Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein–Taybi syndrome: the interconnections of epigenetic machinery disorders

Rubinstein–Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newbornscharacterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is causedby mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60%) or its homologous EP300 (~ 10%).No causative mutation is identified in up to 30% of patients. We performed whole-exome sequencing (WES) on eightRSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative,to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2Dand KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring–Opitz, Kabuki andWiedemann–Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in lossof-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygousvariants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and inthe latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicityremains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatusand the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassingdistinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenicmolecular mechanisms affecting the complex regulation of balance between open and closed chromatin.