PUS3 – Neurodevelopmental Disorder

This summary reviews the association between pathogenic variants in PUS3 (HGNC:25461) and neurodevelopmental disorder (MONDO:0700092), a condition characterized by intellectual disability and developmental delay. Multiple independent studies provide compelling evidence for an autosomal recessive inheritance pattern, with affected individuals frequently presenting with intellectual disability, microcephaly, seizures, hypotonia, and global developmental delay (PMID:32056211).

In a large multi-patient investigation of 103 families, a homozygous frameshift variant was identified in two affected sisters, thereby initiating the evidence base for PUS3-associated neurodevelopmental disorder (PMID:32056211). Subsequent work expanded on these findings by delineating the clinical features in 21 individuals harboring biallelic PUS3 variants; the study reported several variant classes including nonsense, frameshift, and missense changes that segregated with disease (PMID:34415064).

A key genetic finding supporting the association is the recurrent identification of the variant c.838C>T (p.Arg280Ter) across unrelated probands. This, in combination with other pathogenic variants, underpins the strong genetic evidence for loss-of-function mechanisms driving the neurodevelopmental phenotype (PMID:32056211, PMID:34415064).

Further reinforcing the causality, functional studies have demonstrated that pathogenic variants in PUS3 compromise protein stability and reduce pseudouridylation of tRNA. In patient-derived cells and experimental systems, these functional impairments correspond well with the clinical manifestations observed in affected individuals (PMID:36125428, PMID:28134782).

The combined genetic and functional data provide a coherent narrative: multiple variant types, clear autosomal recessive segregation (including affected siblings), and experimental validation together support a strong gene-disease association. Although additional supporting data exist beyond the scoring maximum, the current evidence robustly underpins the use of PUS3 for diagnostic decision‑making, commercial genetic testing, and future research publications.

Key Take‑home: Biallelic loss‑of‑function variants in PUS3 represent a strong and clinically actionable cause of neurodevelopmental disorder.

References

• Clinical Genetics • 2020 • Genetic basis of neurodevelopmental disorders in 103 Jordanian families PMID:32056211
• Clinical Genetics • 2021 • Clinical and molecular delineation of PUS3-associated neurodevelopmental disorders PMID:34415064
• Human Mutation • 2022 • Destabilization of mutated human PUS3 protein causes intellectual disability PMID:36125428
• Biomolecules • 2017 • Role of Pseudouridine Formation by Deg1 for Functionality of Two Glutamine Isoacceptor tRNAs PMID:28134782

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