionally encountered among Jouberts syndrome-related disorder patients. Here, we describe four novel families showing evidence of linkage to two of these loci, provide a 3.6Mb refinement of the JBTS2 locus, and perform a detailed comparison of all linked families identified so far, to define the clinical and radiographical hallmarks for each genetic condition. We find that JBTS1 and -3 primarily show features restricted to the central nervous system, with JBTS1 showing largely pure cerebellar and midbrain-hindbrain junction involvement, and JBTS3 displaying cerebellar, midbrain-hindbrain junction, and cerebral cortical features, most notably polymicrogyria. Conversely, JBTS2 is associated with multiorgan involvement of kidney, retina, and liver, in addition to the central nervous system features, and results in extreme phenotypic variability. This provides a useful framework for genetic testing strategies and prediction of which patients are most likely to experience development of systemic complications.
authors.affiliation: IRCCS CSS, Mendel Institute, Rome, Italy.
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Marsh
authors.forename: Marco
authors.initials: M
authors.lastname: Castori
authors.forename: Tracy
authors.initials: T
authors.lastname: Dixon-Salazar
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Jean
authors.initials: J
authors.lastname: Messer
authors.forename: Clara
authors.initials: C
authors.lastname: Barbot
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Eugen
authors.initials: E
authors.lastname: Boltshauser
authors.forename: Asma A
authors.initials: AA
authors.lastname: Al-Tawari
authors.forename: Carmelo D
authors.initials: CD
authors.lastname: Salpietro
authors.forename: Hulya
authors.initials: H
authors.lastname: Kayserili
authors.forename: László
authors.initials: L
authors.lastname: Sztriha
authors.forename: Moez
authors.initials: M
authors.lastname: Gribaa
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000328:Adult; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D025063:Chromosome Disorders; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D010375:Pedigree