Genotype-Phenotype Correlation in Children: The Impact of FBN1 Variants on Pediatric Marfan Care

Abstract

Currently, no reliable genotype-phenotype correlation is available for pediatric Marfan patients in everyday clinical practice. We investigated correlations of FBN1 variants with the prevalence and age of onset of Marfan manifestations in childhood and differentiated three groups: missense/in-frame, splice, and nonsense/frameshift variants. In addition, we differentiated missense variants destroying or generating a cysteine (cys-missense) and alterations not affecting cysteine. We categorized 105 FBN1-positive pediatric patients. Patients with cys-missense more frequently developed aortic dilatation (p = 0.03) requiring medication (p = 0.003), tricuspid valve prolapse (p = 0.03), and earlier onset of myopia (p = 0.02) than those with other missense variants. Missense variants correlated with a higher prevalence of ectopia lentis (p = 0.002) and earlier onset of pulmonary artery dilatation (p = 0.03) than nonsense/frameshift, and dural ectasia was more common in the latter (p = 0.005). Pectus excavatum (p = 0.007) appeared more often in patients with splice compared with missense/in-frame variants, while hernia (p = 0.04) appeared earlier in the latter. Findings on genotype-phenotype correlations in Marfan-affected children can improve interdisciplinary therapy. In patients with cys-missense variants, early medical treatment of aortic dilatation seems reasonable and early regular ophthalmologic follow-up essential. Patients with nonsense/frameshift and splice variants require early involvement of orthopedic specialists to support the growing child.

Keywords: FBN1 variant; Marfan syndrome; childhood; genetic testing; genotype–phenotype; variant spectrum.

Figure 1

Flow chart of the patient cohort. We examined 587 children and diagnosed MFS in 202 of them. We performed genetic analysis in 327 patients, among whom 131 were FBN1-positive. A total of 105 patients with a detailed genetic background were included in our analysis.

Figure 2

Type and percentage of FBN1 variants identified in our cohort (n = 105): missense affecting a cysteine residue (cys-missense; blue), missense not affecting a cysteine residue (non-cys-missense; purple), in-frame (pink), nonsense (light red), frameshift (orange), splicing (yellow), entire FBN1 gene deletion (dark blue).

Figure 3

Dural ectasia is more common in patients with nonsense/frameshift than missense/in-frame. Ectopia lentis is more common in patients with missense/in-frame than nonsense/frameshift. Pectus excavatum is more common in patients with splicing than missense/in-frame. More cardiovascular (SV dilatation, dilatation of sinus Valsalva; medication; TVP, tricuspid valve prolapse) in patients with missense variants involving cysteine (cys-missense) than missense variants without cysteine involvement (non-cys missense).

Figure 4

Pulmonary artery (PA) dilatation appears earlier in missense than in nonsense/frameshift variants. Myopia appears earlier in patients with cys-missense than non-cys missense. Hernia appears earlier in patients with missense/in-frame than splicing.