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Clin Epigenetics. 2019 Apr 27;11(1):64. doi: 10.1186/s13148-019-0658-5.

Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome.

Author information

1
Greenwood Genetic Center, 106 Gregor Mendel Cir, Greenwood, SC, 29646, USA.
2
PreventionGenetics, Marshfield, WI, USA.
3
Department of Pathology and Laboratory Medicine, Western University, 800 Commissioner's Road E, London, ON, N6A 5W9, Canada.
4
Molecular Genetics Laboratory, Victoria Hospital, London Health Sciences Centre, London, ON, Canada.
5
Al DuPont Hospital for Children, Wilmington, DE, USA.
6
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
7
Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
8
Spectrum Health, Grand Rapids, MI, USA.
9
Levine Children's Hospital, Carolinas Medical Center, Charlotte, NC, USA.
10
Department of Pediatrics, Biochemistry and Oncology, Western University, London, ON, Canada.
11
Greenwood Genetic Center, 106 Gregor Mendel Cir, Greenwood, SC, 29646, USA. ceschwartz@ggc.org.
12
Department of Pathology and Laboratory Medicine, Western University, 800 Commissioner's Road E, London, ON, N6A 5W9, Canada. bekim.sadikovic@lhsc.on.ca.
13
Molecular Genetics Laboratory, Victoria Hospital, London Health Sciences Centre, London, ON, Canada. bekim.sadikovic@lhsc.on.ca.

Abstract

BACKGROUND:

ADNP syndrome is a rare Mendelian disorder characterized by global developmental delay, intellectual disability, and autism. It is caused by truncating mutations in ADNP, which is involved in chromatin regulation. We hypothesized that the disruption of chromatin regulation might result in specific DNA methylation patterns that could be used in the molecular diagnosis of ADNP syndrome.

RESULTS:

We identified two distinct and partially opposing genomic DNA methylation episignatures in the peripheral blood samples from 22 patients with ADNP syndrome. The "epi-ADNP-1" episignature included ~ 6000 mostly hypomethylated CpGs, and the "epi-ADNP-2" episignature included ~ 1000 predominantly hypermethylated CpGs. The two signatures correlated with the locations of the ADNP mutations. Epi-ADNP-1 mutations occupy the N- and C-terminus, and epi-ADNP-2 mutations are centered on the nuclear localization signal. The episignatures were enriched for genes involved in neuronal system development and function. A classifier trained on these profiles yielded full sensitivity and specificity in detecting patients with either of the two episignatures. Applying this model to seven patients with uncertain clinical diagnosis enabled reclassification of genetic variants of uncertain significance and assigned new diagnosis when the primary clinical suspicion was not correct. When applied to a large cohort of unresolved patients with developmental delay (N = 1150), the model predicted three additional previously undiagnosed patients to have ADNP syndrome. DNA sequencing of these subjects, wherever available, identified pathogenic mutations within the gene domains predicted by the model.

CONCLUSIONS:

We describe the first Mendelian condition with two distinct episignatures caused by mutations in a single gene. These highly sensitive and specific DNA methylation episignatures enable diagnosis, screening, and genetic variant classifications in ADNP syndrome.

KEYWORDS:

ADNP; Autism; DNA methylation; Disease screening; Epigenetics; Episignature; Helsmoortel-Van der Aa syndrome; Intellectual disability; Unresolved clinical cases

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