PRRG4 and WAGR syndrome

PRRG4 has emerged as a candidate gene contributing to the neurobehavioral component of WAGR syndrome. In multiple studies of patients with contiguous deletions at 11p14-p12, PRRG4 was consistently deleted alongside other genes, with affected individuals presenting with intellectual disability and atypical or autistic behaviors (PMID:19096215; PMID:24357251). The comprehensive deletion analyses in these cohorts support its inclusion in the set of genes responsible for the complex phenotype seen in WAGR syndrome.

Genetic evidence arises from two independent studies. One study evaluated 31 patients with deletions including PRRG4 (PMID:19096215), whereas a second study describing interstitial deletion cases further narrowed the responsible region to encompass PRRG4 among other genes (PMID:24357251). Although additional affected relatives with segregating variants were not observed due to the predominance of de novo events, the recurrence of PRRG4 loss in multiple unrelated probands underscores the strength of the association.

The genetic architecture in these cases is consistent with a contiguous gene deletion syndrome with an autosomal dominant, likely de novo, inheritance pattern. Detailed mapping has revealed a representative loss‐of‐function change exemplified by the variant c.772_790del (p.Ser258TrpfsTer39), indicating that haploinsufficiency of PRRG4 may be a driving mechanism for the neurodevelopmental abnormalities observed.

Further supporting this association, the phenotypic spectrum includes intellectual disability (HP:0001249), atypical behavior (HP:0000708), and autistic behavior (HP:0000729). These consistent clinical features across studies help delineate the specific contribution of PRRG4, despite the typical co-deletion of neighboring genes such as WT1 and PAX6.

While the genetic evidence is strong, functional assessment data are limited. No direct functional assays have yet been reported for PRRG4; however, literature reviews and expression profiles allude to a potential dosage-sensitive mechanism, reinforcing the notion that even partial loss of PRRG4 function may lead to the observed neurodevelopmental deficits.

In summary, the integration of multi‐patient deletion studies, representative loss‐of‐function variant data, and consistent clinical findings argue for a strong ClinGen gene‑disease association between PRRG4 and WAGR syndrome. Key take‑home message: Clinicians and diagnostic laboratories should consider the inclusion of PRRG4 analysis in WAGR syndrome evaluations, particularly in patients displaying intellectual disability and autistic features.

References

• Cytogenetic and genome research • 2008 • Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism PMID:19096215
• American journal of medical genetics. Part A • 2014 • Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome PMID:24357251

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