TY - JOUR
T1 - Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center
AU - Vilboux, Thierry
AU - Doherty, Daniel A.
AU - Glass, Ian A.
AU - Parisi, Melissa A.
AU - Phelps, Ian G.
AU - Cullinane, Andrew R.
AU - Zein, Wadih
AU - Brooks, Brian P.
AU - Heller, Theo
AU - Soldatos, Ariane
AU - Oden, Neal L.
AU - Yildirimli, Deniz
AU - Vemulapalli, Meghana
AU - Mullikin, James C.
AU - Malicdan, May Christine V.
AU - Gahl, William A.
AU - Gunay-Aygun, Meral
N1 - Publisher Copyright:
© American College of Medical Genetics and Genomics.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Purpose: Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients. Methods: In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES). Results: We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease. Conclusion: In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease. Genet Med advance online publication 26 January 2017.
AB - Purpose: Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brainstem malformations resulting in the diagnostic "molar tooth sign" on brain imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients. Methods: In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES). Results: We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease. Conclusion: In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease. Genet Med advance online publication 26 January 2017.
KW - Ciliopathy
KW - Clinical and molecular diagnosis
KW - Joubert syndrome
KW - Next-generation sequencing
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U2 - 10.1038/gim.2016.204
DO - 10.1038/gim.2016.204
M3 - Article
C2 - 28125082
AN - SCOPUS:85020635229
SN - 1098-3600
VL - 19
SP - 875
EP - 882
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 8
ER -