RESUMO
Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.
Assuntos
Autoantígenos/genética , Síndrome de Beckwith-Wiedemann/genética , Diabetes Mellitus/genética , Impressão Genômica/genética , Doenças do Recém-Nascido/genética , Síndrome de Silver-Russell/genética , Aborto Espontâneo/genética , Adolescente , Adulto , Transtorno Autístico/genética , Simulação por Computador , Variações do Número de Cópias de DNA , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Mola Hidatiforme/genética , Infertilidade Feminina/genética , Masculino , Proteínas Mitocondriais , Mães , Mutação , Proteínas Nucleares , Obesidade/genética , Reação em Cadeia da Polimerase , Gravidez , Análise de Sequência de DNA , Gêmeos Monozigóticos , Neoplasias Uterinas/genética , Adulto JovemRESUMO
BACKGROUND: Genomic imprinting is allelic restriction of gene expression potential depending on parent of origin, maintained by epigenetic mechanisms including parent of origin-specific DNA methylation. Among approximately 70 known imprinted genes are some causing disorders affecting growth, metabolism and cancer predisposition. Some imprinting disorder patients have hypomethylation of several imprinted loci (HIL) throughout the genome and may have atypically severe clinical features. Here we used array analysis in HIL patients to define patterns of aberrant methylation throughout the genome. DESIGN: We developed a novel informatic pipeline capable of small sample number analysis, and profiled 10 HIL patients with two clinical presentations (Beckwith-Wiedemann syndrome and neonatal diabetes) using the Illumina Infinium Human Methylation450 BeadChip array to identify candidate imprinted regions. We used robust statistical criteria to quantify DNA methylation. RESULTS: We detected hypomethylation at known imprinted loci, and 25 further candidate imprinted regions (nine shared between patient groups) including one in the Down syndrome critical region (WRB) and another previously associated with bipolar disorder (PPIEL). Targeted analysis of three candidate regions (NHP2L1, WRB and PPIEL) showed allelic expression, methylation patterns consistent with allelic maternal methylation and frequent hypomethylation among an additional cohort of HIL patients, including six with Silver-Russell syndrome presentations and one with pseudohypoparathyroidism 1B. CONCLUSIONS: This study identified novel candidate imprinted genes, revealed remarkable epigenetic convergence among clinically divergent patients, and highlights the potential of epigenomic profiling to expand our understanding of the normal methylome and its disruption in human disease.