Identification of a novel deep intronic variant associated with Joubert syndrome through combined whole-genome sequencing and RNA sequencing.
10.3760/cma.j.cn511374-20250401-00193
- Author:
Fang LIU
1
;
Yan JIANG
;
Xin GUI
;
Yangxue XIAO
;
Xiaohang ZHANG
;
Xuemei ZHANG
;
Yali GAO
Author Information
1. Prenatal Diagnosis Center, Women and Children's Hospital Affiliated to Chongqing Medical University, Chongqing 400014, China. 258351054@qq.com.
- Publication Type:English Abstract
- MeSH:
Female;
Humans;
Pregnancy;
Abnormalities, Multiple/genetics*;
Antigens, Neoplasm/genetics*;
Cell Cycle Proteins/genetics*;
Cerebellum/abnormalities*;
Cytoskeletal Proteins/genetics*;
Eye Abnormalities/genetics*;
Introns/genetics*;
Kidney Diseases, Cystic/diagnosis*;
Pedigree;
Retina/abnormalities*;
Sequence Analysis, RNA/methods*;
Whole Genome Sequencing/methods*;
Child
- From:
Chinese Journal of Medical Genetics
2025;42(5):597-602
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To explore the genetic etiology of a Chinese pedigree with recurrent Joubert syndrome with negative results by whole-exome sequencing in the prior proband.
METHODS:Chinese pedigree which opted elective abortion at the Women and Children's Hospital Affiliated to Chongqing Medical University in December 2024 was selected as the study subject. Whole-genome sequencing was carried out on fetal tissue after termination of pregnancy. Candidate variants were validated by Sanger sequencing and interpreted, while non-coding variant was analyzed using in silico prediction tools. RNA sequencing and cDNA sequencing were conducted on fetal brain tissue. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.2024YL045-02).
RESULTS:Both the fetus and the affected child were found to harbor compound heterozygous variants of the CEP290 gene, namely c.7341dup (p.Leu2448fs*8) (pathogenic, maternally inherited) and c.1523-408G>A (likely pathogenic, paternally inherited). Both in silico analysis and fetal brain RNA sequencing confirmed aberrant RNA splicing caused by the intronic variant.
CONCLUSION:This case has highlighted the value of combining whole-genome sequencing with RNA functional validation. Above results not only enriched the spectrum of CEP290 gene mutations but also underscored its diagnostic value in resolving complex prenatal cases, providing critical clues for the prenatal diagnosis and recurrence risk assessment in genetic counseling.
