Abstract
BackgroundAlpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene ATRX. The mechanisms involved in the ATR-X pathology are not completely understood, but may involve epigenetic modifications. ATRX has been linked to the regulation of histone H3 and DNA methylation, while mutations in the ATRX gene may lead to the downstream epigenetic and transcriptional effects. Elucidating the underlying epigenetic mechanisms altered in ATR-X will provide a better understanding about the pathobiology of this disease, as well as provide novel diagnostic biomarkers.ResultsWe performed genome-wide DNA methylation assessment of the peripheral blood samples from 18 patients with ATR-X and compared it to 210 controls. We demonstrated the evidence of a unique and highly specific DNA methylation “epi-signature” in the peripheral blood of ATRX patients, which was corroborated by targeted bisulfite sequencing experiments. Although genomically represented, differentially methylated regions showed evidence of preferential clustering in pericentromeric and telometric chromosomal regions, areas where ATRX has multiple functions related to maintenance of heterochromatin and genomic integrity.ConclusionMost significant methylation changes in the 14 genomic loci provide a unique epigenetic signature for this syndrome that may be used as a highly sensitive and specific diagnostic biomarker to support the diagnosis of ATR-X, particularly in patients with phenotypic complexity and in patients with ATRX gene sequence variants of unknown significance.
Highlights
Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene alpha thalassemia/mental retardation X-linked (ATRX)
The epi‐signature identified in blood samples from ATR‐X patients The genome-wide DNA methylation array of 20 blood samples obtained from ATR-X patients was compared with a reference cohort
13 regions showed hypermethylation and three regions showed hypomethylation. These regions were distributed across the genome both outside (n = 5) and within CpG islands (n = 11), including seven regions at gene promoter CpG islands and two intragenic CpG islands (Table 1). This epi-signature was specific to ATR-X patients and did not correlate with the type of mutation at the ATRX gene locus
Summary
Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene ATRX. Building on several decades of evidence regarding the functions of covalent DNA methylation [2, 3] and histone modifications [4] in regulating gene transcription, it is evident Along with these discoveries came the opportunity, for the elucidation of underlying molecular mechanisms altered in these disorders, and for the identification of epi-signatures that can be diagnostically useful, where patients express a subset of clinical manifestations associated with a phenotypic spectrum shared across more than one syndrome, making a specific clinical diagnosis difficult to reach. ATRX protein is involved in cellular processes such as meiosis, mitosis, DNA repair and regulation of transcription through an effect on chromatin [11,12,13,14,15] Disruption of these activities may contribute to developmental abnormalities associated with the ATR-X syndrome
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