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Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings.
Hum Genomics. 2020 Jun 29; 14(1):26.HG

Abstract

BACKGROUND

Joubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem malformation, cerebellar vermis hypoplasia, and consequent "molar tooth sign" (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. Here, we investigated two male siblings with JS and uncovered a novel pathogenesis through combined methods.

RESULTS

The siblings shared similar features of nystagmus, disorders of intellectual development, typical MTS, and abnormal morphology in fourth ventricle. Whole-exome sequencing (WES) and chromosome comparative genomic hybridization (CGH) were then performed on the proband. Strikingly, a maternal inherited nonsense variant (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exons 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: quantitative PCR and PCR sequencing.

CONCLUSIONS

In this study, we first reported a novel causative mechanism of Joubert syndrome: a copy number variation (CNV) combined with a single-nucleotide variant in CEP290 gene, which can be helpful in the genetic diagnosis of this disease.

Authors+Show Affiliations

Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, 610041, China.Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. yingcaishen01@163.com.Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. hongqian.liu@163.com. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, 610041, China. hongqian.liu@163.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32600475

Citation

Wang, Xiang, et al. "Novel Biallelic Loss-of-function Variants in CEP290 Cause Joubert Syndrome in Two Siblings." Human Genomics, vol. 14, no. 1, 2020, p. 26.
Wang X, Zhang Z, Zhang X, et al. Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings. Hum Genomics. 2020;14(1):26.
Wang, X., Zhang, Z., Zhang, X., Shen, Y., & Liu, H. (2020). Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings. Human Genomics, 14(1), 26. https://doi.org/10.1186/s40246-020-00274-4
Wang X, et al. Novel Biallelic Loss-of-function Variants in CEP290 Cause Joubert Syndrome in Two Siblings. Hum Genomics. 2020 Jun 29;14(1):26. PubMed PMID: 32600475.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel biallelic loss-of-function variants in CEP290 cause Joubert syndrome in two siblings. AU - Wang,Xiang, AU - Zhang,Zhu, AU - Zhang,Xueguang, AU - Shen,Ying, AU - Liu,Hongqian, Y1 - 2020/06/29/ PY - 2020/01/09/received PY - 2020/06/11/accepted PY - 2020/7/1/entrez PY - 2020/7/1/pubmed PY - 2020/7/1/medline KW - CGH KW - Compound heterozygous variants KW - Copy number variation KW - Joubert syndrome KW - WES SP - 26 EP - 26 JF - Human genomics JO - Hum. Genomics VL - 14 IS - 1 N2 - BACKGROUND: Joubert syndrome (JS) is a rare genetic disorder, which can be defined by brain stem malformation, cerebellar vermis hypoplasia, and consequent "molar tooth sign" (MTS). JS always shares variety of phenotypes in development defects. With the development of next-generation sequencing, dozens of causative genes have been identified to JS so far. Here, we investigated two male siblings with JS and uncovered a novel pathogenesis through combined methods. RESULTS: The siblings shared similar features of nystagmus, disorders of intellectual development, typical MTS, and abnormal morphology in fourth ventricle. Whole-exome sequencing (WES) and chromosome comparative genomic hybridization (CGH) were then performed on the proband. Strikingly, a maternal inherited nonsense variant (NM_025114.3: c.5953G>T [p.E1985*]) in CEP290 gene and a paternal inherited deletion in 12q21.32 including exons 1 to 10 of CEP290 gene were identified in the two affected siblings. We further confirmed the two variants by in vitro experiments: quantitative PCR and PCR sequencing. CONCLUSIONS: In this study, we first reported a novel causative mechanism of Joubert syndrome: a copy number variation (CNV) combined with a single-nucleotide variant in CEP290 gene, which can be helpful in the genetic diagnosis of this disease. SN - 1479-7364 UR - https://www.unboundmedicine.com/medline/citation/32600475/Novel_biallelic_loss-of-function_variants_in_CEP290_cause_Joubert_syndrome_in_two_siblings L2 - https://humgenomics.biomedcentral.com/articles/10.1186/s40246-020-00274-4 DB - PRIME DP - Unbound Medicine ER -
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