DLL3 and Spondylocostal Dysostosis

DLL3 has been implicated in spondylocostal dysostosis, a disorder characterized by vertebral segmentation defects, short-trunk short stature, and rib anomalies. Multiple independent studies—including single‐case reports and cohort analyses—have established a reproducible association between pathogenic variants in DLL3 and the clinical phenotype of spondylocostal dysostosis (PMID:33082787, PMID:10742114).

The overall clinical validity of this gene–disease relationship is evaluated as strong. Several studies have reported deleterious variants in DLL3 across genetically unrelated individuals and families, with evidence of autosomal recessive inheritance. For example, one study identified a novel homozygous nonsense variant, c.535G>T (p.Glu179Ter), in a consanguineous Pakistani family (PMID:37323197). Additional reports, including clusters of affected relatives (with up to 8 affected individuals in one study (PMID:12791036)) and multi‐patient cohort studies, consolidate the gene–disease association.

Genetic evidence shows a clear pattern of loss‐of‑function mutations in DLL3. Cases include multiple truncating variants and frameshift mutations, with the recurrent identification of variants such as c.535G>T (p.Glu179Ter) supporting a deleterious mechanism. The segregation of these variants in families with an autosomal recessive pattern further strengthens their pathogenic role (PMID:10742114).

In addition to the genetic findings, segregation analysis across different families has revealed that additional affected relatives consistently harbor the mutant allele. The presence of up to 8 additional affected relatives in some families underscores the robust inheritance pattern of the disease (PMID:12791036).

Functional and experimental studies provide moderate but consistent evidence of the pathogenic mechanism. Animal models and in vitro assays have demonstrated that loss of DLL3 function leads to disruption of Notch signaling and perturbed somitogenesis, phenomena that mirror the axial skeletal defects seen clinically in spondylocostal dysostosis (PMID:11923214, PMID:16385447).

In conclusion, the integration of multiple independent case reports, segregation analyses, and functional experiments confirms that pathogenic variants in DLL3 are strongly associated with spondylocostal dysostosis. This comprehensive evidence supports its utility in diagnostic decision‑making, genetic counseling, and carrier testing, and highlights the clinical value of incorporating DLL3 variant analysis into screening protocols.

References

• Case reports in medicine • 2020 • Spondylocostal Dysplasia in a 7-Year-Old Sri Lankan Girl Causing Restrictive Lung Disease: A Case Report and Review of the Literature PMID:33082787
• Molecular syndromology • 2023 • Identification of a Novel Nonsense Variant in the DLL3 Gene Underlying Spondylocostal Dysostosis in a Consanguineous Pakistani Family PMID:37323197
• Nature Genetics • 2000 • Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis PMID:10742114
• Clinical Genetics • 2003 • A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village PMID:12791036
• Development (Cambridge, England) • 2002 • Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm PMID:11923214
• American Journal of Human Genetics • 2006 • Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype PMID:16385447

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