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

TitleExploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders.
Publication TypeJournal Article
Year of Publication2019
AuthorsNegri, G, Magini, P, Milani, D, Crippa, M, Biamino, E, Piccione, M, Sotgiu, S, Perrìa, C, Vitiello, G, Frontali, M, Boni, A, Di Fede, E, Gandini, MChiara, Colombo, EAdele, Bamshad, MJ, Nickerson, DA, Smith, JD, Loddo, I, Finelli, P, Seri, M, Pippucci, T, Larizza, L, Gervasini, C
JournalHum Genet
Date Published2019 Mar
KeywordsChild, Child, Preschool, Comparative Genomic Hybridization, CREB-Binding Protein, E1A-Associated p300 Protein, Epigenesis, Genetic, Facies, Female, Genetic Association Studies, Humans, Infant, Infant, Newborn, Male, Mutation, Phenotype, Rubinstein-Taybi Syndrome, Whole Exome Sequencing

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 epi-gene. 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.

Alternate JournalHum. Genet.
PubMed ID30806792
PubMed Central IDPMC6736609
Grant ListUM1 HG006493 / HG / NHGRI NIH HHS / United States
Dotazione d'ateneo linea 2 del piano di sostegno alla ricerca / / Università degli Studi di Milano /
Digirare / / Associazione "RTS Una Vita Speciale ONLUS /
08C623_2016 / / Ministry of Italian Health /