NSUN2 – Dubowitz syndrome

NSUN2 (HGNC:25994) encodes a conserved RNA cytosine methyltransferase. Dubowitz syndrome is an autosomal recessive disorder characterized by mild microcephaly, growth delay, intellectual disability, eczematoid dermatitis, and peculiar facies. The first molecular cause for this Dubowitz-like phenotype was reported in a consanguineous Emirati family, linking NSUN2 to this clinical spectrum.

Affected individuals from the multiplex family presented with mild microcephaly (HP:0040196), growth retardation (HP:0001510), intellectual disability (HP:0001249), and eczematoid dermatitis (HP:0000964). The inheritance was autosomal recessive, consistent with familial segregation of the phenotype.

Whole-exome sequencing identified a homozygous splice-site mutation c.96+1G>C in NSUN2, abolishing the canonical acceptor site of exon 2 and causing mRNA instability and degradation (PMID:22577224). The variant co-segregated with disease in multiple affected siblings in the consanguineous pedigree, confirming its pathogenicity.

Replication in a larger cohort revealed biallelic NSUN2 variants in 1 of 27 families with Dubowitz-like disease, supporting genetic association of NSUN2 (PMID:33098347). No other recurrent NSUN2 variants were reported among the remaining families, indicating locus heterogeneity.

Functional studies demonstrated complete loss of NSUN2 protein by immunostaining and western blotting, and resultant loss of site-specific 5-cytosine methylation at known tRNA(Asp GTC) targets, establishing a loss-of-function mechanism (PMID:22577224). These assays confirm that NSUN2 deficiency underlies tRNA hypomethylation and Dubowitz syndrome pathogenesis.

Despite extensive locus heterogeneity in Dubowitz syndrome, NSUN2 mutations explain a small subset of cases. The gene–disease link achieves a Moderate level of clinical validity with supportive segregation, replication, and experimental evidence. Key Take-home: Identification of NSUN2 biallelic loss-of-function mutations provides a molecular diagnosis for a subset of Dubowitz syndrome cases and underpins clinical genetic testing and management strategies.

References

• Journal of medical genetics • 2012 • Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. PMID:22577224
• American journal of medical genetics. Part A • 2021 • Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome. PMID:33098347
• American journal of medical genetics. Part C, Seminars in medical genetics • 2018 • Clinical and genetic heterogeneity in Dubowitz syndrome: Implications for diagnosis, management and further research. PMID:30580484

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