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Enhanced Reduced Representation Bisulfite Sequencing for Assessment of DNA Methylation at Base Pair Resolution
Published on: February 24, 2015
Methylation profiling in individuals with Russell-Silver syndrome
Maria S Peñaherrera1, Susanne Weindler, Margot I Van Allen
1Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
American Journal of Medical Genetics. Part A
|January 19, 2010
Summary
Russell-Silver syndrome (RSS) is linked to abnormal methylation patterns, particularly hypomethylation at the H19/IGF2 imprinting control region 1 (ICR1). This finding aids in understanding RSS genetics but complicates clinical diagnosis due to continuous methylation variations.
Area of Science:
- Genetics
- Epigenetics
- Developmental Biology
Background:
- Russell-Silver syndrome (RSS) is a complex growth disorder characterized by prenatal and postnatal growth restriction and relative macrocephaly.
- Genetic and epigenetic factors, including imprinted genes on chromosomes 7 and 11p15.5, are implicated in RSS etiology.
Purpose of the Study:
- To investigate the role of epimutations in RSS by evaluating DNA methylation patterns.
- To assess methylation status at key imprinting control regions (ICRs) and other growth-related imprinted genes in RSS patients.
Main Methods:
- Methylation analysis of 11p15.5 ICR1 (H19/IGF2) and ICR2 (KvDMR1) in 35 RSS patients and 22 controls.
- Evaluation of methylation at PLAGL1, GCE, and PEG10 promoter regions in RSS patients.
- Genome-wide methylation profiling using the Illumina GoldenGate methylation array on a subset of 22 RSS patients.
Main Results:
- Thirteen out of 35 RSS patients exhibited hypomethylation at ICR1, significantly below control levels.
- Three RSS patients with upd(7)mat showed hypermethylation at the SCGE promoter.
- Global methylation analysis identified H19 promoter CpG sites as differentially methylated in RSS patients, but no other known imprinted genes showed significant alterations.
Conclusions:
- Hypomethylation at the H19/IGF2 ICR1 is a key epigenetic alteration in Russell-Silver syndrome.
- While specific methylation defects are identified, the continuous distribution of methylation values presents challenges for establishing definitive clinical diagnostic cut-offs.
