Rubinstein Taybi syndrome caused by EP300 gene mutation: what we learned from two cases and literature review

Abstract

Introduction: Rubinstein-Taybi syndrome is an extremely rare autosomal dominant genetic disease. The incidence of RSTS ranges from 1/100 000 to 125 000.

Methods: We retrospectively reviewed the phenotype and genotype of two children who were diagnosed with RSTS in Hunan Province Children's Hospital from January 2022 to December 2023. Clinical data of the children were collected. Whole-exome sequencing was performed on the children. The candidate variants were verified by Sanger sequencing in the pedigree, followed by pathogenicity analysis.

Results: The main clinical presentations of the two cases were growth retardation, special facial features, and mild intellectual disability. Three mutations were detected by exome sequencing, all of which were sporadic mutations verified by Sanger sequencing. In case 1, pathological mutations were detected in EP300 gene and NSD1 gene. A heterozygous mutation c. 3934C>T (p. Arg1312Ter) was detected in exon 24 of EP300 gene. A heterozygous mutation c. 5843G>A (p. Arg1948 His) was detected in exon 18 of NSD1 gene. In case 2, a heterozygous mutation (c.2749C>T) (p. Gln917 *) was detected in exon 14 of EP300 gene, which has not been reported in the literature so far. According to ACMG guidelines, this mutation was preliminarily determined to be pathogenic. Comparative analysis of phenotypic differences between the Chinese cohort and the Cohen JL and Fergelot P. cohorts revealed that arched eyebrows, downslanting palpebral fissures, and low-set ears were significantly more common in the Chinese population.

Discussion: EP300 gene c.2749C>T heterozygous mutation may be the genetic cause of Rubinstein Taybi syndrome. EP300 gene combined with NSD1 gene mutation may lead to atypical clinical presentations. These findings further enrich the variation spectrum of EP300 gene.

Keywords: EP300 gene; NSD1 gene; Rubinstein-Taybi syndrome; children; growth retardation.

FIGURE 1

The facial features and other phenotypes of the cases: In Case 1, (a) shows microtia, broad nasal bridge, prominent nasal ridge, deviated nasal septum, down-slanting outer canthus, and exotropia; (b) shows thick eyebrows and micrognathia; (c) shows webbed neck, hypertrichosis, and low posterior hairline; (d) shows a slightly broad big toe; (e) shows no obvious broad thumb or fifth finger flexion deformity. In Case 2, (f) shows microcephaly, down-slanting outer canthus, and prominent nasal ridge.

FIGURE 2

The metacarpal and phalangeal bones and cranial MRI of Case 1: (a) shows a bone age of 11 years, with an actual age of 10 years and 9 months, indicating the bone age is neither advanced nor delayed. (b) shows that the cranial MRI indicates slightly widened cerebellar sulci on the left side (red arrow), a markedly rightward deviation of the nasal septum in the middle (red arrow), and hypertrophy of the bilateral inferior nasal turbinates.

FIGURE 3

Case 1 carries a heterozygous mutation in exon 24 of the EP300 gene: c.3934C>T (p.Arg1312Ter). Genetic testing of the parents showed no variation at this locus, confirming it as a de novo mutation. Additionally, Case 1 exhibits a heterozygous mutation in exon 18 of the NSD1 gene: c.5843G>A (p.Arg1948His). Parental testing at this locus similarly revealed no variations, indicating another de novo mutation. Case 2 has a heterozygous mutation in exon 14 of the EP300 gene: c.2749C>T (p.Gln917*). Testing of both parents demonstrated no genetic variation at this site, confirming it as a de novo mutation.

FIGURE 4

(a–c) show the EP300 gene wild type, c.3934C>T (p.Arg1312Ter) mutation, and c.2749C>T (p.Gln917*) mutation, respectively. (d,e) show the NSD1 gene wild type and c.5843G>A (p.Arg1948His) mutation, respectively.

FIGURE 5

This figure revealed that arched eyebrows, downslanting palpebral fissures, and low-set ears were significantly more common in the Chinese population. *p < 0.05.