Characterisation of Type-1 Fibrillinopathies in a Sri Lankan Cohort: Genotype-Phenotype Correlations and Novel FBN1...

Type-1 fibrillinopathies, caused by pathogenic variants in the FBN1 gene, show complex genotype-phenotype correlations. Studying these patterns in under-researched populations like Sri Lanka can provide valuable insights into their genetic basis. The objective of this study was to analyse genotype-phenotype correlations in Sri Lankan patients with type-1 fibrillinopathies.

The genotype and clinical data of all patients undergoing exome sequencing in our centre have been maintained in a database since 2014. In January 2024, this database was searched to identify all patients who were reported to have variants in the FBN1 (NM_000138.5) gene. The genotype and phenotype data of these patients were analysed using bioinformatics tools and standard descriptive statistics.

There were 12 unrelated patients. A total of 6 (50%) were male. Age ranged from 1 to 18 years. All were sporadic and had a distinct heterozygous variant. The phenotype found in these patients together with the associated genotype was as follows: Marfan syndrome - 6 (50%) [c.7487G>C, c.6496G>A, c.4245delT, c.3037G>A, c.2797_2807delTTCAAGTGTCA, c.3472G>A]; MASS syndrome - 5 (41.7%) [c.2926C>T, c.2419G>A, c.5674A>G, c.3338-1G>C, c.3089A>G]; and ectopia lentis syndrome - 1 (8.3%) [c.355T>G]. Four (33.3%) variants were novel. Frameshift and splice-site variants were associated with pronounced skeletal and facial dysmorphic features. However, neonatal region variants did not consistently cause severe disease.

This is the first study to report type-1 fibrillinopathies in the Sri Lankan population. The lack of strong genotype-phenotype correlation suggests the possibility of other genetic modifiers in the Sri Lankan population.