What does being heterozygous (having two different alleles) for the EP300 (E1A binding protein p300) gene mean?

What Does Being Heterozygous for the EP300 Gene Mean?

Being heterozygous for the EP300 gene means you have one normal copy and one altered (mutant) copy of the gene, which can cause Rubinstein-Taybi syndrome type 2 (RSTS2) or increase susceptibility to certain health conditions, even with just one affected copy. 1

Genetic Definition

• Heterozygosity means having two different alleles (gene variants) at a specific chromosomal location - in this case, one normal EP300 gene copy and one variant copy 1
• The EP300 gene encodes the p300 protein, which functions as an acetyltransferase and global transcriptional coactivator involved in gene regulation 1
• EP300 is located on chromosome 22q13, a region that frequently shows loss of heterozygosity in various cancers 2

Clinical Implications of EP300 Heterozygosity

Rubinstein-Taybi Syndrome Type 2 (RSTS2)

Heterozygous pathogenic variants in EP300 cause RSTS2, though the phenotype can be highly variable and may not always include classic features: 3

• Typical features include: distinctive facial dysmorphisms, broad thumbs and halluces (though these may be milder or absent in EP300-related cases compared to CREBBP-related RSTS1), short stature, and moderate-to-severe intellectual disability 4, 3
• Congenital anomalies occur frequently: genitourinary anomalies (38%), cardiovascular anomalies (25%), spinal/vertebral anomalies (19%), skeletal anomalies (19%), brain anomalies (13%), and renal anomalies (6%) 5
• Atypical presentations are increasingly recognized: severe early-onset high myopia, unilateral renal agenesis, myelomeningocele, and other features not traditionally associated with RSTS 4, 5
• The diagnosis must be expanded beyond classic features - three of the first four reported EP300 mutation patients exhibited much milder skeletal findings than typically seen in RSTS 3

Phenotypic Variability and Sex Bias

• Females appear disproportionately represented among EP300 cases identified through genome-wide sequencing compared to those diagnosed clinically (p = 0.01), suggesting possible sex-related differences in phenotypic expression 6
• The clinical spectrum continues to expand as more cases are identified through hypothesis-free genomic methods (microarray, exome, and whole-genome sequencing) rather than targeted testing 6, 5

Inheritance Pattern and Family Implications

EP300-related RSTS2 typically occurs as a de novo (new) mutation, meaning it arises spontaneously and is not inherited from parents: 4, 5

• If you are heterozygous for a pathogenic EP300 variant, your biological relatives may need cascade genetic testing to determine if they carry the same variant 7
• Your offspring have a 50% chance of inheriting the variant if you carry a heterozygous pathogenic mutation 1
• Your siblings have a low risk if your mutation was de novo, but testing should be discussed if there is clinical suspicion 1
• Parents of an affected individual are typically unaffected carriers or have normal alleles, as most cases arise de novo 4

Potential Health Risks Beyond RSTS2

Cancer Susceptibility

• EP300 functions as a putative tumor suppressor gene, and loss of heterozygosity at the EP300 locus occurs in 38% of colon cancers, 36% of breast cancers, and 49% of ovarian cancers 2
• However, somatic mutations in EP300 are rare in primary tumors (none found in 203 primary breast, colon, and ovarian tumors analyzed), though mutations were identified in 4 of 17 colorectal cancer cell lines 2
• Haploinsufficiency (having only one functional copy) may be sufficient to contribute to tumorigenesis in some contexts, though the exact mechanism remains unclear 2

Management Recommendations

Pre-test and post-test genetic counseling is essential when EP300 variants are identified: 7

• Confirm the variant classification using standardized frameworks (benign, likely benign, uncertain significance, likely pathogenic, or pathogenic) 7
• Comprehensive clinical evaluation should assess for RSTS2 features: facial dysmorphisms, limb abnormalities, growth parameters, neurodevelopmental status, and screening for associated congenital anomalies (cardiac, renal, genitourinary, skeletal, neurological) 4, 5, 3
• Surveillance protocols should be established based on the specific phenotype and associated anomalies identified 7
• Periodic review of variant interpretation is recommended as classifications may change over time with new evidence 7

Common Pitfalls to Avoid

• Do not assume all EP300 heterozygotes will have classic RSTS features - broad thumbs and halluces may be mild or absent 3
• Avoid treating variants of uncertain significance (VUS) as definitively pathogenic or benign, as this can lead to inappropriate clinical management 7
• Do not overlook the need for family cascade testing when a pathogenic variant is identified 7
• Recognize that mRNA expression levels may be reduced even with heterozygous variants, affecting gene function 4