TMEM199 and TMEM199-CDG

TMEM199-CDG is an ultra‐rare congenital disorder of glycosylation characterized by a non‐encephalopathic chronic liver phenotype. Multiple independent studies have provided both genetic and functional evidence that the TMEM199 gene is associated with TMEM199-CDG (PMID:36706865) and support its clinical relevance for diagnostic decision‑making.

Clinical observations include a total of eight probands reported in one study (PMID:36706865) and three additional patients in another (PMID:29321044). In several families, segregation analysis revealed that affected relatives (including a sibling pair) carried the same pathogenic variants, underscoring an autosomal recessive inheritance pattern and strengthening the genetic association.

Genetic evidence is robust with the recurrent observation of the missense variant c.92G>C (p.Arg31Pro) in 4 out of 7 families (PMID:36706865). Additional variants, including frameshift (e.g. c.13_14del resulting in p.Leu5fs) and splicing variants (c.211+1G>A), have been reported, further supporting the deleterious role of TMEM199 deficiency in this disorder.

Detailed variant analysis confirms that the c.92G>C (p.Arg31Pro) allele is consistently identified in patients from Mediterranean populations, with a striking prevalence in southern Italy and Greece. This recurrent finding is highly suggestive of a founder effect in this region and provides a useful molecular diagnostic marker.

Functional studies have demonstrated abnormal N- and O-protein glycosylation and reduced TMEM199 protein levels in patient fibroblasts. These results, in turn, indicate a defect in Golgi homeostasis that is consistent with the clinical presentation and lend moderate support to the pathogenic mechanism of TMEM199 variants (PMID:36706865).

In summary, the integration of strong genetic findings with supportive functional experimentation provides a coherent narrative for a strong gene-disease association between TMEM199 and TMEM199-CDG. This evidence not only informs diagnostic evaluation and clinical management but also emphasizes the utility of genetic testing in patients with isolated liver disease, particularly in populations from the southern Mediterranean area.

References

• European Journal of Medical Genetics • 2023 • Higher frequency of TMEM199-CDG in the southern mediterranean area is associated with c.92G>C (p.Arg31Pro) mutation PMID:36706865
• Orphanet Journal of Rare Diseases • 2018 • Three unreported cases of TMEM199-CDG, a rare genetic liver disease with abnormal glycosylation PMID:29321044

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