Joubert Syndrome 2 (JBTS2) in Ashkenazi Jews Is Associated with a TMEM216 Mutation

Edvardson, Simon; Shaag, Avraham; Zenvirt, Shamir; Erlich, Yaniv; Hannon, Gregory J.; Shanske, Alan; Gomori, John M.; Ekstein, Joseph; Elpeleg, Orly

doi:10.1016/j.ajhg.2010.01.022

Cited by 11 publications

(18 citation statements)

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“…15 In fact, mutations in MKS genes have been reported to cause other ciliopathies, for example, MKS1 and BardetBiedl syndrome, 16 TMEM216 and Joubert syndrome, 17 TMEM67 and Joubert syndrome and nephrophthisis, 18,19 CEP290 in non-syndromic retinal dystrophy, Senior-Loken syndrome, nephronophthisis, Joubert syndrome, and Bardet-Biedl syndrome, 20 RPGRIP1L and Joubert syndrome, 21 and CC2D2A and Joubert syndrome. 22 The factors that determine the ultimate clinical phenotype are not completely understood but there is growing evidence that ciliopathies represent a spectrum of clinical severity that correlates to some extent with the severity of the ciliary defect.…”

Section: Introductionmentioning

confidence: 99%

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

et al. 2012

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Meckel-Gruber syndrome (MKS, OMIM #249000) is a multiple congenital malformation syndrome that represents the severe end of the ciliopathy phenotypic spectrum. Despite the relatively common occurrence of this syndrome among Arabs, little is known about its genetic architecture in this population. This is a series of 18 Arab families with MKS, who were evaluated clinically and studied using autozygome-guided mutation analysis and exome sequencing. We show that autozygome-guided candidate gene analysis identified the underlying mutation in the majority (n ¼ 12, 71%). Exome sequencing revealed a likely pathogenic mutation in three novel candidate MKS disease genes. These include C5orf42, Ellis-van-Creveld disease gene EVC2 and SEC8 (also known as EXOC4), which encodes an exocyst protein with an established role in ciliogenesis. This is the largest and most comprehensive genomic study on MKS in Arabs and the results, in addition to revealing genetic and allelic heterogeneity, suggest that previously reported disease genes and the novel candidates uncovered by this study account for the overwhelming majority of MKS patients in our population.

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Section: Introductionmentioning

confidence: 99%

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

et al. 2012

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“…One ug of blood derived DNA was prepared from whole exome sequencing using the Illumina platform as previously described (Edvardson et al, 2010). Each sample was sequenced on two lanes of Illumina GAIIx using 76bp paired-end protocol.…”

Section: Illumina Sequencingmentioning

confidence: 99%

Blood Ties: Chimerism Can Mask Twin Discordance in High-Throughput Sequencing

Erlich¹

2011

Twin Res Hum Genet

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Twin studies have long provided a means to separate the contributions of genetic and environmental factors. A recent pioneering report by Baranzini et al. presented an analysis of the complete genomes and epigenomes of a monozygotic (MZ) twin pair discordant for multiple sclerosis. This failed to find any difference between the twins, raising doubts regarding the value of whole-genome twin studies for defining disease susceptibility alleles. However, the study was carried out with DNA extracted from blood. In many cases, the hematopoietic lineages of MZ twins are chimeric due to twin-to-twin exchange of hematopoietic stem cells during embryogenesis. We therefore wondered how chimerism might impact the ability to identify genetic differences. We inferred the blood chimerism rates and profiles of more than 30 discordant twin cases from a wide variety of medical conditions. We found that the genotype compositions of the twins were highly similar. We then benchmarked the performance of SNP callers to detect discordant variations using high-throughput sequencing data. Our analysis revealed that chimerism patterns, well within the range normally observed in MZ twins, greatly reduce the sensitivity of SNP calls. This raises questions regarding any conclusions of genomic homogeneity that might be drawn from studies of blood-derived twin DNA.

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“…These defects in cilia are associated with a range of human diseases, such as primary ciliary dyskinesia, hydrocephalus, polycystic liver and kidney disease, and some forms of retinal degeneration (26). Using WES, mutations that cause ciliopathy diseases were found: Van Den Ende-Gupta, Sensenbrenner, Joubert, Bardet-Biedl syndromes, Leber congenital amaurosis, polycystic kidney disease, primary ciliary dyskinesia (21)(22)(23)(24)(27)(28)(29)(30)(31). Exome sequencing effectively confirmed that the nonsynonymous mutation chr22:19115386 C>T in the SCARF2 gene, which is expressed during development, is responsible for Van Den Ende-Gupta syndrome that affects multi-system (21).…”

Section: Discussionmentioning

confidence: 99%

“…In disease studies, exome sequencing is used both as a basis research and as a way to confirm that gene mutation actually causes a disease. Combined use of exome sequencing and homozygosity mapping was applied in the study of Van Den Ende-Gupta syndrome, Joubert syndrome and other disorders (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Next-generation whole-exome sequencing contribution to identification of rare autosomal recessive diseases

Rančelis

Kučinskas²

2013

AML

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A rare disease is any disease that affects a small percentage of the population. In the European Union a disease is defined as rare if it affects less than 1 in 2,000 people. Despite a small percentage of affected people by one disease, the total number of rare diseases is estimated to be around 7,000–8,000, thus, because of their large number they have an impact on many people and even 30 million of European Union citizens may be suffering from them. Research of rare diseases may help to explain their mechanism or to develop more advanced diagnostics. Classical strategies for studies of rare autosomal recessive diseases encounter with additional problems (multiple genetic variants, de novo mutations, extremely rare cases) that make these strategies not enough effective. Next generation whole-exome sequencing (WES) opened a new page in Mendelian disease gene discovery – enabling to study autosomal recessive diseases in a new way. During 3 years of WES usage many novel mutations of autosomal recessive disease genes were discovered.

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Joubert Syndrome 2 (JBTS2) in Ashkenazi Jews Is Associated with a TMEM216 Mutation

Cited by 11 publications

References 0 publications

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

Blood Ties: Chimerism Can Mask Twin Discordance in High-Throughput Sequencing

Next-generation whole-exome sequencing contribution to identification of rare autosomal recessive diseases

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