High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects

Abstract

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

Keywords: Marfan syndrome (MFS); congenital contractural arachnodactyly (CAA); dextro-transposition of the great arteries (D-TGA); neonatal Marfan syndrome (nMFS); whole-exome sequencing (WES); whole-genome SNP microarray.

Figure 1

Schematic illustration of FBN1 and protein structure domains. The FBN1 gene is located on chromosome 15q21.1. The coding sequence consists of 65 exons. The hotspot neonatal region encodes a series of cbEGF-like domains. The cbEGF-like domain: homologous to calcium-binding epidermal growth factor; TGFβ-like domain: homologous to those in latent transforming growth factor beta; EGF-like domain: homologous to epidermal growth factor.

Figure 2

Schematic illustration of FBN2 and protein structure domains. The FBN2 gene is located on chromosome 5q23.3. The coding sequence consists of over 65 exons. The congenital contractural arachnodactyly region encodes a series of cbEGF-like and TGFβ-like domains.

Figure 3

Clinical features of proband A suggesting neonatal Marfan syndrome. (A,B) Representative photographs of proband A face (A) showing and extremities (B). (C) Representative chest X-ray on day of life 2 (DOL2) showing cardiomegaly and abnormal rib cage. (D) Representative echocardiography images on DOL 2. (I) Parasternal long axis view showing dilated aortic root (Z-score: +5.7); (II) normal left aortic arch with normal pattern branching; (III) Color Doppler (CD) interrogation across the tricuspid valve (TV) showing tricuspid regurgitation; (IV) CD interrogation across the aortic valve showing mild aortic insufficiency; and (V) CD interrogation across the mitral valve (MV) showing mild eccentric MV regurgitation, a feature commonly seen in dysplastic valves. Also, refer to supplemental Video S1. (E) Representative kidney ultrasound images on DOL 2. (I) Left kidney hydronephrosis SFU grade 3; (II) right kidney.

Figure 4

Summary of clinical time course of proband A. Graphs depict clinical parameters throughout the hospital course including the average values of partial pressure of oxygen in the arterial blood (avg PaO2), the average values of mean arterial pressure (Avg MAP), and the peak tricuspid regurgitation (TR) pressure gradient measured on serial echocardiography. x-axis: day of life. y-axis: measurement absolute value. The text boxes depict important clinical events and treatment interventions over time. CPAP, SIMV, HFOV: different modalities of mechanical respiratory support; pRBC: packed red blood cells.

Figure 5

Clinical features of proband B. (A) Representative chest X-ray on day of life 0 (DOL 0) showing cardiomegaly. L: Left. (B) Representative echocardiography images on DOL 0. (I) Color Doppler image across the intra-atrial communication after atrial balloon septoplasty; (II) Color Doppler image showing patent ductus arteriosus. (C) Representative echocardiography images on DOL 6. (I,II) Color Doppler images across the tricuspid valve (I) and the mitral valve (II); (III) Color Doppler image of aortic arch after arterial switch operation; (IV) B-mode and color doppler images of branch pulmonary arteries after arterial switch operation.