Myoclonus-dystonia and Silver-Russell syndrome resulting from maternal uniparental disomy of chromosome 7

Abstract

Myoclonus-dystonia (M-D) is a movement disorder that is often associated with mutations in epsilon-sarcoglycan (SGCE), a maternally imprinted gene at 7q21.3. We report a 24-year-old male with short stature (<5th percentile) and a movement disorder clinically consistent with M-D. Single nucleotide polymorphism (SNP) array did not identify significant copy number changes, but revealed three long continuous stretches of homozygosity on chromosome 7 suggestive of uniparental disomy. Parental SNP arrays confirmed that the proband had maternal uniparental disomy of chromosome 7 (mUPD7) with regions of heterodisomy and isodisomy. mUPD7 is the cause of approximately 5-10% of Silver-Russell syndrome (SRS), a disorder characterized by prenatal and postnatal growth retardation. Although SRS was not suspected in our patient, these findings explain his short stature. SGCE methylation testing showed loss of the unmethylated paternal allele. Our findings provide a unifying diagnosis for his short stature and M-D and help to optimize his medication regimen. In conclusion, we show that M-D is a clinical feature that may be associated with SRS due to mUPD7. Individuals with mUPD7 should be monitored for the development of movement disorders. Conversely, individuals with M-D and short stature should be evaluated for SRS.

Keywords: Silver-Russell syndrome; epsilon-sarcoglycan; maternal uniparental disomy of chromosome 7; myoclonus-dystonia.

Figure 1. Illumina Omni1-Quad SNP array indicates three regions with loss of heterozygosity (LOH) on chromosome 7

(A) B allele frequencies of single SNPs across the entire length of chromosome 7 are represented as blue data points. The three regions of LOH lack heterozygous (AB) calls and are shaded in light blue. Arrows indicate the locations of the five cross-over events. (B) Log R Ratio for individual probes on chromosome 7 are represented as blue data points. There are no significant copy number gains or losses on chromosome 7. These plots were generated using GenomeStudio software.

Figure 2. Loss of the unmethylated SGCE allele in the proband

(A) A diagram of the genomic location of the CpG island in the SGCE promoter. The methylation status of the four underlined CpG dinucleotides was assessed in the patient and his family members using sodium bisulfite treatment followed by pyrosequencing. This graphic was constructed using the UCSC Genome Browser (GRCh37/hg19). (B) Summary of SGCE promoter CpG methylation studies.