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

Human Genetics
Gloria NegriCristina Gervasini

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 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 ...Continue Reading

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Citations

Oct 1, 2019·Molecular Genetics & Genomic Medicine·Virginia Pérez-GrijalbaElena Domínguez-Garrido
Jul 10, 2020·European Journal of Human Genetics : EJHG·Elisabetta Di FedeCristina Gervasini
Jun 20, 2020·Journal of Ultrasound·Francesco D'AmbrosiEnrico Ferrazzi
Dec 23, 2020·Genesis : the Journal of Genetics and Development·Janina Schwenty-LaraAnnette Borchers
Apr 7, 2021·American Journal of Medical Genetics. Part a·Elisabetta Di FedeAglaia Vignoli
Apr 22, 2021·International Journal of General Medicine·Yu-Xiong GuoQiong-Xiang Zhai
Jul 3, 2021·Genes·Julien Van GilsDidier Lacombe
Jul 8, 2021·Human Molecular Genetics·Roser UfartesSilke Pauli
Aug 25, 2021·Molecular Genetics & Genomic Medicine·Naye ChoiJung Min Ko

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Methods Mentioned

BETA
exome sequencing
PCR
cesarean section

Software Mentioned

Clustal
Agilent CytoGenomics
Panther
ClinVar

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