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Description
Background: The metopic, bi-coronal, sagittal, and lambdoid sutures of the human cranium remain patent at different times after birth to allow for cranial growth that accommodates the developing brain. Craniosynostosis occurs when these sutures fuse prematurely, affecting brain development. Around 30% of craniosynostosis cases are syndromic, caused by single gene mutations and rarely by chromosomal anomalies. This study identified variants in FGFR2 and other genes involved in the aetiology of CS in a Ghanaian cohort exhibiting phenotypes characteristic of FGFR2-related syndromes.
Methods: Whole exome sequencing (WES) was conducted on DNA from 8 Ghanaian families, utilising Illumina HiSeq at 100X based on GRCh38. After quality control, alignment of reads and variant calling were conducted employing the Sentieon 202112.01 workflow. VCF files were normalised using bcftools 1.13 and variants were annotated using Ensembl VEP. Variants with MAF ≤ 0.01 were filtered for. Pathogenicity of variants was ascertained using 12 dbNSFP tools, ClinVar and SpliceAI. Genes and variants were prioritised using VarElect and American College of Medical Genetics and Genomics (ACMG) guidelines.
Results and Discussions: A novel FGFR2 variant (c.815_817del;p.Gly272del) was observed in an individual with Crouzon Syndrome. Three other FGFR2 variants (c.1007A>G;p.Asp336Gly, c.1025G>C;p.Cys342Ser, 1024T>G; p.Cys342Gly) were observed in three probands with Crouzon Syndrome. In four probands with Apert Syndrome, three had c.755C>G (p.Ser252Trp), whereas one had c.758C>G (p.Pro253Arg) in FGFR2. Notably, all these variants occurred close to or within the extracellular Ig-like C2-type 3 FGFR2 domain, which directly interacts with fibroblast growth factors and whose alternative splicing is crucial for ligand selectivity. We also observed probable modifier variants in other craniofacial genes, such as ARVCF, VPS8, ATP2C2, CRISPLD2, FRMD7, GJB2, GNPTAB and ATR.
Conclusions: De novo FGFR2 variants cause genetic syndromes presenting with craniosynostosis. Moreover, co-occurring genetic variants may account for the phenotypic variability observed in individuals with Crouzon and Apert syndromes.