Which dystrophy is caused by contraction of D4Z4 repeats on 4q35 and is inherited in an autosomal dominant fashion?

• A. Becker muscular dystrophy
• B. Facioscapulohumeral muscular dystrophy type 1 (FSHD1)
• C. Duchenne muscular dystrophy
• D. Myotonic dystrophy type 1

Answer: (B)

FSHD1 is caused by contraction of the D4Z4 repeats at the 4q35 subtelomere. When the repeat array is shortened below a threshold, the DUX4 gene can be inappropriately expressed in skeletal muscle, driving the muscle weakness seen in this dystrophy. This condition is inherited in an autosomal dominant manner with variable expression. A permissive 4qA haplotype containing a polyadenylation signal is also needed for DUX4 transcript stability, so disease occurs when the contraction sits on that background. In contrast, the other dystrophies listed arise from different genetic mechanisms: Becker and Duchenne are due to dystrophin gene mutations on the X chromosome, and myotonic dystrophy type 1 results from a CTG repeat expansion in the DMPK gene and is autosomal dominant.