Using patient-derived iPSCs and multi-omics profiling, it is demonstrated that early-truncating variants cause loss-of-function via nonsense-mediated decay (NMD), while late-truncating variants that escape NMD cause gain-of-function effects.
Abstract
Arboleda-Tham Syndrome (ARTHS), caused by truncating variants in KAT6A, is currently diagnosed as a single neurodevelopmental syndrome with variable severity of intellectual disability and multi-system findings. Here, we reveal that this clinical stratification reflects fundamentally distinct molecular mechanisms driven by variant position in the gene. Using patient-derived iPSCs and multi-omics profiling, we demonstrate that early-truncating variants (exons 1-15) cause loss-of-function via nonsense-mediated decay (NMD), while late-truncating variants (exons 16-17) that escape NMD cause gain-of-function effects. These opposite mechanisms are reflected in distinctive facial gestalt features and DNA-methylation episignatures and invert the direction of change across neuronal gene regulation, metabolism, and mitochondrial physiology. This mechanistic distinction enables precision therapeutics: late-truncating variants are amenable to KAT6A inhibition, while early-truncating variants require loss-of-function rescue. Variant-level stratification is therefore essential: mechanistic understanding, not gene-level diagnosis alone, is prerequisite for developing rational therapeutic strategies in rare Mendelian disease.
An integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.
Marina Boon, Meghan R. Mulligan, Jolijn J A Verseput et al.· American Journal of Human Ge...· 0 citations
PPP1R21-related neurodevelopmental disorder (PPP1R21-NDD) is an ultra-rare autosomal-recessive encephalopathy caused by dysfunction of the Five-subunit Endosomal Rab5 and RNA/ribosome intermediarY (FERRY) complex. To delineate the clinical, neuroimaging, and molecular spectrum of PPP1R21-NDD and outline diagnostic and research priorities. Targeted searches of PubMed, EMBASE, Scopus, Web of Science, and Google Scholar through January 2026 were performed. Eligible reports included molecularly confirmed biallelic PPP1R21 cases and related functional studies. Two researchers independently extracted individual-level data following narrative review quality criteria. Twenty-five individuals from 21 families harbored 17 distinct variants (15 loss-of-function, 2 missense), all homozygous, reflecting high consanguinity. Profound global developmental delay/intellectual disability was universal; hypotonia near-universal (22/25, 88%). Ambulation was delayed and ataxic when achieved; expressive language was minimal or absent. A recognizable coarse facial gestalt was observed with thick eyebrows, broad nasal bridge, thick lips, and low-set ears. Systemic features included feeding dysfunction and respiratory morbidity requiring gastrostomy or tracheostomy in severe cases. Mortality was 17% (4/24). Neuroimaging showed callosal thinning, white-matter volume loss, ventricular enlargement, and vermian hypoplasia. Patient fibroblasts showed delayed transferrin clearance and elevated proteasome activity, suggesting endosomal dysfunction and proteasome hyperactivation. PPP1R21-NDD is a severe recessive encephalopathy with a convergent phenotype and evidence of endo-lysosomal dysfunction. Diagnosis should be pursued with exome or genome sequencing in patients with characteristic clinical and neuroimaging features, particularly in consanguineous families. Research priorities include natural history studies, standardized magnetic resonance imaging (MRI) protocols, neural disease models, and therapeutic strategies targeting endosomal trafficking.
F. Comisi, G. Di Pasquale, A. Comisi et al.· Neurogenetics· 0 citations
A case series of an additional 13 affected individuals with RNF13 variants (2 missense, 11 truncating) supports and broadens previous reports and helps to define a narrow but critical region of the protein that is intolerant to truncating variation, although the gene is not highly constrained.
D. Latner, S. Hiatt, C. Finnila et al.· American Journal of Medical...· 0 citations
ASXL3 patient truncations in neurodevelopmental condition Bainbridge-Ropers syndrome are shown to mediates gain-of-function (GOF) by escaping nonsense-mediated decay and Cullin 4-dependent degradation, resulting in aberrant protein accumulation, widespread transcriptional dysregulation, and altered chromatin accessibility.
Y. Nakamura, T. Nguyen, N. Mor et al.· medRxiv· 0 citations
Findings provide strong genetic and functional evidence for a disease-causing role of NEK1 kinase disruption in NEK1-ALS and provide immediate diagnostic and therapeutic implications, particularly for the functional interpretation of missense variants of uncertain significance and the development of targeted treatment strategies.
David Brenner, Anna Ponomarenko, Iris Petrut et al.· Acta Neuropathologica Commun...· 1 citation
These findings establish DLG4 haploinsufficiency as a shared consequence of pathogenic DLG4 variants, while revealing additional variant-associated effects on neuronal structure and activity, rescued by AAV9-mediated neuronal restoration.
Dania Abdellatif, Mustafa Obeid, Rami I. Aqeilan· bioRxiv· 0 citations