Mother and Daughter Carrying of the Same Pathogenic Variant in FGFR2 with Discordant Phenotype

Area of Science:

• Genetics
• Molecular Biology
• Medical Genetics

Background:

• Craniosynostosis encompasses genetic disorders marked by premature fusion of skull bones, with Crouzon, Apert, and Pfeiffer syndromes being common examples.
• Fibroblast growth factor receptor 2 (FGFR2), encoded by a gene on chromosome 10, is a key gene implicated in these autosomal dominant conditions, often exhibiting incomplete penetrance.

Observation:

• A report details an FGFR2 gene variant in a mother and daughter with Crouzon syndrome, displaying discordant clinical phenotypes.
• The daughter exhibited more severe facial and oral cavity manifestations than her mother.

Findings:

• A specific c.1032G>A transition in FGFR2 exon 8, previously noted as a synonymous variant, was found to activate a novel splice site.
• This activation resulted in a 51-nucleotide deletion, leading to the in-frame removal of 17 amino acids and reduced FGFR2 transcriptional and translational levels in the more severely affected daughter.

Implications:

• The identified FGFR2 variant and its downstream effects on gene expression and protein levels offer insights into the variable expressivity of Crouzon syndrome.
• Functional assays and molecular modeling provide a deeper understanding of the molecular mechanisms underlying phenotypic discordance in genetic conditions.