Identification of bi‐allelic LFNG variants in three patients and further clinical and molecular refinement of spondylocostal dysostosis 3

• Published in: Clinical genetics Vol. 104; no. 2; pp. 230 - 237
• Main Authors: Lecca, Mauro, Bedeschi, Maria Francesca, Izzi, Claudia, Dordoni, Chiara, Rinaldi, Berardo, Peluso, Francesca, Caraffi, Stefano Giuseppe, Prefumo, Federico, Signorelli, Marino, Zanzucchi, Matteo, Bione, Silvia, Ghigna, Claudia, Sassi, Silvia, Novelli, Antonio, Valente, Enza Maria, Superti‐Furga, Andrea, Garavelli, Livia, Errichiello, Edoardo
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2023
• Subjects: Abnormalities, Multiple - genetics; Alleles; Dysostosis; exome sequencing; Fetuses; Hernia, Diaphragmatic - genetics; Humans; Infant, Newborn; Intracellular Signaling Peptides and Proteins - genetics; LFNG; Membrane Proteins - genetics; neonatal; Neonates; notch signaling pathway; prenatal; respiratory distress; Segmentation; Signal transduction; Somitogenesis; Spine - abnormalities; splicing; spondylocostal dysostosis; T-Box Domain Proteins - genetics; Vertebrae; LFNG; exome sequencing; prenatal; neonatal; spondylocostal dysostosis; splicing; notch signaling pathway; respiratory distress
• DOI: 10.1111/cge.14336
• ISSN: 0009-9163; 1399-0004

Spondylocostal dysostosis (SCD), a condition characterized by multiple segmentation defects of the vertebrae and rib malformations, is caused by bi‐allelic variants in one of the genes involved in the Notch signaling pathway that tunes the “segmentation clock” of somitogenesis: DLL3, HES7, LFNG, MESP2, RIPPLY2, and TBX6. To date, seven individuals with LFNG variants have been reported in the literature. In this study we describe two newborns and one fetus with SCD, who were found by trio‐based exome sequencing (trio‐ES) to carry homozygous (c.822‐5C>T) or compound heterozygous (c.[863dup];[1063G>A]) and (c.[521G>T];[890T>G]) variants in LFNG. Notably, the c.822‐5C>T change, affecting the polypyrimidine tract of intron 5, is the first non‐coding variant reported in LFNG. This study further refines the clinical and molecular features of spondylocostal dysostosis 3 and adds to the numerous investigations supporting the usefulness of trio‐ES approach in prenatal and neonatal settings. Five unpublished biallelic variants in LFNG, including one non‐exonic affecting the polypyrimidine tract, were identified by trio‐based whole exome sequencing in three subjects (two newborns and one fetus) from three independent pedigrees with definitive diagnosis of spondylocostal dysostosis (SCD; upper panel). All LFNG variants described so far in SCD patients are expected to exert a loss‐of‐function effect, being nonsense/frameshift variants or missense changes affecting the critical Fringe domain (lower panel).