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This summary integrates multiple lines of evidence that support the association between LFNG and spondylocostal dysostosis. LFNG encodes a glycosyltransferase essential for proper Notch signaling, and perturbations in its function have been implicated in disrupted somite formation and vertebral segmentation. The clinical phenotype comprises multiple vertebral and rib malformations that are characteristic of spondylocostal dysostosis. The reproducible findings across diverse populations and methodologies reinforce the gene–disease link for diagnostic and clinical purposes. Biomolecular studies further underscore a loss-of-function mechanism predisposing to the condition. The review of available studies highlights that the genetic disruption of LFNG has significant implications for both prenatal and postnatal diagnostic evaluation.
In the case report by a Japanese group, a patient with spondylocostal dysostosis was identified as a compound heterozygote harboring a frameshift and a missense variant. One of these variants, c.601G>A (p.Asp201Asn), was confirmed to impair the glycosyltransferase activity by in vitro enzymatic assays (PMID:30531807). This study provided robust evidence by demonstrating that the missense change affecting the conserved DxD motif leads to loss of enzyme function, which is directly linked to the disrupted segmentation process.
A subsequent case series expanded the genetic evidence by reporting bi-allelic LFNG variants in three additional patients, including cases with homozygous and compound heterozygous mutations. These reports consistently observed similar clinical manifestations and demonstrated familial segregation of the variants, thereby strengthening the gene–disease correlation (PMID:37038048). The collective data from these independent investigations emphasize that LFNG mutations are recurrent in spondylocostal dysostosis and that their pathogenicity is supported by both genetic and segregation analyses.
The variant spectrum reported in these studies encompasses missense changes, small deletions, splice-region alterations, and non-coding variants. The use of the variant c.601G>A (p.Asp201Asn) in the summary reflects a prototypical example where a complete coding change with both nucleotide and protein level descriptions was identified. This variant, along with others in the spectrum, has been found in a compound heterozygous state and has been linked unequivocally to the clinical phenotype, consistent with a loss-of-function mechanism (PMID:30531807).
Functional and experimental studies have further solidified the pathogenic role of LFNG in spondylocostal dysostosis. In vitro assays examining LFNG enzyme activity demonstrated that disease-associated variants lead to mislocalization and loss of function. Complementary evidence from animal models and cell-based systems indicates that disruptions of the Notch signaling pathway mirror the skeletal defects observed in patients (PMID:16385447). These studies provide a mechanistic basis for understanding how LFNG mutations contribute to abnormal somitogenesis and subsequent vertebral malformations in affected individuals.
In conclusion, converging evidence from genetic, segregation, and functional studies robustly supports a strong association between LFNG and spondylocostal dysostosis. Although additional studies may further refine the genotype–phenotype correlations, the current data exceed ClinGen scoring thresholds and offer clear diagnostic utility. Key take‑home message: LFNG mutation testing should be considered in patients with vertebral segmentation defects as it has direct implications for molecular diagnosis and targeted management of spondylocostal dysostosis.
Gene–Disease AssociationStrongCompound heterozygous and homozygous LFNG variants have been identified in at least 7 probands across multiple studies with robust segregation evidence and consistent functional deficits confirmed by enzymatic assays (PMID:30531807, PMID:37038048). Genetic EvidenceStrongVariants including c.601G>A (p.Asp201Asn) and other frameshift and non‑coding mutations have been reported in disparate families, with evidence of pathogenicity through loss‑of‑function mechanisms and familial segregation (PMID:30531807, PMID:37038048). Functional EvidenceModerateFunctional assays demonstrate loss of LFNG enzyme activity and disrupted Notch signaling, supporting its role in the pathogenesis of spondylocostal dysostosis (PMID:16385447). |