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

Gloria K. E. Zodanu; John H. Hwang; Zubin Mehta; Carlos Sisniega; Alexander Barsegian; Xuedong Kang; Reshma Biniwale; Ming-Sing Si; Gary M. Satou; Nancy Halnon; UCLA Congenital Heart Defect BioCore Faculty; Wayne W. Grody; Glen S. Van Arsdell; Stanley F. Nelson; Marlin Touma

doi:10.3390/ijms25105469

International Journal of Molecular Sciences (May 2024)

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

Gloria K. E. Zodanu,
John H. Hwang,
Zubin Mehta,
Carlos Sisniega,
Alexander Barsegian,
Xuedong Kang,
Reshma Biniwale,
Ming-Sing Si,
Gary M. Satou,
Nancy Halnon,
UCLA Congenital Heart Defect BioCore Faculty,
Wayne W. Grody,
Glen S. Van Arsdell,
Stanley F. Nelson,
Marlin Touma

Affiliations

Gloria K. E. Zodanu: Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
John H. Hwang: Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Zubin Mehta: Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Carlos Sisniega: Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Alexander Barsegian: Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Xuedong Kang: Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Reshma Biniwale: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Ming-Sing Si: Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Gary M. Satou: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Nancy Halnon: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
UCLA Congenital Heart Defect BioCore Faculty: Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Wayne W. Grody: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Glen S. Van Arsdell: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Stanley F. Nelson: Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
Marlin Touma: Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA

DOI: https://doi.org/10.3390/ijms25105469
Journal volume & issue: Vol. 25, no. 10
p. 5469

Abstract

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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.

Published in International Journal of Molecular Sciences

ISSN: 1661-6596 (Print); 1422-0067 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General); Science: Chemistry
Website: http://www.mdpi.com/journal/ijms

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