Early onset or syndromic epilepsy

Gene: NUSAP1

Green List (high evidence)

Comment on list classification: 4 patients with de novo truncating NMD-escaping variants and consistent phenotype reported. Sufficient evidence to promote to Green at the next GMS panel update.

Created: 29 Oct 2026, 2:32 p.m. | Last Modified: 29 Oct 2026, 2:32 p.m.

Panel Version: 9.94

Nonsense-mediated decay (NMD)-escaping truncating variants in NUSAP1 are associated with a syndromic neurodevelopmental phenotype characterised by congenital microcephaly, profound developmental impairment, neonatal-onset refractory epilepsy, and structural brain malformations.

Mo et al., 2023 (PMID 37005340). A de novo NUSAP1 variant, c.1209C>A, p.(Tyr403Ter), was identified by trio exome sequencing in two unrelated probands. Both had severe congenital microcephaly (<1st centile and <5th centile), severe/profound developmental delay, neonatal-onset refractory epilepsy, complex structural brain malformations, and hypotonia. Transcript studies suggested NMD-escape. Both cases were characterised by fetal anomalies on prenatal USS (microcephaly, agenesis of the CC, small hindbrain in individual II‐2 and microcephaly, inter‐hemispheric cyst in individual II‐1).

Jacob et al., 2026 (PMID 42706591): Trio exome and genome sequencing in two probands, ID#1 and ID#2, identified de novo heterozygous truncating variants in NUSAP1: c.1264C>T, p.(Arg422Ter), and c.1213C>T p.(Gln405Ter), respectively. Seizures began on the first day of life in ID#1 and on day 8 of life in ID#2; congenital microcephaly was also noted (<1st percentile in ID#1). Additional shared features included developmental delay, profound intellectual disability, and variable structural abnormalities on brain MRI. Both cases where characterised by abnormal fetal USS (intrauterine growth restriction and oligohydramnios in ID#1, and microcephaly and ventriculomegaly in ID#2).
The authors also reported unchanged NUSAP1 expression by RNA sequencing in one affected individual. They delineated a critical region at the 3′ end of NUSAP1, where nonsense variants introduce a premature termination codon and escape NMD. Such variants are absent from healthy controls (gnomAD), whereas frameshift variants producing C-terminal elongations appear tolerated, consistent with gene-level nonsense constraint (https://www.deciphergenomics.org/gene/NUSAP1/overview/protein-genomic-info)

Four unrelated affected individuals are reported (with three distinct de novo NMD-escaping truncating variants) and a consistent phenotype including severe-profound developmental impairment and intellectual disability, epilepsy, severe microcephaly, and structural brain anomalies. A green rating is recommended for intellectual disability, early onset or syndromic epilepsy, severe microcephaly, and fetal anomalies panels at the next GMS panel update.

NUSAP1 is not currently associated with any disease/ phenotype in OMIM, Gene2Phenotype, ClinGen (10/2026).
Sources: Literature

Created: 29 Oct 2026, 2:09 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
microcephaly(MONDO:0001149); neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities(MONDO:0030063)

Publications

• 37005340
• 42706591

Mode of pathogenicity
Other