NSMCE2 is located on chromosome 8q24.13 and encodes a SUMO E3 ligase that functions within the SMC5/6 complex, essential for DNA damage repair, resolution of replication stress, and chromosome stability. It promotes SUMOylation of SMC6, a process enhanced upon DNA damage, linking its activity to the DNA damage response.
Pathogenic variants in NSMCE2 were first reported in two patients with clinical features suggestive of Seckel syndrome, a recessive disorder characterized by poor growth, microcephaly, and intellectual disability, by Payne et al. (2014, PMID: 25105364). Biallelic pathogenic variants in SMC5 that is another cardinal component of SMC5/6 also disrupt NSMCE2 function that was seen in two publications with microcephaly, short stature, and developmental delay due to impaired binding with SMC5, SLF2, and SMC6 (Grange et al, 2022, PMID: 36333305; Zhu et al, PMID: 36627765).
Loss of NSMCE2 results in stalled replication forks, defective double-strand break formation, and chromosomal instability, evidenced by increased micronuclei and nucleoplasmic bridges in fibroblasts. Hydroxyurea treatment exacerbates replication stress, and BrdU pulse-chase experiments in patient-derived lymphoblastoid cell lines reveal impaired S-phase progression. These findings underscore NSMCE2’s critical role in genome maintenance and human developmental disorders.
Two frameshift variants have been reported in humans and the information of four other variants (frameshift, nonsense and exonic deletion) in NSMCE2 is available in the ClinVar database. This gene-disease relationship is supported by biochemical function studies, protein interaction, non-human model organism studies, and functional alteration analysis. (Payne et al. 2014, PMID: 25105364; Atkins 2020, PMID: 33200984; Zhu et al, PMID: 36627765).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date February 5th, 2025 (SOP Version 11).
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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