Joubert syndrome: genotyping a Northern European patient cohort

Abstract

Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with 420 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel-Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding.

In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations

“…Mutations in more than 30 genes can cause JSRD phenotypes(Kroes et al, 2016; Suzuki et al, 2016), and at least 20 genes are associated with LCA(den Hollander, 2016; Jacobson et al, 2016). CEP290 mutations can result in multiple divergent phenotypes, including JSRD and LCA.…”

Combining targeted panel-based resequencing and copy-number variation analysis for the diagnosis of inherited syndromic retinopathies and associated ciliopathies

“…Clinical diagnosis is often challenging, as some of the characteristic systemic features may not develop until later in infancy and adulthood or may even evolve and change over time. Several multigene panel approaches have been used for molecular characterization of specific retinal ciliopathies, such as BBS, Joubert syndrome, and Usher syndrome, yielding variable diagnostic rates 7,18,19,46,47 . Here, we first studied a more heterogeneous and large cohort of “non-naive”, i.e.…”

“…Next-generation sequencing (NGS) is a cost-effective approach for the genetic diagnosis of retinal diseases 16,17 . Several studies have focused on specific retinal ciliopathies, such as Bardet-Biedl syndrome (BBS) 18 and Joubert syndrome 7,19–21 , with a wide range of reported mutation detection rates depending on the number of targeted genes, NGS platform, and use of pre-screened or “naive” cases. In patients with complex atypical phenotypes, chromosomal microarray analysis may also be very useful for assessing contiguous gene deletion syndromes as a cause of disease co-occurrence 22 .…”

A Common Ancestral Asn242Ser Mutation in <b><i>TMEM67</i></b> Identified in Multiple Iranian Families with Joubert Syndrome

“…There was only one carrier, a Central Asian individual, in the Greater Middle East Variome database. The p.Asn242Ser allele was previously reported in patients with JS from studying two large cohort [5][6][7] . The same homozygous mutation was also reported in a 21-year-old male diagnosed with COACH syndrome [9] .…”

“…TMEM67 is one of the most frequently mutated JS genes in patients from northern European and Japanese populations [5][6][7] . However, based on currently available data, it is not the common cause in the Middle Eastern and North African Arab populations [8] .…”