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CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders.

ABSTRACT: Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype). Here, we performed comprehensive CEP290-mutation analysis on two nonoverlapping cohorts of JSRD-affected patients with a proven MTS. We identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only two patients. The data suggest that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.

SUBMITTER: Brancati F

PROVIDER: S-EPMC1950920 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders.

Brancati Francesco F Barrano Giuseppe G Silhavy Jennifer L JL Marsh Sarah E SE Travaglini Lorena L Bielas Stephanie L SL Amorini Maria M Zablocka Dominika D Kayserili Hulya H Al-Gazali Lihadh L Bertini Enrico E Boltshauser Eugen E D'Hooghe Marc M Fazzi Elisa E Fenerci Elif Y EY Hennekam Raoul C M RC Kiss Andrea A Lees Melissa M MM Marco Elysa E Phadke Shubha R SR Rigoli Luciana L Romano Stephane S Salpietro Carmelo D CD Sherr Elliott H EH Signorini Sabrina S Stromme Petter P Stuart Bernard B Sztriha Laszlo L Viskochil David H DH Yuksel Adnan A Dallapiccola Bruno B Valente Enza Maria EM Gleeson Joseph G JG

American journal of human genetics 20070518 1

Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurological, ocular, and renal manifestations. Mutations in the CEP290 gene were recently identified in families with the MTS-related neurological features, many of which showed oculo-renal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype). Here, we performed ...[more]

PMID: 17564967

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Project description:Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign (MTS), a complex midbrain-hindbrain malformation visible on brain imaging, first recognized in JS. Estimates of the incidence of JSRD range between 1/80,000 and 1/100,000 live births, although these figures may represent an underestimate. The neurological features of JSRD include hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing dysregulation. These may be associated with multiorgan involvement, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. JSRD are classified in six phenotypic subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defects; JS with hepatic defect; JS with orofaciodigital defects. With the exception of rare X-linked recessive cases, JSRD follow autosomal recessive inheritance and are genetically heterogeneous. Ten causative genes have been identified to date, all encoding for proteins of the primary cilium or the centrosome, making JSRD part of an expanding group of diseases called "ciliopathies". Mutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. Differential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis and Senior-Loken syndrome), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations. Recurrence risk is 25% in most families, although X-linked inheritance should also be considered. The identification of the molecular defect in couples at risk allows early prenatal genetic testing, whereas fetal brain neuroimaging may remain uninformative until the end of the second trimester of pregnancy. Detection of the MTS should be followed by a diagnostic protocol to assess multiorgan involvement. Optimal management requires a multidisciplinary approach, with particular attention to respiratory and feeding problems in neonates and infants. Cognitive and behavioral assessments are also recommended to provide young patients with adequate neuropsychological support and rehabilitation. After the first months of life, global prognosis varies considerably among JSRD subgroups, depending on the extent and severity of organ involvement.

Dataset Information

CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders.

Publications

CEP290 mutations are frequently identified in the oculo-renal form of Joubert syndrome-related disorders.

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