Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Maternal uniparental disomy 14 [upd(14)mat] is associated with a recognizable phenotype that includes pre- and postnatal growth retardation, neonatal hypotonia, feeding problems and precocious puberty. Chromosome 14 contains an imprinted gene cluster, which is regulated by a differentially methylated region (IG-DMR) between DLK1 and GTL2. Here we report on four patients with clinical features of upd(14)mat who show a maternal-only methylation pattern, but biparental inheritance for chromosome 14. In three of the patients loss of paternal methylation appears to be a primary epimutation, whereas the other patient has a paternally derived deletion of -1 Mb that includes the imprinted DLK1-GTL2 gene cluster. These findings demonstrate that the upd(14)mat phenotype is caused by altered expression of genes within this cluster.
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PMID:Clinical features of maternal uniparental disomy 14 in patients with an epimutation and a deletion of the imprinted DLK1/GTL2 gene cluster. 1845 53

Maternal uniparental disomy for chromosome 14 (upd(14)mat) causes clinically discernible features such as pre- and/or postnatal growth failure, hypotonia, obesity, small hands, and early onset of puberty. The monoallelic expression patterns at the 14q32.2 imprinted region are tightly related to methylation status of the DLK1-MEG3 intergenic differential methylation region (DMR) and the MEG3-DMR that are severely hypermethylated after paternal transmission and grossly hypomethylated after maternal transmission. We examined this imprinted region in a 2 2/12-year-old Japanese patient who was born with a normal birth size (length, +0.2 SD; weight, -0.5 SD) and showed postnatal growth failure (height, -3.1 SD; weight, -3.4 SD), hypotonia, frontal bossing, micrognathia, and small hands. Methylation analysis, genotyping analysis, and deletion analysis were performed with blood samples of the patient and the parents, showing that the DMRs of this patient were grossly hypomethylated in the absence of upd(14)mat and deletion of the DMRs. The results indicate the occurrence of an epimutation (hypomethylation) affecting the normally methylated DMRs of paternal origin, and imply that epimutations should be examined in patients with upd(14)mat-like phenotype.
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PMID:Epimutation (hypomethylation) affecting the chromosome 14q32.2 imprinted region in a girl with upd(14)mat-like phenotype. 1847 39

Uniparental disomy (UPD) for imprinted chromosomes can cause abnormal phenotypes due to absent or overexpression of imprinted genes. UPD(14)pat causes a unique constellation of features including thoracic skeletal anomalies, polyhydramnios, placentomegaly, and limited survival; its hypothesized cause is overexpression of paternally expressed RTL1, due to absent regulatory effects of maternally expressed RTL1as. UPD(14)mat causes a milder condition with hypotonia, growth failure, and precocious puberty; its hypothesized cause is absence of paternally expressed DLK1. To more clearly establish how gains and losses of imprinted genes can cause disease, we report six individuals with copy number variations of the imprinted 14q32 region identified through clinical microarray-based comparative genomic hybridization. Three individuals presented with UPD(14)mat-like phenotypes (Temple syndrome) and had apparently de novo deletions spanning the imprinted region, including DLK1. One of these deletions was shown to be on the paternal chromosome. Two individuals with UPD(14)pat-like phenotypes had 122-154kb deletions on their maternal chromosomes that included RTL1as but not the differentially methylated regions that regulate imprinted gene expression, providing further support for RTL1 overexpression as a cause for the UPD(14)pat phenotype. The sixth individual is tetrasomic for a 1.7Mb segment, including the imprinted region, and presents with intellectual disability and seizures but lacks significant phenotypic overlap with either UPD(14) syndrome. Therefore, the 14q32 imprinted region is dosage sensitive, with deletions of different critical regions causing UPD(14)mat- and UPD(14)pat-like phenotypes, while copy gains are likely insufficient to recapitulate these phenotypes.
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PMID:Clinical features associated with copy number variations of the 14q32 imprinted gene cluster. 2575 53