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

FGFR3

FGFR3 missense variants (p.Asp513Asn, p.Pro250Arg, p.Asn540Ser, p.Asn540Lys), a gene causing dominant skeletal dysplasias through gain of function

This Chinese multicentre study used targeted next-generation sequencing of FGFR3 in 39,104 newborns to estimate, without ascertainment bias, carrier frequency, variant spectrum and disease prevalence. Four pathogenic or likely pathogenic variants were found in 13 newborns, about 1 in 3008: p.Asp513Asn (8 cases), p.Pro250Arg (3), p.Asn540Ser (1) and p.Asn540Lys (1). The achondroplasia-specific hotspot p.Gly380Arg was absent; estimated prevalence was about 1 in 13,000 for Muenke syndrome and 1 in 19,500 for hypochondroplasia. Telephone follow-up after genetic counselling revealed a broad phenotypic spectrum, from classical skeletal dysplasia to mild or clinically unrecognisable presentations, even among heterozygous carriers of established pathogenic variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The value lies in the population view: in genomic newborn screening, a pathogenic FGFR3 variant does not always predict an overt phenotype, which complicates reporting and counselling. The absence of p.Gly380Arg among live births is attributed by the authors to the effect of prenatal diagnosis on the observed spectrum, a plausible but undemonstrated hypothesis here. Only thirteen carriers and follow-up limited to early telephone interviews: true penetrance remains to be measured.

Analysis by Dr Thibaut Benquey