An intronic variant disrupts mRNA splicing and causes FGFR3-related skeletal dysplasia
Author:
Xu Ting12, Shi Liang12, Dai Weiqian12, Gu Xuefan1, Yu Yongguo123ORCID, Fan Yanjie123
Affiliation:
1. Department of Pediatric Endocrinology and Genetics , Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Institute for Pediatric Research , Shanghai , China 2. Clinical Genetics Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Institute for Pediatric Research , Shanghai , China 3. Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition , 200092 , Shanghai , China
Abstract
Abstract
Objectives
Achondroplasia and hypochondroplasia are the most common forms of disproportionate short stature, of which the vast majority of cases can be attributed to the hotspot missense mutations in the gene FGFR3. Here we presented cases with a novel cryptic splicing variant of FGFR3 gene and aimed to interrogate the variant pathogenicity.
Case presentaiton
In whole exome sequencing of two patients with hypochondroplasia-like features, a de novo intronic variant c.1075 + 95C>G was identified, predicted to alter mRNA splicing. Minigene assay showed that this intronic variant caused retention of a 90-nucleotide segment of intron 8 in mRNA, resulting in a 30-amino acid insertion at the extracellular domain of the protein. This is the first likely pathogenic splicing variant identified in the FGFR3 gene and was detected in one additional patient among 26 genetically unresolved patients.
Conclustions
Our results strongly suggest that c.1075 + 95C>G is a recurrent mutation and should be included in genetic testing of FGFR3 especially for those patients with equivocal clinical findings and no exonic mutations identified.
Publisher
Walter de Gruyter GmbH
Subject
Endocrinology,Endocrinology, Diabetes and Metabolism,Pediatrics, Perinatology, and Child Health
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