Severe microcephaly

Gene: NSMCE2

Comment on publications: Peduto et al., 2026 paper is now in PubMed: 42661287 so added to list.

Created: 2 Oct 2026, 10:56 a.m. | Last Modified: 2 Oct 2026, 10:56 a.m.

Panel Version: 9.33

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 short stature and primary microcephaly. Taken together, there is enough evidence in literature to promote this gene to Green at the next update.

Created: 3 Sep 2026, 4:13 p.m. | Last Modified: 3 Sep 2026, 4:13 p.m.

Panel Version: 9.27

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.
Functional evidence: in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE.

Additional evidence (Decipher case):
Patient: 573598 - female fetus, comp het for NSMCE2 variants: c.25​del, 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).

Created: 3 Sep 2026, 3:52 p.m. | Last Modified: 3 Sep 2026, 4:07 p.m.

Panel Version: 9.26

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

I don't know

As discussed with the GMS Neurology Specialist Test Group webex call 11thJuly 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Red

Created: 29 Jul 2019, 4:18 p.m. | Last Modified: 29 Jul 2019, 4:18 p.m.

Panel Version: 1.62

Animal model: Payne et al. (2014, PMID: 25105364) knockeddown the NSMCE2 ortholog in zebrafish and produced dwarfism, which was attenuated by re-expression of human wildtype NMSCE2.

Created: 2 Mar 2017, 3:55 p.m.

Only 2 cases: In 2 unrelated women with severe microcephalic dwarfism, marked insulin resistance, and primary gonadal failure (Seckel syndrome-10; MIM:617253), Payne et al. (2014, PMID: 25105364) identified compound heterozygosity for the same 2 frameshift mutations in the NSMCE2 gene.

Created: 20 Feb 2017, 2:53 p.m.