PhenoModifier-Variant Detail

Variant "DNMT3B:rs889145646"

Search result: 1 record

Variant information

Gene:

DNMT3B

Variant:

DNMT3B:rs889145646

dbSNP ID:

rs889145646

GWAS trait:

no data

Modifier statisitcs

Record:

1

Disorder:

1

Reference:

1

Effect type:

Penetrance(1)

Modifier effect:

Altered incidence(1)

Detail：

Target disease:

Facioscapulohumeral dystrophy (Orphanet_269)

Effect type:

Penetrance

Modifier effect:

Altered incidence

Evidence:

Pedigree analysis

Effect:

Heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD.

Reference:

PMID27153398

Title:

Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy.

Species studied:

Human

Abstract:

Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.