Evidence for anticipation and association of deletion size with severity in facioscapulohumerd muscular dystrophy

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Abstract
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by marked inter and intrafamilial heterogeneity in its clinical expression. The contribution of genetic factors to this variability is not well characterized. We examined the relationship of phenotype to genotype in a clinically and genetically well‐defined FSHD population. Quantitative isometric myometry (QMT) scores, normalized for age, gender, and height, were used to quantify disease severity. We found a significant (r = 0.92, p < 0.004) correlation between disease severity and the size of the 4q35‐associated deletion. In addition, when relative disease severity of parent‐offspring pairs was compared, the offspring were found to be significantly more severely affected (p = 0.01 1). This generational effect suggests the presence of anticipation in FSHD and raises the possibility of an underlying dynamic mutation.