Biallelic SUPT4H1 variants cause a multisystem neurodevelopmental disorder associated with disrupted transcription

We aimed to define the clinical and genetic basis of an autosomal recessive neurodevelopmental disorder identified in 3 unrelated families with an overlapping multisystem phenotype.

Exome or genome sequencing was performed in 6 affected individuals from 3 families, revealing biallelic variants in SUPT4H1. Functional effects were evaluated using CRISPR and RNAi knockdown in C. elegans. Transcriptomic and proteomic profiling were conducted on patient-derived fibroblasts. Phylogenetic profiling assessed evolutionary conservation and coevolution. Dopamine response was evaluated in 2 affected siblings.

All individuals carried biallelic SUPT4H1 variants-1 frameshift and 2 missense variants. Shared features included intellectual disability, dystonia, speech impairment, craniofacial dysmorphism, skeletal anomalies, and enamel hypoplasia. Functional modeling in C. elegans confirmed pathogenicity through neuromotor deficits. Multiomics analyses revealed dysregulation of developmental gene networks and the transcriptional machinery with disrupted RNA polymerase complexes and cell-cycle regulators. Dopamine treatment improved motor symptoms and normalized cerebrospinal neurotransmitter levels in 2 siblings.

Biallelic variants in SUPT4H1 cause a previously unrecognized multisystem neurodevelopmental disorder. These findings underscore the importance of disrupted transcription in human disease and demonstrate how integrated multiomics and cross-species modeling can reveal underlying mechanisms and provide a foundation for future studies of transcriptional regulation.