What is the typical inheritance pattern for FSHD1?

• A. Autosomal recessive
• B. Autosomal dominant (with a permissive 4qA haplotype)
• C. X-linked recessive
• D. Mitochondrial inheritance

Answer: (B)

FSHD1 follows an autosomal dominant pattern, meaning a single pathogenic allele can cause the disease in a family. What makes it specific is that the disease only manifests when the D4Z4 repeat contraction on chromosome 4q35 occurs on a chromosome with the permissive 4qA haplotype. That 4qA haplotype provides the necessary polyadenylation signal for DUX4, so the misexpressed DUX4 gene leads to muscle weakness. If the contraction sits on a non-permissive 4qB haplotype, DUX4 isn’t properly expressed and the disease doesn’t occur. So the inheritance is autosomal dominant with a haplotype requirement, though penetrance and age of onset can vary.