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

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.

journal_name

Clin Epigenetics

journal_title

Clinical epigenetics

authors

Bend EG,Aref-Eshghi E,Everman DB,Rogers RC,Cathey SS,Prijoles EJ,Lyons MJ,Davis H,Clarkson K,Gripp KW,Li D,Bhoj E,Zackai E,Mark P,Hakonarson H,Demmer LA,Levy MA,Kerkhof J,Stuart A,Rodenhiser D,Friez MJ,Stevenson

doi

10.1186/s13148-019-0658-5

subject

Has Abstract

pub_date

2019-04-27 00:00:00

pages

issue

eissn

1868-7075

issn

1868-7083

pii

10.1186/s13148-019-0658-5

journal_volume

pub_type

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