D4Z4

D4Z4 refers to a macrosatellite repeat located in the subtelomeric region of chromosome 4 at 4q35. Each unit is about 3.3 kilobases long, and the array typically contains roughly 8 to over 100 repeats in healthy individuals. A related, nonpathogenic copy exists at 10q26 but lacks the regulatory features that make the 4q35 array disease-associated.

Pathogenesis and genetic context: D4Z4 repeats normally exist in a compact, methylated state that represses expression of the nearby DUX4 gene. In facioscapulohumeral muscular dystrophy (FSHD), disease arises when this repression is disrupted. In FSHD type 1 (FSHD1), contraction of the D4Z4 array to 1–10 repeats leads to hypomethylation and derepression of DUX4 in skeletal muscle. The DUX4 open reading frame resides in the last D4Z4 unit and requires a permissive 4qA haplotype, which provides a functional polyadenylation signal (pLAM) to stabilize DUX4 transcripts. On 4q35, the combination of a contracted repeat and a 4qA haplotype enables pathogenic DUX4-FL expression.

FSHD type 2 (FSHD2) mechanistically resembles the disease but occurs without a contracted repeat. Mutations in SMCHD1 or other chromatin modifiers reduce methylation of the D4Z4 array, permitting DUX4 expression especially when a 4qA haplotype is present.

Clinical features: FSHD is a progressive muscular dystrophy characterized by weakness in the face, shoulders, and upper arms, with scapular winging. Onset is often during adolescence or early adulthood, and clinical severity varies due to genetic background and epigenetic factors.

Note: The 4qB haplotype lacks the permissive polyadenylation signal and is non-permissive for stable DUX4 transcript; the 10q26 array is similar but typically non-permissive for pathogenic DUX4 expression.