A familial disorder of altered DNA-methylation.
BACKGROUND
In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare.


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.
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
Almuth
A
Caliebe
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
Julia
J
Richter
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
Ole
O
Ammerpohl
Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
Deniz
D
Kanber
Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
Jasmin
J
Beygo
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
Susanne
S
Bens
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
Andrea
A
Haake
Institute of Pathology, University Hospital Schleswig-Holstein Campus Kiel/Christian- Albrechts University Kiel, Kiel, Germany.
Eva
E
Jüttner
Friedrich-Miescher Institute for Biomedical Research, Basel, Switzerland.
Bernhard
B
Korn
Human Genetics and Genomic Medicine/Faculty of Medicine, University of Southampton, Southampton, UK.
Deborah J G
DJ
Mackay
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
José I
JI
Martin-Subero
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
Inga
I
Nagel
Department of Histopathology, Great Ormond Street Hospital, London, UK.
Neil J
NJ
Sebire
Department of Pediatric Pathology, Johannes Gutenberg Universität, Mainz, Germany.
Larissa
L
Seidmann
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
Inga
I
Vater
Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany.
Constantin Sylvius
CS
von Kaisenberg
Human Genetics and Genomic Medicine/Faculty of Medicine, University of Southampton, Southampton, UK.
I Karen
IK
Temple
Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
Bernhard
B
Horsthemke
Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
Karin
K
Buiting
Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany.
Reiner
R
Siebert
D000483:Alleles; D019175:DNA Methylation / Q000235:genetics*; D004252:DNA Mutational Analysis; D057890:Epigenomics; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree
Clinical genetics; Epigenetics; Genetics; Imprinting; hypomethylation syndrome