Correlations between phenotype and gene region-specific episignatures in Rubinstein-Taybi syndrome and Menke-Hennekam syndrome.

Abstract

Rubinstein-Taybi syndrome (RSTS) and Menke-Hennekam syndrome (MKHK) are two rare Mendelian disorders presented with variable degrees of intellectual disability and different facial dysmorphism. They are caused by loss-of-function (LOF) variants or missense/inframe deletion variants in the exon 30 and 31 of the CREBBP gene respectively. This study aimed to refine the phenotype and provide characterization of genome-wide DNA methylation (DNAm) in RSTS and MKHK. We integrated and analyzed clinical data of 151 patients with RSTS and 36 patients with MKHK from this study and literatures. Meanwhile, genome-wide DNAm analysis were carried out on 51 blood samples (RSTS n = 9, MKHK n = 8, control n = 33), and 21 human induced pluripotent cell (hiPSC) samples (RSTS n = 5, MKHK n = 4, control n = 12). Phenotype analysis showed that patients with RSTS variants downstream the last 50 nt of the penultimate exon had atypical facial malformation and severer medical problems compared to the classical RSTS caused by LOF CREBBP variants. Individuals with MKHK variants in intrinsically disordered region (IDR) showed resemblant features. Meanwhile, DNAm analysis identified two specific blood DNA methylation patterns (episignatures): RSTS and MKHK_IDR compared to matched normal controls. Samples with MKHK variants outside the IDR did not obey the MKHK_IDR episignature. By interrogating DNAm in hiPSCs of patients with RSTS and MKHK, we observed differentially methylated genes play a role in embryonic development and organogenesis. In conclusion, our results suggest that phenotypic features and DNA methylation episignatures may differ for each genomic region.