NSUN2 was first reported in relation to autosomal recessive syndromic intellectual disability in 2012 (Abbasi-Moheb et al., PMID: 22541559; Khan et al., PMID: 22541562; Martinez et al., PMID: 22577224). The clinical presentation includes global developmental delay, intellectual disability, microcephaly, short stature, delayed puberty, infertility, dysmorphic facial features and a wide-range of ocular-related abnormalities.
Twelve NSUN2 variants (splice site, nonsense, frameshift, missense) that have been reported in 11 probands are included in this curation. Variants in this gene segregated with disease in 14 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Both consanguineous and non-consanguineous families from different ethnicities have been reported. The mechanism for disease is biallelic loss of function.
Of note, an individual with a homozygous frameshift variant in NSUN2, scored here, was described as having facial features reminiscent of Noonan syndrome (PMID: 24102521). This assertion was assessed separately by the ClinGen RASopathy Gene Curation Expert Panel and the relationship between NSUN2 and RASopathies was disputed.
NSUN2 encodes an RNA methyltransferase that modifies transfer RNAs crucial for protein synthesis. Experimental evidence supporting this gene-disease relationship includes knockout models in mice (PMIDs: 22144916, 25063673, 3438972) and drosophila (PMID: 22541559).
In summary, there is definitive evidence to support the relationship between NSUN2 and syndromic intellectual disability. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 6, 2019. It was re-evaluated on October 18, 2023. As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of new literature (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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