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

Abstract

Rubinstein–Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by 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 eight RSTS-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, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring–Opitz, Kabuki and Wiedemann–Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epigene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.

Screening of a large Rubinstein–Taybi cohort identified many novel variants and emphasizes the importance of the CREBBP histone acetyltransferase domain

“…Obtaining a “pure” RSTS cohort is difficult due to the phenotypic overlap with other epigenetic regulation syndromes like Bohring‐Opitz, Kabuki, and Wiedemann‐Steiner (Bjornsson, 2015; Negri et al, 2019), and variants in EP300 have recently been linked with Cornelia de Lange syndrome (Cucco et al, 2020). In addition, variants in genes that interact with the CBP or p300 proteins can cause similar phenotypes, for example, Floating‐Harbor syndrome due to SRCAP variants (Spena et al, 2015).…”

KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies

“…As outlined above, at least five recognized human developmental syndromes currently are linked to germline mutations in K CD COM proteins (KMT2C/D, KDM6A) or associated chromatin-activating molecules (p300/CBP). The genetic and molecular links between these diseases are further strengthened by the substantial phenotypic overlap noted in subjects diagnosed with these syndromes (see Table 2) [125]. In addition to prominent intellectual impairment and behavioral abnormalities, key structural defects also occur with high frequency across all three conditions, including short stature, skeletal abnormalities, cardiovascular defects, and craniofacial defects, which are further detailed below.…”

New point mutation in CREBBP Gene cause Rubinstein-Taybi syndrome: A case report

“…Despite previous research reports that the size and the severity of the disease is related, and some children die shortly after birth [15] .But the protein structure changes caused by different mutation points are different, and the resulting clinical manifestations are also different, the genotype-phenotype correspondence relationship is currently inconclusive [16] . Children with RSTS need a multi-system evaluation after clinical diagnosis.…”