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NSUN5 – Williams syndrome

NSUN5 is one of the genes encompassed in the commonly deleted 7q11.23 region in Williams syndrome (PMID:12073013). Two independent multi‐patient studies have reported that deletions, ranging from the typical 1.5 Mb to atypical sizes involving NSUN5, are observed in patients with Williams syndrome, with one study identifying 31 patients carrying the expected deletion (PMID:31204697). Although these large-scale deletion studies implicate NSUN5 as a component of the contiguous gene deletion responsible for the clinical phenotype of Williams syndrome, no gene‐specific point mutations or clear familial segregation data have been reported. A focused functional study provided additional supportive evidence by demonstrating that NSUN5 haploinsufficiency in patient‐derived fibroblasts leads to a partial loss of 28S ribosomal RNA m5C modification and impaired protein synthesis (PMID:31722427). This functional deficit aligns with aspects of the developmental delay and other features seen in Williams syndrome and adds a mechanistic layer to the genetic findings.

Despite the consistent observation of NSUN5 deletion in Williams syndrome, the evidence remains confounded by its occurrence within a multi‐gene deletion, and isolated genetic disruption of NSUN5 has not been documented. Consequently, while the functional data provide biologically plausible support for its role in modulating ribosomal function, the overall gene‑disease association is currently limited. Key take‑home: Incorporating NSUN5 testing into broader deletion analysis can enhance diagnostic resolution in Williams syndrome, but caution is warranted in assigning pathogenicity to NSUN5 independently.

References

  • Human genetics • 2002 • Identification of additional transcripts in the Williams-Beuren syndrome critical region. PMID:12073013
  • Journal of genetics • 2019 • Williams-Beuren syndrome in Mexican patients confirmed by FISH and assessed by aCGH. PMID:31204697
  • Nucleic acids research • 2019 • Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth. PMID:31722427

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

NSUN5 is consistently deleted in Williams syndrome cases (31 probands [PMID:31204697]; additional transcript identification strengthens its involvement [PMID:12073013]), yet isolated segregation or gene‑specific mutation data are lacking.

Genetic Evidence

Limited

Multi‑patient deletion studies provide genetic evidence via the consistent loss of NSUN5, but the contribution is confounded by contiguous gene deletion effects which limit a higher genetic evidence tier.

Functional Evidence

Moderate

Functional assays in patient‐derived fibroblasts show that NSUN5 haploinsufficiency results in decreased m5C modification and impaired protein synthesis (PMID:31722427), supporting a contributory role in the syndrome.