Pathogenicity of NUSAP1 Variants Is Defined by NMD-Escape: Evidence From Two Novel Cases and Systematic Population-Based Variant Analysis.

NUSAP1

De novo nonsense variants in the 3' region of NUSAP1 escaping nonsense-mediated mRNA decay (NMD) and producing an aberrant truncated protein

Protein-truncating variants in the 3' region of a transcript escape nonsense-mediated mRNA decay (NMD) and give rise to aberrant truncated proteins, an underrecognised mechanism in Mendelian disease. The authors report two individuals with heterozygous de novo nonsense variants in the penultimate and last exon of NUSAP1, presenting with early-onset refractory epilepsy, global developmental delay, congenital microcephaly and a recognisable facial gestalt. RNA sequencing performed in one individual showed no reduction in expression, consistent with escape of aberrant transcripts from NMD. Systematic analysis of gnomAD population data delineates a critical 3' region of NUSAP1 where nonsense variants introduce a premature termination codon escaping NMD and are absent from healthy controls, while frameshift variants producing C-terminal elongations appear tolerated.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This is interpretation work more than discovery: it provides a position-dependent rule directly usable for a 3' truncating variant in NUSAP1, where ACMG criteria hesitate between loss of function and uncertain effect. Two cases remain two cases, and RNA sequencing was performed in only one of them; the rule needs testing against further carriers before being applied without reservation. The underlying logic — mapping the NMD-escape region in gnomAD — deserves to be reused gene by gene in exome reanalysis.

Analysis by Dr Thibaut Benquey