ESPE Abstracts

Background: In the vast majority of cases, achondroplasia and hypochondroplasia are attributable to hotspot missense mutations in the FGFR3 gene. 96% of patients have a G(1138)A and 3% have a G(1138)C point mutation. We report on a family whose members have a deep intronic mutation that leads to a novel cryptic splicing variant of the FGFR3 gene, and via this pathway results in new pathogenicity manifesting as achondroplasia.

Case presentation: A family of two affected parents and two children with achondroplasia presented to us for treatment. The parents’ second-born child, a boy with thanatophoric dysplasia, had died previously. Both surviving children, a 7-year-old girl and a 2-year-old boy, were of short stature height standard deviation scores of −6.7 and −7.2 SDS, respectively. The girl also exhibited typical signs of achondroplasia on x-ray imaging. Trio exome sequencing (proband and both parents) of all four family members identified a new de novo intronic variant, c.1075 + 95C>G, in the mother and the two surviving children with achondroplasia-like features. The father was found to have the classic c.1138G>A variant. A recently published case report revealed that the new intronic variant alters mRNA splicing by causing retention of a 90-nucleotide segment of intron 8 in the mRNA, resulting in a 30-amino-acid insertion in the extracellular domain of the protein. The family we studied is the first known family with demonstrated inheritance of this newly described, likely pathogenic splice variant identified in the FGFR3 gene. Based on a recent report on three boys with the de novo c.1075 + 95C>G variant and the first identified example of a two-generation family pedigree as described above, the novel intronic variant is classified as likely pathogenic from a human genetics perspective.

Conclusions: Our genetic studies confirm previously reported results strongly suggesting that c.1075 + 95C>G is a recurrent mutation and should be included in genetic testing for FGFR3 mutations, especially in patients with unclear clinical findings and no identifiable exonic variant. We conclude that genetic testing for achondroplasia requires intronic sequence analysis of exome data, if available. In the absence of such data, or if no intronic disease-causing variant is detected, whole-genome sequencing or other diagnostic methods, such as long-read sequencing, can be useful.

Reference: Xu T, Shi L, Dai W, Gu X, Yu Y, Fan Y. An intronic variant disrupts mRNA splicing and causes FGFR3-related skeletal dysplasia. J Pediatr Endocrinol Metab. 2021;34(10):1323-1328. https://doi.org/10.1515/jpem-2020-0679.