Fetal anomalies
Gene: NSMCE2

NSMCE2 (NSE2/MMS21 homolog, SMC5-SMC6 complex SUMO ligase)
EnsemblGeneIds (GRCh38): ENSG00000156831
EnsemblGeneIds (GRCh37): ENSG00000156831
OMIM: 617246, Gene2Phenotype
NSMCE2 is in 4 panels

1 review

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There are now 3 probands reported in literature (2 with a shared ancestral haplotype) with biallelic frameshift NSMCE2 variants and features consistent with Seckel syndrome 10 (microcephalic primordial dwarfism). There is also a supportive zebrafish model, where nsmce2 knockout resulted in dwarfism - rescued by injection of WT NSMCE2 but not mutant mRNA with patient variants. In addition, a patient reported in Decipher has biallelic NSMCE2 frameshift variants and features consistent with Seckel syndrome, including IUGR and oligohydramnios noted on prenatal scans. Taken together, there is enough evidence in literature to promote this gene to Green at the next update.
Created: 3 Sep 2026, 4:24 p.m. | Last Modified: 3 Sep 2026, 4:24 p.m.

Panel Version: 8.7

https://doi.org/10.1002/ajmg.a.70286 Peduto et al., 2026 - online before print
Study described an 11-year-old French male with compound heterozygous NSMCE2 variants (c.346del, p.Ser116Leufs*18 & c.697_700dupAGGG, p.Ala234Glufs*4) and a phenotype consistent with microcephalic primordial dwarfism / Seckel syndrome 10, including severe pre- and postnatal growth restriction, marked microcephaly, feeding difficulties, characteristic dysmorphic features, dental anomalies, severe insulin resistance with hypertriglyceridemia and hepatic steatosis, primary gonadal failure, renal lithiasis, and skeletal anomalies, including platyspondyly and right-hip osteochondritis. Neuroimaging revealed bifrontal gyral simplification and a cavernous carotid aneurysm. In addition, the proband exhibited a bilateral developmental maculopathy, an ocular feature not previously associated with NSMCE2 deficiency. Pregnancy was complicated by oligohydramnios, early intrauterine growth retardation (IUGR), and cerebral gyration delay. Parents are not consanguineous. Seq method: Exome seq, variants confirmed in trans.
His measurements at birth were: weight 1125 g (−5.61 SD), length 37 cm (−6.98 SD), and occipitofrontal circumference (OFC) 25 cm (−7.06 SD).

PMID: 39184883 Tatiya, Kesri, and Ukey, 2024
14-year-old female patient with clinical diagnosis of 'Seckel syndrome', including microcephaly (head circumference of 36cm at 13 yrs old), but no genetic molecular diagnosis made.

PMID: 25105364 Payne et al., 2014
Report of 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure - comp het for the same 2 frameshift mutations in the NSMCE2 gene. Both families are of European ancestry, and while not immediately related, they had shared common ancestral haplotypes.
Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by re-expression of WT, but not SUMO-ligase–deficient NSMCE.

Additional evidence (Decipher case):
Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25del, p.Ser9GlnfsTer12 & c.697_700dup, p.Ala234GlufsTer4 - confirmed in trans. Clinical features: macrotia, IUGR, oligohydramnios, short stature, primary microcephaly, micrognathia, bilateral clubfoot, abnormal cerebellum morphology, abnormal cerebral cortex morphology, ventriculomegaly. Pregnancy was lost at 34 weeks.

The association between NSMCE2 and AR Seckel syndrome 10 has been classified as Moderate in ClinGen (Feb 2025, Syndromic Disorders GCEP). The gene is also associated with AR Seckel syndrome 10, MIM:617253 in OMIM (accessed 2rd Sept 2026).
Sources: Literature
Created: 3 Sep 2026, 4:22 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Seckel syndrome 10, OMIM:617253; Seckel syndrome, MONDO:0014991

Publications

25105364
https://doi.org/10.1002/ajmg.a.70286

Created: 3 Sep 2026, 4:22 p.m.

Panel version: 8.6

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber
Literature

Phenotypes

Seckel syndrome 10, OMIM:617253
Seckel syndrome, MONDO:0014991

Tags

Q3_26_promote_green

OMIM

617246

Clinvar variants

Variants in NSMCE2

Penetrance

None

Publications

25105364
https://doi.org/10.1002/ajmg.a.70286

Panels with this gene

History Filter Activity

3 Sep 2026, Gel status: 2

Entity classified by Genomics England curator

Ida Ertmanska (Genomics England Curator)

Gene: nsmce2 has been classified as Amber List (Moderate Evidence).

3 Sep 2026, Gel status: 1

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes

Ida Ertmanska (Genomics England Curator)

gene: NSMCE2 was added gene: NSMCE2 was added to Fetal anomalies. Sources: Literature Q3_26_promote_green tags were added to gene: NSMCE2. Mode of inheritance for gene: NSMCE2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NSMCE2 were set to 25105364; https://doi.org/10.1002/ajmg.a.70286 Phenotypes for gene: NSMCE2 were set to Seckel syndrome 10, OMIM:617253; Seckel syndrome, MONDO:0014991 Review for gene: NSMCE2 was set to GREEN

Fetal anomalies Gene: NSMCE2