CEP290 Mutations Are Frequently Identified in the Oculo-Renal Form of Joubert Syndrome–Related Disorders

Brancati, Francesco; Barrano, Giuseppe; Silhavy, Jennifer L.; Marsh, Sarah Arnaud; Travaglini, Lorena; Bielas, Stephanie; Amorini, Maria; Zablocka, D.; Kayserili, Hülya; Al‐Gazali, Lihadh; Bertini, Enrico; Boltshauser, Eugen; D’Hooghe, Marc; Fazzi, Elisa; Fenerci, Elif Yosunkaya; Hennekam, Raoul C. M.; Kiss, Andrea; Lees, Melissa; Marco, Elysa J.; Phadke, Shubha R.; Rigoli, Luciana; Romano, S.; Salpietro, Carmelo; Sherr, Elliott H.; Signorini, Sabrina; Strømme, Petter; Stuart, Bernard; Sztriha, László; Viskochil, David; Yüksel, Adnan; Dallapiccola, Bruno; Valente, Enza Maria; Gleeson, Joseph G.

doi:10.1086/519026

Cited by 139 publications

(144 citation statements)

References 30 publications

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“…Mutations in this exon are known to cause Joubert and Meckel syndromes and LCA, so we considered this mutation highly likely to be pathogenic, but we were unable to identify the 2nd mutation despite good coverage across the gene. 7,26 Thirty-one percent of the mutations we identified were novel, indicating that screening methods, which only detect for known mutations, would have missed a significant number of these in our data set.…”

Section: Discussionmentioning

confidence: 99%

Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease

et al. 2012

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Inherited retinal degeneration (IRD) is a common cause of visual impairment (prevalence B1/3500). There is considerable phenotype and genotype heterogeneity, making a specific diagnosis very difficult without molecular testing. We investigated targeted capture combined with next-generation sequencing using Nimblegen 12plex arrays and the Roche 454 sequencing platform to explore its potential for clinical diagnostics in two common types of IRD, retinitis pigmentosa and cone-rod dystrophy. 50 patients (36 unknowns and 14 positive controls) were screened, and pathogenic mutations were identified in 25% of patients in the unknown, with 53% in the early-onset cases. All patients with new mutations detected had an age of onset o21 years and 44% had a family history. Thirty-one percent of mutations detected were novel. A de novo mutation in rhodopsin was identified in one early-onset case without a family history. Bioinformatic pipelines were developed to identify likely pathogenic mutations and stringent criteria were used for assignment of pathogenicity. Analysis of sequencing metrics revealed significant variability in capture efficiency and depth of coverage. We conclude that targeted capture and next-generation sequencing are likely to be very useful in a diagnostic setting, but patients with earlier onset of disease are more likely to benefit from using this strategy. The mutation-detection rate suggests that many patients are likely to have mutations in novel genes.

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Section: Discussionmentioning

confidence: 99%

Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease

et al. 2012

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“…The INPP5E phenotypic spectrum appears to largely overlap with that related to AHI1 mutations; 18 conversely, none of the INPP5E-mutated patients presented polydactyly or encephalocele, two features that are often associated with mutations in genes also causative of MKS, such as TMEM216, CEP290, TMEM67 or RPGRIP1L. 5,[19][20][21] In one patient with pure JS (COR28), only a single heterozygous INPP5E mutation could be detected, despite complete sequencing of the coding regions and canonical splice sites, and search for genomic rearrangements. Although we cannot exclude the possibility that a second pathogenic mutation resides within intronic or regulatory regions of the gene, it is also plausible that the identified change could act as a genetic modifier of the clinical phenotype in an oligogenic context, and that digenic mutations may reside in another gene.…”

Section: Discussionmentioning

confidence: 98%

“…Interestingly, in these patients retinal disease was never severe; in fact, none of them presented with Leber congenital amaurosis, that is the typical retinopathy found in patients mutated in CEP290. 5 Pure JS is also a frequent presentation, occurring in five families (28%), while other phenotypes such as JS with liver disease (COACH syndrome) and JS with renal disease are extremely rare, being reported only in two and one families, respectively. However, it must be noted that age of examination of some patients was too young to safely exclude the development of a progressive renal disease such as NPH.…”

Section: Discussionmentioning

confidence: 99%

“…2 It is estimated that known genes overall account for about half of cases, suggesting further genetic heterogeneity; moreover, genotype-phenotype correlates have been clearly established only for few JSRD-causative genes. [5][6][7][8][9] In 2009, Jacoby et al 10 identified INPP5E mutations in a family with MORM syndrome, a rare autosomal recessive condition related to Bardet-Biedl syndrome. In the same year, we identified homozygous INPP5E mutations in seven consanguineous families genetically linked to the first JSRD locus (JBTS1) on 9q34.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

et al. 2013

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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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“…Finally, one JSRD patient with a proven CEP290 mutation displayed complete situs inversus. Together, these data suggest a link between JSRD and other ciliopathies [41]. But what could the role of cilia proteins be in the developing cerebellum?…”

Section: Joubert Syndrome and Related Disordersmentioning

confidence: 89%

Cerebellar development and disease

Millen¹,

Gleeson²

2008

Current Opinion in Neurobiology

171

141

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The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitterspecific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum.

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CEP290 Mutations Are Frequently Identified in the Oculo-Renal Form of Joubert Syndrome–Related Disorders

Cited by 139 publications

References 30 publications

Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease

Next-generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Cerebellar development and disease

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