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Heterozygous variants in IRF2BPL (HGNC:14282) cause a progressive neurodevelopmental disorder characterized by regression, abnormal movements, loss of speech, and epilepsy, collectively termed NEDAMSS (MONDO:0060759). Affected children present with spasticity, dystonia, ataxia, and cognitive decline in early childhood. Dyskinesia, refractory seizures, and complete loss of expressive language are hallmark features. This condition was first identified via postmortem brain pathology showing DRPLA-like polyglutamine inclusions. Subsequent genetic studies have confirmed de novo truncating and missense IRF2BPL alleles. Inclusion of IRF2BPL in diagnostic gene panels for progressive neurodevelopmental disorders is warranted.
To date, at least 36 unrelated NEDAMSS patients harbor de novo IRF2BPL variants, including loss-of-function and deleterious missense alleles such as c.562C>T (p.Tyr173Ter) (PMID:39031186, PMID:39224955, PMID:38481258). A systematic review identified 32 published cases and one novel patient (PMID:39031186). An Orphanet series added three additional probands with developmental delay and epilepsy (PMID:38481258). All variants meet ACMG criteria for pathogenicity, with truncating mutations predominating. No recurrent or founder alleles have been described, and these variants are absent from large population databases.
NEDAMSS inheritance is autosomal dominant, with nearly all IRF2BPL variants arising de novo and confirmed by trio sequencing. There is minimal evidence for familial transmission, although incomplete penetrance has been suggested by rare asymptomatic adult carriers with late-onset ataxia (PMID:38235039). No consanguineous or recessive cases have been reported. Segregation analysis in affected trios supports a haploinsufficiency mechanism. No additional affected relatives beyond probands have been consistently identified. These data reinforce a dominant-negative or loss-of-function model.
The variant spectrum comprises at least 27 truncating alleles (nonsense and frameshift) and nine missense changes across conserved domains. The recurrent truncating c.562C>T (p.Tyr173Ter) allele resides distal to the polyQ tract. Other missense variants, such as p.Arg391Cys and p.Thr386Met, affect zinc-finger and regulatory motifs. No deep-intronic or structural variants have been reported in NEDAMSS to date. Hypomorphic alleles have not been described, and splice defects appear rare.
Functional studies support IRF2BPL haploinsufficiency. Postmortem brain tissue from an affected child showed decreased IRF2BPL mRNA, protein destabilization, and DRPLA-like polyglutamine inclusions (PMID:39224955). Patient-derived cells exhibit reduced ubiquitinated protein levels and altered IRF2BPL localization (PMID:33278788). Zebrafish irf2bpl crispants display reduced body length and spontaneous ictal-like discharges, recapitulating core human phenotypes (PMID:38481258). These concordant findings in human tissue, cellular assays, and animal models underline a loss-of-function disease mechanism.
There is no conflicting evidence disputing the IRF2BPL–NEDAMSS association. The accumulated genetic and experimental data fulfill ClinGen criteria for a Strong clinical validity classification. IRF2BPL testing is recommended for pediatric patients presenting with early regression, movement disorders, speech loss, and seizures. Future studies should explore therapeutic avenues targeting haploinsufficiency. Key Take-home: Heterozygous IRF2BPL variants cause NEDAMSS via haploinsufficiency, enabling accurate diagnosis and informed management.
Gene–Disease AssociationStrong36 unrelated probands with de novo truncating and missense IRF2BPL variants showing consistent phenotype and functional concordance Genetic EvidenceStrong36 de novo pathogenic IRF2BPL variants in unrelated NEDAMSS patients; de novo enrichment and ACMG criteria met Functional EvidenceModeratePostmortem brain pathology with DRPLA-like inclusions, patient cell assays showing RNA/protein instability, and zebrafish model recapitulating seizures and neurodevelopmental defects |