Population-based genomic screening of FGFR3 reveals variant spectrum, disease burden and clinical outcomes in 39,104 newborns.

BACKGROUND

Fibroblast growth factor receptor 3 (FGFR3) mutation is classically known to cause a spectrum of autosomal dominant skeletal dysplasias through gain-of-function mechanisms. However, because most genetic studies are limited to symptomatic individuals or high-risk families, the unbiased variant carrier frequency, variants spectrum, and disease prevalence in newborns remain largely uncharacterized.

METHODS

We performed high-throughput targeted next-generation sequencing of the FGFR3 gene on 39,104 Chinese newborns from a multi-center cohort. Variants were classified according to the American College of Medical Genetics and Genomics guidelines. All newborns carrying pathogenic or likely pathogenic FGFR3 variants received genetic counseling, and telephone follow-up was performed to assess early clinical outcomes.

RESULTS

In total, four distinct variants, including p.Asp513Asn (n = 8), p.Pro250Arg (n = 3), p.Asn540Ser (n = 1), and p.Asn540Lys (n = 1), were identified in 13 newborns, representing an overall frequency of approximately 1 in 3008 (0.332‰). The highly specific achondroplasia-causing hotspot variant p.Gly380Arg was absent. Disease-specific estimates were approximately 1 in 13,000 for Muenke syndrome, and 1 in 19,500 for hypochondroplasia. Follow-up identified a broad phenotypic spectrum, ranging from classical skeletal dysplasia to mild or clinically unrecognizable manifestations, even among heterozygous individuals carrying established pathogenic variants.

CONCLUSIONS

Population-based newborn genomic screening reveals a substantially broader phenotypic spectrum of FGFR3 variants than that observed in clinical patients cohorts. The absence of the classical p.Gly380Arg hotspot among live-born newborns, together with the marked variability observed during follow-up, highlights the influence of prenatal detection on the live-born mutation spectrum and underscores the importance of longitudinal clinical assessment for genotype-positive individuals. These findings provide population-based evidence for variant interpretation, disease burden estimation, genetic counseling, and long-term follow-up strategies for FGFR3-related disorders.