Enokizono M, Aida N, Niwa T, Osaka H, Naruto T, Kurosawa K, Ohba C, Suzuki T, Saitsu H, Goto T, Matsumoto N. Neuroimaging findings in Joubert syndrome with C5orf42 gene mutations: A milder form of molar tooth sign and vermian hypoplasia. J Neurol Sci. 2017 May 15;376:7-12. doi: 10.1016/j.jns.2017.02.065. Epub 2017 Mar 1. PMID: 28431631.
Abstract
Purpose: Little is known regarding neuroimaging-genotype correlations in Joubert syndrome (JBTS). To elucidate one of these correlations, we investigated the neuroimaging findings of JBTS patients with C5orf42 mutations.
Materials and methods: Neuroimaging findings in five JBTS patients with C5orf42 mutations were retrospectively assessed with regard to the infratentorial and supratentorial structures on T1-magnetization prepared rapid gradient echo (MPRAGE), T2-weighted images, and color-coded fractional anisotropy (FA) maps; the findings were compared to those in four JBTS patients with mutations in other genes (including three with AHI1 and one with TMEM67 mutations).
Results: In C5orf42-mutant patients, the infratentorial magnetic resonance (MR) images showed normal or minimally thickened and minimally elongated superior cerebellar peduncles (SCP), normal or minimally deepened interpeduncular fossa (IF), and mild vermian hypoplasia (VH). However, in other patients, all had severe abnormalities in the SCP and IF, and moderate to marked VH. Supratentorial abnormalities were found in one individual in other JBTS. In JBTS with all mutations, color-coded FA maps showed the absence of decussation of the SCP (DSCP).
Conclusion: The morphological neuroimaging findings in C5orf42-mutant JBTS were distinctly mild and made diagnosis difficult. However, the absence of DSCP on color-coded FA maps may facilitate the diagnosis of JBTS.
Zhang C, Sun Z, Xu L, Che F, Liu S. Novel compound heterozygous CPLANE1 variants identified in a Chinese family with Joubert syndrome. Int J Dev Neurosci. 2021 Oct;81(6):529-538. doi: 10.1002/jdn.10135. Epub 2021 Jun 25. PMID: 34091942.
Abstract
Joubert syndrome (JS) and JS-related disorders (JSRD) are a group of neurodevelopmental diseases that share the "molar tooth sign" on axial brain magnetic resonance imaging (MRI), accompanied by cerebellar vermis hypoplasia, ataxia, hypotonia, and developmental delay. To identify variants responsible for the clinical symptoms of a Chinese family with JS and to explore the genotype-phenotype associations, we conducted a series of clinical examinations, including blood tests, brain MRI scans, ultrasound imaging, and ophthalmologic examination. Genomic DNA was extracted from the peripheral blood of the six-person family, and the pathogenic variants were detected by whole-exome sequencing (WES) and verified by Sanger sequencing. WES revealed two novel compound heterozygous variants in CPLANE1: c.1270C>T (p.Arg424*) in exon 10 and c.8901C>A (p.Tyr2967*) in exon 48 of one child, inherited from each parent. Both variants were absent in ethnically matched Chinese control individuals and were either absent or present at very low frequencies in public databases, suggesting that these variants could be the pathogenic triggers of the JS phenotype. Notably, these CPLANE1 sequence variants were related to the pathogenesis of autosomal recessive JS in this study. The newly discovered variants expand the mutation spectrum of CPLANE1, which assists in understanding the molecular mechanism underlying JS and improving the recognition of genetic counseling, particularly for families with a history of autosomal recessive JS.
Zhu H, Chen W, Ren H, Zhang Y, Niu Y, Wu D, Jiang L. Non-classic splicing mutation in the CPLANE1 (C5orf42) gene cause Joubert syndrome in a fetus with severe craniocerebral dysplasia. Eur J Med Genet. 2021 Jun;64(6):104212. doi: 10.1016/j.ejmg.2021.104212. Epub 2021 Mar 30. PMID: 33794348.
Abstract
Backgroud: Joubert syndrome is a rare neurodevelopmental disorder characterized by clinical and genetic heterogeneity. The characteristic molar tooth sign, which resulted from cerebellar vermis hypoplasia and midbrain anomalies, is expected to be the key diagnostic feature for this disease. However, it is not easy to make a definite diagnosis in prenatal only based on the imageology due to its clinical heterogeneity.
Case report: We report on a fetus who was detected cerebellum dysplasia and encephalocele by ultrasound at 19 and 23 gestational weeks and confirmed by MRI examination. The pregnancy was terminated at 23 weeks of gestation. Postaxial polydactyly and deficiency in occipital bone and skin were identified in the induced fetus.
Results: The whole exome sequencing identified a novel compound heterozygous variation in the CPLANE1 gene related with Joubert syndrome, including a 2-bp insertion, NM_023073.3:c.1383_1384dup; p.(Gly462Glufs*3) and a non-classic splicing variation, NC_000005.10(NM_023073.3):c.7691-5_7691-4del. The pathogenicity of the non-classic splicing variation was further confirmed by cDNA level sequencing, which showed a exon 39 skipping that would introduce a premature termination. The novel compound heterozygous variation caused a complete function loss of the CPLANE1 gene.
Conclusion: The cerebellum dysplasia fetus without obvious molar tooth sign was finally diagnosed as Joubert syndrome, combined with genetic detecting and the postnatal clinical symptoms. We also highlight the clinical heterogeneity of encephalodysplasia in Joubert syndrome, which increases the clinical diagnosis difficulty, especially for prenatal diagnosis. Our findings provided a new perspective for the prenatal diagnosis of Joubert syndrome with severe craniocerebral dysplasia and expanded the variation spectrum of the CPLANE1 gene.
Liu Q, Wang H, Zhao J, Liu Z, Sun D, Yuan A, Luo G, Wei W, Hou M. Four novel compound heterozygous mutations in C5orf42 gene in patients with pure and mild Joubert syndrome. Int J Dev Neurosci. 2020 Oct;80(6):455-463. doi: 10.1002/jdn.10029. Epub 2020 Jul 31. PMID: 32233090.
Abstract
Joubert syndrome (JS) is a rare clinically and genetically heterogeneous disease. Using whole or targeted exome sequencing, we identified four novel compound heterozygous mutations in chromosome 5 open reading frame 42 gene (C5orf42), including c.2876C>T (missense mutation) and c.3921+1G>A (splicing mutation), c.2292 -2delA (splicing mutation) and c.4067C>T (missense mutation), c.6997_6998insT (frameshift mutation) and c.8710C>T (nonsense mutation), c.3981G>C (nonsense mutation) and c.230 _233del (frameshift mutation), in four Chinese JS families. They were all inherited from their heterozygosis parents in the autosomal recessive inheritance mode. Pure JS clinical manifestations and mild neuroimaging findings were found in these patients. These verified the previous findings that C5orf42 mutations generally resulted in a purely neurological Joubert phenotype, and neuroimaging findings were mild in JS with C5orf42 mutations. Our report analyzed these C5orf42 mutations-associated phenotypes and neuroimaging findings in JS and updated the genetic variation spectrum of JS caused by C5orf42.These will help clinicians and geneticists reach a more accurate diagnosis for JS.
Mardani R, Taghizadeh E, Taheri F, Raeisi M, Karimzadeh MR, Rostami D, Ferns GA, Ghayour-Mobarhan M. A novel variant in C5ORF42 gene is associated with Joubert syndrome. Mol Biol Rep. 2020 May;47(5):4099-4103. doi: 10.1007/s11033-020-05465-9. Epub 2020 May 4. PMID: 32367316.
Abstract
Joubert syndrome (JS) disease is a clinically and genetically heterogeneous disorder with mutations in more than 35 genes involved in its pathogenicity. Molecular genetic methods including next generation sequencing (NGS) and Sanger sequencing are effective techniques used for identifying rare genetic variants that have a strong effect on disease pathogenesis. In this study, we tested a large pedigree with a history of several affected members with JS. At first the proband was sequenced by NGS technique then, confirmed by sanger sequencing method. After this, all available members of the pedigree were subjected to molecular analysis by sanger sequencing technique. The results of this study showed a novel variant in the C5ORF42 gene c.3080A > T: p. D1027V leading to a substitution of a valine for aspartic acid (D1027V) and may be associated with JS. This variant was present in proband compatible with autosomal recessive pattern. Also this variant was present in all parents (both father and mother) of affected individuals in a heterozygous state. It seems that mutations in C5ORF42 gene are associated with JS. However, the substantial mechanism requires further investigation.
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