Caliebe, A., Richter, J., Ammerpohl, O., Kanber, D., Beygo, J., Bens, S., Haake, A., Juttner, E., Korn, B., Mackay, D.J.G., Martin-Subero, J.I., Nagel, I., Sebire, N.J., Seidmann, L., Vater, I., von Kaisenberg, C.S., Temple, I.K., Horsthemke, B., Buiting, K. and Siebert, R. (2014) A familial disorder of altered DNA-methylation. Journal of Medical Genetics, 51 (6), 407-412. (doi:10.1136/jmedgenet-2013-102149). (PMID: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.
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