Genotype variant screening and phenotypic analysis of FBN1 in Chinese patients with isolated ectopia lentis

Abstract

Isolated ectopia lentis (IEL) can lead to blindness as result of severe complications, such as retinal detachment and secondary glaucoma. Pathogenic variants in the fibrillin 1 (FBN1) gene are a common cause of IEL. The aim of the present study was to investigate the frequency of pathogenic FBN1 variants in twelve probands with IEL and to evaluate their associated phenotypes. Systemic clinical examination of the twelve probands indicated that all had bilateral EL with a median age at diagnosis of three years. High myopia was the most common feature among the probands (83.3%; 10/12 cases). No extraocular symptoms (either cardiovascular or skeletal) were observed among these patients. Genomic DNA was extracted from peripheral blood leukocytes from all patients for targeted exome sequencing. Seven heterozygous missense variants in FBN1 were identified by bioinformatics analysis and further verified using Sanger sequencing. The seven variants were all classified as pathogenic after segregation analysis on available family members according to the American College of Medical Genetics and Genomics standards and guidelines. Of the seven variants, three were novel, namely c.2179T>C, c.2496T>G and c.3346G>C. The remaining four, namely c.184C>T, c.367T>C, c.1879C>T and c.4096G>A have been reported in previous studies. The seven pathogenic variants were identified in 8/12 (66.7%) probands with IEL. These results expand the variant spectrum of the FBN1 gene as well as the understanding of the molecular pathogenesis of IEL.

Keywords: ectopia lentis; fibrillin‑1; variant; Marfan syndrome.

Figure 1.

Pedigrees of eight families with fibrillin-1 variants. The filled squares (male) and circles (female) are the affected individuals. The + symbol indicates carriers of the wild-type gene. I and II indicate the generation. F, family; M, mutant.

Figure 2.

Fragment of FBN1 cDNA sequence in probands 5, 6 and 7. Sequencing traces from probands 5, 6 and 7 with the c.2179T>C, c.2496T>G and c.3346G>C variants, respectively. FBN1, fibrillin 1.

Figure 3.

Schematic presentation of FBN1 variants. The position of reported FBN1 variants associated with isolated ectopia lentis from the present study and the literature (29). FBN1, fibrillin 1; EGF, epidermal growth factor; cbEGF, calcium-binding epidermal growth factor; UTR, untranslated region.

Figure 4.

The Anterior segment photography of proband 2 with a heterozygous c. 367T>C (p.Cys123Arg) fibrillin 1 variant. The left panel shows a clear dislocation of the lens, while the right panel shows the elongated lens zonule using slit lamp photography.

Figure 5.

The mutation distributions from different diagnosis ages of MFS and IES patients. Comparison of age at diagnosis (A) and genomic position of the fibrillin 1 variants (B) in patients with Marfan syndrome or isolated ectopia lentis. chr15, chromosome 15.