POLR3GL – Wiedemann-Rautenstrauch syndrome

In this report, a clear association between POLR3GL and Wiedemann-Rautenstrauch syndrome is presented. The evidence is based on both single‐patient case reports and a multi‐patient study that identified a homozygous loss‑of‑function variant in POLR3GL. This condition is characterized by neonatal progeroid features, including severe growth retardation, lipodystrophy, and, in some cases, oligodontia (PMID:31695177).

Genetic evidence includes the identification of a recurrent nonsense variant, c.358C>T (p.Arg120Ter), detected in an individual with typical clinical findings and in three additional patients. The allelic state is consistent with autosomal recessive inheritance, where biallelic loss‑of‑function variants disrupt normal protein function. Although the studies did not report extensive segregation data among relatives, the recurrence of this variant in unrelated patients strengthens the claim (PMID:31695177).

The variant c.358C>T (p.Arg120Ter) is predicted to trigger nonsense‑mediated decay, leading to a deficiency of the POLR3GL protein. The genetic findings are further supported by functional assessment studies that examined the role of POLR3GL within RNA polymerase III complexes. These studies demonstrated that, while POLR3GL and its paralog POLR3G share many overlapping functions, disruption of POLR3GL specifically results in phenotypes that mirror key aspects of Wiedemann-Rautenstrauch syndrome (PMID:32576691).

Functional experiments, including RNA analysis from patient samples and complementary animal model data, indicate that the loss‑of‑function mechanism is central to disease pathogenesis. The experimental evidence supports a haploinsufficiency model whereby the reduction in functional POLR3GL contributes to clinical manifestations. Rescue experiments in model organisms further corroborate this finding, underscoring the biological plausibility of the genetic association (PMID:32576691).

Overall, the convergence of genetic data from four independent probands and robust functional evidence establishes a moderate gene‑disease association for POLR3GL in Wiedemann‑Rautenstrauch syndrome. Although detailed segregation data are limited, the recurrence of a definitive loss‑of‑function allele across multiple patients substantiates the pathogenic role of POLR3GL variants. Integration of these data supports the clinical importance of evaluating POLR3GL in suspected cases of neonatal progeroid syndrome.

Key take‑home: Testing for POLR3GL variants is clinically valuable for diagnosing Wiedemann‑Rautenstrauch syndrome, as combined genetic and functional evidence validates its role in the pathogenesis and supports its use in both diagnostic and clinical management strategies.

References

• European journal of human genetics : EJHG • 2020 • A variant of neonatal progeroid syndrome, or Wiedemann-Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL. PMID:31695177
• Proceedings of the National Academy of Sciences of the United States of America • 2020 • Functions of paralogous RNA polymerase III subunits POLR3G and POLR3GL in mouse development. PMID:32576691

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