A Familial Disorder of Altered DNA-Methylation
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.
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.
Genomic imprinting leads to parent-of-origin-specific DNA-methylation and gene expression. Imprinting defects in humans contribute to several recognisable syndromes such as Beckwith–Wiedemann (BWS), Silver–Russell (SRS), Prader–Willi (PWS) or Angelman (AS) syndrome. These imprinting disorders show DNA-methylation changes at the disease-specific imprinted locus; however, more recent studies suggest that a subset of individuals with imprinting disorders shows changes of DNA-methylation at multiple imprinted loci. These multilocus imprinting disorders seem to be particularly prevalent in individuals with BWS, SRS and transient neonatal diabetes mellitus, the latter has been associated with a 'maternal hypomethylation syndrome'.
Familial occurrence of true imprinting defects, that is, changes of DNA-methylation at imprinted loci without causative mutations at the imprinted locus itself in cis, is rare. An autosomal-recessive trait has been described in a subset of the 'maternal hypomethylation syndromes', in which affected individuals carry biallelic mutations in the ZFP57 gene. An alternative mechanism leading to familial occurrence of imprinting defects is the presence of 'maternal effect mutations' in genes important for establishing or maintaining genomic imprints in early development. Indeed, two evolutionary closely related genes located head-to-head in chromosomal region 19q13, NLRP2 and NLRP7, have been associated with such 'maternal effect mutations'. A homozygous mutation in NLRP2 has been described in a woman giving birth to siblings with BWS due to an imprinting defect in 11p15 and partial loss of methylation in PEG1 in one child. In women with biallelic mutations of NLRP7, pregnancies completely fail to develop properly but instead result in hydatidiform moles, which also show alterations at multiple imprinted loci (for an overview, see ref.). Recently, in women with familial biparental hydatidiform moles without NLRP7 mutations, changes in KHDC3L were observed.
Here we describe a family in which two fetuses and one child of a couple showed altered DNA-methylation patterns not only of maternally and paternally imprinted genes but also of various other genes, suggesting a more widespread disorder of DNA-methylation.
Abstract and Introduction
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.
Introduction
Genomic imprinting leads to parent-of-origin-specific DNA-methylation and gene expression. Imprinting defects in humans contribute to several recognisable syndromes such as Beckwith–Wiedemann (BWS), Silver–Russell (SRS), Prader–Willi (PWS) or Angelman (AS) syndrome. These imprinting disorders show DNA-methylation changes at the disease-specific imprinted locus; however, more recent studies suggest that a subset of individuals with imprinting disorders shows changes of DNA-methylation at multiple imprinted loci. These multilocus imprinting disorders seem to be particularly prevalent in individuals with BWS, SRS and transient neonatal diabetes mellitus, the latter has been associated with a 'maternal hypomethylation syndrome'.
Familial occurrence of true imprinting defects, that is, changes of DNA-methylation at imprinted loci without causative mutations at the imprinted locus itself in cis, is rare. An autosomal-recessive trait has been described in a subset of the 'maternal hypomethylation syndromes', in which affected individuals carry biallelic mutations in the ZFP57 gene. An alternative mechanism leading to familial occurrence of imprinting defects is the presence of 'maternal effect mutations' in genes important for establishing or maintaining genomic imprints in early development. Indeed, two evolutionary closely related genes located head-to-head in chromosomal region 19q13, NLRP2 and NLRP7, have been associated with such 'maternal effect mutations'. A homozygous mutation in NLRP2 has been described in a woman giving birth to siblings with BWS due to an imprinting defect in 11p15 and partial loss of methylation in PEG1 in one child. In women with biallelic mutations of NLRP7, pregnancies completely fail to develop properly but instead result in hydatidiform moles, which also show alterations at multiple imprinted loci (for an overview, see ref.). Recently, in women with familial biparental hydatidiform moles without NLRP7 mutations, changes in KHDC3L were observed.
Here we describe a family in which two fetuses and one child of a couple showed altered DNA-methylation patterns not only of maternally and paternally imprinted genes but also of various other genes, suggesting a more widespread disorder of DNA-methylation.
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