Novel EP300 and NSD1 variants in Chinese pediatric patients with Rubinstein-Taybi syndrome: evidence for oligogenic inheritance and phenotypic expansion.

BACKGROUND

Rubinstein–Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disorder caused by heterozygous loss-of-function variants in CREBBP or EP300. EP300-related cases often show milder clinical features, but their full phenotypic spectrum and the potential role of oligogenic inheritance remain unclear.

METHODS

We retrospectively studied seven Chinese pediatric RSTS patients. Genomic analyses included whole-exome sequencing (WES), chromosomal microarray analysis (CMA) and Sanger validation. Variants were classified by ACMG/AMP guidelines. Protein structural impacts were assessed by homology modeling. Phenotypic frequencies in our EP300-related patients were compared with published European/American cohorts using Fisher’s exact test or χ² test (p < 0.05 as significant).

RESULTS

Two de novo EP300 nonsense variants (c.3934 C > T, p.Arg1312Ter; c.2749 C > T, p.Gln917Ter) were identified; one of these patients also harbored a de novo NSD1 missense variant (c.5843G > A, p.Arg1948His). Five other patients carried pathogenic CREBBP variants or deletions. The patient with both EP300 and NSD1 variants exhibited additional anomalies (cryptorchidism, congenital cataracts, strabismus), suggesting synergistic epigenetic dysregulation. Homology models predicted truncation of the EP300 HAT and bromodomain regions and disruption of the NSD1 SET domain. Compared with European/American cohorts, our Chinese EP300-related patients had significantly higher rates of arched eyebrows, downslanting palpebral fissures and low-set ears (p < 0.05). To our knowledge, this is the first clinical evidence of an oligogenic inheritance pattern in RSTS involving both EP300 and NSD1.

CONCLUSIONS

Our findings expand the genotypic and phenotypic landscape of RSTS in a Chinese population, delineate distinctions between EP300- and CREBBP-related cases, and underscore the value of comprehensive genomic analysis for accurate diagnosis, genetic counselling and personalized management.