{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T17:17:07Z","timestamp":1784567827899,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"R25 Education Program in Bioinformatics, Omics, and Computational Biology NIH\/NICHHD","award":["R25Actf HD109116Projectf01A1"],"award-info":[{"award-number":["R25Actf HD109116Projectf01A1"]}]},{"name":"R25 Education Program in Bioinformatics, Omics, and Computational Biology NIH\/NICHHD","award":["1R01 HL153853-01"],"award-info":[{"award-number":["1R01 HL153853-01"]}]},{"name":"UCLA CDI \u201cSeed Award\u201d","award":["R25Actf HD109116Projectf01A1"],"award-info":[{"award-number":["R25Actf HD109116Projectf01A1"]}]},{"name":"UCLA CDI \u201cSeed Award\u201d","award":["1R01 HL153853-01"],"award-info":[{"award-number":["1R01 HL153853-01"]}]},{"name":"UCLA Academic Senate Faculty Research Fund","award":["R25Actf HD109116Projectf01A1"],"award-info":[{"award-number":["R25Actf HD109116Projectf01A1"]}]},{"name":"UCLA Academic Senate Faculty Research Fund","award":["1R01 HL153853-01"],"award-info":[{"award-number":["1R01 HL153853-01"]}]},{"name":"NIH\/NHLBI","award":["R25Actf HD109116Projectf01A1"],"award-info":[{"award-number":["R25Actf HD109116Projectf01A1"]}]},{"name":"NIH\/NHLBI","award":["1R01 HL153853-01"],"award-info":[{"award-number":["1R01 HL153853-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u201330, 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&gt;T and c.8230T&gt;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\u2013genotype 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.<\/jats:p>","DOI":"10.3390\/ijms25105469","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T06:53:49Z","timestamp":1715928829000},"page":"5469","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["High-Throughput Genomics Identify Novel FBN1\/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8748-3604","authenticated-orcid":false,"given":"Gloria","family":"Zodanu","sequence":"first","affiliation":[{"name":"Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7350-407X","authenticated-orcid":false,"given":"John","family":"Hwang","sequence":"additional","affiliation":[{"name":"Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zubin","family":"Mehta","sequence":"additional","affiliation":[{"name":"Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Sisniega","sequence":"additional","affiliation":[{"name":"Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Barsegian","sequence":"additional","affiliation":[{"name":"Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuedong","family":"Kang","sequence":"additional","affiliation":[{"name":"Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reshma","family":"Biniwale","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Sing","family":"Si","sequence":"additional","affiliation":[{"name":"Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Satou","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Halnon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"UCLA Congenital Heart Defect BioCore Faculty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne","family":"Grody","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glen","family":"Van Arsdell","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-4068","authenticated-orcid":false,"given":"Marlin","family":"Touma","sequence":"additional","affiliation":[{"name":"Neonatal Congenital Heart Laboratory, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"},{"name":"Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA"},{"name":"Children\u2019s Discovery and Innovation Institute, University of California, Los Angeles, CA 90095, USA"},{"name":"Eli and Edyth Broad Stem Cell Research Center, University of California, Los Angeles, CA 90095, USA"},{"name":"Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"34605","DOI":"10.1074\/jbc.M303159200","article-title":"Cell Adhesion to Fibrillin-1 Molecules and Microfibrils Is Mediated by \u03b15\u03b21 and \u03b1v\u03b23 Integrins","volume":"278","author":"Bax","year":"2003","journal-title":"J. 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