| Description |
Background Facioscapulohumeral muscular dystrophy (FSHD) is a degenerative disorder that leads to weakness in the muscles of the face, shoulders, upper arms, and lower legs. FSHD is caused by the activation of the transcription factor known as DUX4. The D4Z4 array is heavily methylated limiting the expression of the DUX4 gene located in each repeat. FSHD is caused by de-repression of the D4Z4 repeat as a result of a contraction of the number of D4Z4 repeats or deactivation of a DNA methylation gene. The genetic analysis of FSHD is complicated by the large size of the D4Z4 array on chromosome 4q and the nearly identical array on chromosome 10q. This complication has perpetuated instances of patients with phenotypical FSHD receiving negative genetic test results for FSHD. In our research, we have come across a similar case with a young male who has phenotypic FSHD, but clinical genetic testing was not consistent with FSHD. Methods To determine what epigenetic and genetic factors are leading to his phenotypic FSHD in this patient, we did single molecule nanopore sequencing for the proband and both his parents. DNA libraries were created for the proband and both his parents. Using the base-calling data from nanopore sequencing we were able to identify genetic alterations on the 4q and 10q chromosomes. Results We found that the proband did not have: a mutation on methylation genes that cause FSHD2, a mutation to chromosome 10q's polyadenylation site, or a distal D4Z4 repeat on 4qA that was hypomethylated. iii Conclusion Our results were inconclusive regarding the genetic and epigenetic factors leading to the proband's phenotypic FSHD. However, we did eliminate the possibilities of him having: a variant in a previously known or an unknown methylation gene that caused FSHD2, a mutation to chromosome 10q's polyadenylation site, and a distal D4Z4 repeat on 4qA that was hypomethylated. To determine if the proband truly has FSHD we will be doing a fibroblast test for the activation of genes activated by the DUX4 transcription factor. |
