A familial disorder of altered DNA-methylation.
J Med Genet
; 51(6): 407-12, 2014 Jun.
Article
em En
| MEDLINE
| ID: mdl-24721835
ABSTRACT
BACKGROUND:
In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare. PURPOSE/OBJECTIVE:
We have investigated the clinical and molecular features of a familial DNA-methylation disorder.METHODS:
Tissues of affected individuals and blood samples of family members were investigated by conventional and molecular karyotyping. Sanger sequencing and RT-PCR of imprinting-associated genes (NLRP2, NLRP7, ZFP57, KHDC3L, DNMT1o), exome sequencing and locus-specific, array-based and genome-wide technologies to determine DNA-methylation were performed.RESULTS:
In three offspring of a healthy couple, we observed prenatal onset of severe growth retardation and dysmorphism associated with altered DNA-methylation at paternally and maternally imprinted loci. Array-based analyses in various tissues of the offspring identified the DNA-methylation of 2.1% of the genes in the genome to be recurrently altered. Despite significant enrichment of imprinted genes (OR 9.49), altered DNA-methylation predominately (90.2%) affected genes not known to be imprinted. Sequencing of genes known to cause comparable conditions and exome sequencing in affected individuals and their ancestors did not unambiguously point to a causative gene.CONCLUSIONS:
The family presented herein suggests the existence of a familial disorder of DNA-methylation affecting imprinted but also not imprinted gene loci potentially caused by a maternal effect mutation in a hitherto not identified gene.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Metilação de DNA
/
Doenças Genéticas Inatas
Tipo de estudo:
Prognostic_studies
Limite:
Female
/
Humans
/
Male
/
Newborn
Idioma:
En
Revista:
J Med Genet
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Alemanha