TGDS – Catel-Manzke Syndrome

Multiple independent case reports from diverse studies have established a strong association between TGDS mutations and Catel-Manzke syndrome, a disorder primarily characterized by Pierre‑Robin sequence, specific hand malformations such as clinodactyly, and cardiac defects (PMID:28422407). The clinical reports encompass both prenatal and postnatal presentations, with affected individuals displaying a spectrum of anomalies including talipes, failure to thrive, and in some cases, abnormal heart morphology (PMID:26366375, PMID:31769200).

Genetic evidence indicates an autosomal recessive mode of inheritance, with multiple families demonstrating compound heterozygous or homozygous mutations in TGDS. In several independent studies, roughly 11 probands have been reported where segregating variants were identified, strengthening the gene‑disease correlation (PMID:25480037). Notably, the recurrent variant c.298G>T (p.Ala100Ser) has emerged as a common pathogenic allele among these affected individuals.

The variant spectrum observed in TGDS includes both missense and loss‑of‑function changes, with the recurrent c.298G>T (p.Ala100Ser) variant being highlighted across multiple reports. This variant, which appears in both the abstract and the variant list, exemplifies the mutation types observed in this disorder and reinforces the clinical and molecular consistency across cases (PMID:28422407).

Functional insights into TGDS indicate that a loss‑of‑function mechanism is the likely pathogenic basis for Catel‑Manzke syndrome. While in vitro studies and predicted structural analyses support this hypothesis, robust experimental models and rescue experiments remain limited, leaving some aspects of the functional impact to be fully elucidated (PMID:25480037).

There is minimal conflicting evidence regarding the association; however, one study documented atypical features in a subset of cases, suggesting possible phenotypic overlap with related syndromes. Despite these nuances, the overall evidence from genetic studies remains highly concordant, with recurrent mutations and segregation data reinforcing the role of TGDS in the disease pathogenesis (PMID:31769200).

In summary, robust genetic evidence from multiple independent studies—including the recurrent observation of the c.298G>T (p.Ala100Ser) variant—supports a strong gene‑disease association between TGDS and Catel‑Manzke syndrome. Although additional functional studies are warranted to further validate the pathogenic mechanism, the current data reliably inform diagnostic decision‑making, commercial testing, and future research directions.

References

• American journal of medical genetics. Part A • 2017 • Mutations in TGDS associated with additional malformations of the middle fingers and halluces: Atypical Catel‑Manzke syndrome in a fetus PMID:28422407
• Molecular genetics and metabolism reports • 2015 • Catel‑Manzke Syndrome: Further Delineation of the Phenotype Associated with Pathogenic Variants in TGDS PMID:26366375
• American journal of human genetics • 2014 • Homozygous and compound‑heterozygous mutations in TGDS cause Catel‑Manzke syndrome PMID:25480037
• American journal of medical genetics. Part A • 2020 • TGDS pathogenic variants cause Catel‑Manzke syndrome without hyperphalangy PMID:31769200

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