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Paediatric disorders - additional genes v8.17 NSMCE2 Ida Ertmanska Tag Q3_26_expert_review was removed from gene: NSMCE2.
Paediatric disorders - additional genes v8.17 NSMCE2 Ida Ertmanska changed review comment from: Comment on list classification: 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. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels (not on R27).; to: Comment on list classification: 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.
Paediatric disorders - additional genes v8.17 NSMCE2 Ida Ertmanska changed review comment from: Comment on list classification: 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. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels (not on R27).; to: Comment on list classification: 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. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels (not on R27).
Paediatric disorders - additional genes v8.17 NSMCE2 Ida Ertmanska changed review comment from: Comment on list classification: 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. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels.; to: Comment on list classification: 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. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels (not on R27).
Paediatric disorders - additional genes v8.17 NSMCE2 Ida Ertmanska changed review comment from: Comment on list classification: 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.; to: Comment on list classification: 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. An expert_review tag was added to get expert opinion on whether this is the best R27 panel fit for this gene, or if Skeletal dysplasia might be more appropriate. The gene is already proposed Green for Severe microcephaly and Fetal anomalies panels.
Paediatric disorders - additional genes v8.17 NSMCE2 Ida Ertmanska Classified gene: NSMCE2 as Amber List (moderate evidence)
Paediatric disorders - additional genes v8.17 NSMCE2 Ida Ertmanska Added comment: Comment on list classification: 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.
Paediatric disorders - additional genes v8.17 NSMCE2 Ida Ertmanska Gene: nsmce2 has been classified as Amber List (Moderate Evidence).
Paediatric disorders - additional genes v8.16 NSMCE2 Ida Ertmanska Publications for gene: NSMCE2 were set to 25105364; https://doi.org/10.1002/ajmg.a.70286
Paediatric disorders - additional genes v8.15 NSMCE2 Ida Ertmanska changed review comment from: 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).
Sources: Literature; to: PMID:42661287 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).
Sources: Literature
Paediatric disorders - additional genes v8.15 NSMCE2 Ida Ertmanska edited their review of gene: NSMCE2: Changed publications to: 25105364, 42661287
Paediatric disorders - additional genes v8.15 NSMCE2 Ida Ertmanska gene: NSMCE2 was added
gene: NSMCE2 was added to Paediatric disorders - additional genes. Sources: Literature
Q3_26_expert_review, 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
Added comment: 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).
Sources: Literature