Send to

Choose Destination
Hum Genet. 2019 Mar;138(3):257-269. doi: 10.1007/s00439-019-01985-y. Epub 2019 Feb 26.

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

Author information

Genetica Medica, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.
U.O. Genetica Medica, Policlinico S. Orsola-Malpighi, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Unità di Pediatria ad alta Intensità di Cura, Fondazione IRCCS Ca' Granda, Milan, Italy.
Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
Dipartimento di Pediatria, Università di Torino, Turin, Italy.
Dipartimento Materno Infantile, Azienda Ospedali Riuniti Villa Sofia Cervello, Università di Palermo, Palermo, Italy.
Dipartimento di Medicina Clinica e Sperimentale, U.O.C. Neuropsichiatria Infantile, A.O.U. di Sassari, Sassari, Italy.
Dipartimento di Medicina Traslazionale, Sezione di Pediatria, Università Federico II, Naples, Italy.
Istituto di Farmacologia Traslazionale CNR, Rome, Italy.
IRCCS Istituto delle Scienze Neurologiche di Bologna UOC Neuropsichiatria Infantile, Ospedale Bellaria, Bologna, Italy.
Department of Genome Sciences, Center for Mendelian Genomics, University of Washington, Seattle, WA, USA.
Dipartimento di Medicina di Laboratorio e Biotecnologie Avanzate, IRCCS ISMETT, Palermo, Italy.
Genetica Medica, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.


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.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center