CANT1 – Desbuquois Dysplasia

CANT1, which encodes a calcium‑activated nucleotidase, is firmly implicated in Desbuquois dysplasia, an autosomal recessive skeletal dysplasia marked by severe growth restriction, joint dislocations, and distinct hand anomalies (PMID:20425819). Multiple independent studies across diverse populations have confirmed that pathogenic variants in CANT1 underlie this disorder.

The overall gene–disease association is classified as Strong. At least 23 probands (PMID:20425819) across several unrelated consanguineous families have been reported with confirmed segregation and a consistent clinical phenotype, which collectively support the causative role of CANT1 in Desbuquois dysplasia (PMID:22539336).

Genetic evidence from multiple case reports and series has revealed a diverse variant spectrum including missense, frameshift, splice, and deep‑intronic changes. For example, one representative pathogenic variant is c.902_906dup (p.Ser303fs) (PMID:31587486). Additional studies report several distinct alterations that disrupt protein function, with segregation analyses in extended pedigrees further underscoring autosomal recessive inheritance.

Functional studies have lent critical support to the genetic data. In vitro assays using patient‐derived fibroblasts have demonstrated markedly reduced nucleotidase activity and impaired proteoglycan synthesis, findings that are concordant with the clinical phenotype of Desbuquois dysplasia (PMID:21037275). These experimental results confirm that the identified mutations lead to loss‑of‑function, thereby linking impaired enzymatic activity to disease pathogenesis.

Despite inherent clinical heterogeneity, no study substantially weakens the association between CANT1 and Desbuquois dysplasia. Some variability in the phenotype has been noted among affected individuals; however, this does not detract from its causal role but rather highlights the complexity of genotype–phenotype correlations in skeletal dysplasias.

In summary, the convergence of robust genetic data, clear segregation patterns, and compelling functional evidence consolidates the role of CANT1 in Desbuquois dysplasia. This integrated evidence not only supports diagnostic decision‑making and commercial genetic testing, but also provides a critical framework for future research and publication in the field.

References

• American journal of medical genetics. Part A • 2010 • Mutation of CANT1 causes Desbuquois dysplasia PMID:20425819
• American journal of medical genetics. Part A • 2019 • Prenatal diagnosis of Desbuquois dysplasia Type 1: Utilization of high-density SNP array to map homozygosity and identify the gene PMID:31587486
• International journal of clinical and experimental pathology • 2020 • A novel homozygous variant in CANT1 causes Desbuquois dysplasia type 1 in a Chinese family and review of literatures PMID:32922611
• Human mutation • 2012 • Further delineation of CANT1 phenotypic spectrum and demonstration of its role in proteoglycan synthesis PMID:22539336
• American journal of human genetics • 2009 • Identification of CANT1 mutations in Desbuquois dysplasia PMID:19853239
• Journal of medical genetics • 2011 • CANT1 mutation is also responsible for Desbuquois dysplasia, type 2 and Kim variant PMID:21037275

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