Genetic insights into the 'sandwich fusion' subtype of Klippel-Feil syndrome: novel FGFR2 mutations identified by 21 cases of whole-exome sequencing.

Autor: Xu N; Department of Orthopaedics, Peking University Third Hospital, Haidian District, 49 North Garden Road, Beijing, 100191, China.; Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China.; Beijing Key Laboratory of Spinal Disease Research, Beijing, China., Hung KL; Department of Orthopaedics, Peking University Third Hospital, Haidian District, 49 North Garden Road, Beijing, 100191, China.; Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China.; Beijing Key Laboratory of Spinal Disease Research, Beijing, China., Gong X; Department of Obstetrics and Gynecology, Peking University Third Hospital, Haidian District, 49 North Garden Road, Beijing, 100191, China., Fan D; Department of Orthopaedics, Peking University Third Hospital, Haidian District, 49 North Garden Road, Beijing, 100191, China.; Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China.; Beijing Key Laboratory of Spinal Disease Research, Beijing, China., Tian Y; Department of Orthopaedics, Peking University Third Hospital, Haidian District, 49 North Garden Road, Beijing, 100191, China.; Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China.; Beijing Key Laboratory of Spinal Disease Research, Beijing, China., Yan M; Department of Orthopaedics, Peking University Third Hospital, Haidian District, 49 North Garden Road, Beijing, 100191, China.; Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China.; Beijing Key Laboratory of Spinal Disease Research, Beijing, China., Wei Y; Department of Obstetrics and Gynecology, Peking University Third Hospital, Haidian District, 49 North Garden Road, Beijing, 100191, China. weiyuanbysy@163.com., Wang S; Department of Orthopaedics, Peking University Third Hospital, Haidian District, 49 North Garden Road, Beijing, 100191, China. pkuwsl@126.com.; Engineering Research Center of Bone and Joint Precision Medicine, Beijing, China. pkuwsl@126.com.; Beijing Key Laboratory of Spinal Disease Research, Beijing, China. pkuwsl@126.com.
Jazyk: angličtina
Zdroj: Orphanet journal of rare diseases [Orphanet J Rare Dis] 2024 Apr 01; Vol. 19 (1), pp. 141. Date of Electronic Publication: 2024 Apr 01.
DOI: 10.1186/s13023-024-03134-9
Abstrakt: Background: Klippel-Feil syndrome (KFS) is a rare congenital disorder characterized by the fusion of two or more cervical vertebrae during early prenatal development. This fusion results from a failure of segmentation during the first trimester. Although six genes have previously been associated with KFS, they account for only a small proportion of cases. Among the distinct subtypes of KFS, "sandwich fusion" involving concurrent fusion of C0-1 and C2-3 vertebrae is particularly noteworthy due to its heightened risk for atlantoaxial dislocation. In this study, we aimed to investigate novel candidate mutations in patients with "sandwich fusion."
Methods: We collected and analyzed clinical data from 21 patients diagnosed with "sandwich fusion." Whole-exome sequencing (WES) was performed, followed by rigorous bioinformatics analyses. Our focus was on the six known KFS-related genes (GDF3, GDF6, MEOX1, PAX1, RIPPLY2, and MYO18). Suspicious mutations were subsequently validated through in vitro experiments.
Results: Our investigation revealed two novel exonic mutations in the FGFR2 gene, which had not previously been associated with KFS. Notably, the c.1750A > G variant in Exon 13 of FGFR2 was situated within the tyrosine kinase domain of the protein, in close proximity to several established post-translational modification sites. In vitro experiments demonstrated that this certain mutation significantly impacted the function of FGFR2. Furthermore, we identified four heterozygous candidate variants in two genes (PAX1 and MYO18B) in two patients, with three of these variants predicted to have potential clinical significance directly linked to KFS.
Conclusions: This study encompassed the largest cohort of patients with the unique "sandwich fusion" subtype of KFS and employed WES to explore candidate mutations associated with this condition. Our findings unveiled novel variants in PAX1, MYO18B, and FGFR2 as potential risk mutations specific to this subtype of KFS.
(© 2024. The Author(s).)
Databáze: MEDLINE
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