Data from: A family-based study into penetrance in facioscapulohumeral muscular dystrophy type 1

Objective: An observational cross-sectional study was conducted in a national facioscapulohumeral muscular dystrophy (FSHD) expertise center to estimate the penetrance of FSHD1 and to evaluate phenotype–genotype correlations.

Methods: Ten FSHD1 probands carrying 4–9 D4Z4 unit alleles and 140 relatives were examined. All 150 participants were genetically characterized, including D4Z4 methylation levels in the mutation carriers. Mutation carriers were classified as (1) symptomatic: with symptoms of muscle weakness on history and muscle FSHD signs on examination; (2) asymptomatic: without symptoms of muscle weakness but with muscle FSHD signs on examination; and (3) nonpenetrant: without symptoms of muscle weakness on history and without muscle FSHD signs on examination. We assessed the relationship between age-corrected clinical severity score and repeat size, sex, and D4Z4 methylation levels.

Results: The maximum likelihood estimates of symptomatic and those of symptomatic plus asymptomatic FSHD showed that penetrance depends on repeat size and increases until late adulthood. We observed many asymptomatic carriers with subtle facial weakness with or without mild shoulder girdle weakness (25% [17/69]). Nonpenetrance was observed less frequently than in recent population studies (17% [12/69]), and most asymptomatic patients reported some shoulder pain. D4Z4 methylation tended to be lower in moderately to severely affected mutation carriers with 7 or 9 repeats.

Discussion: This family-based study detected a lower overall nonpenetrance than previously observed, probably due to many asymptomatic mutation carriers identified by careful examination of facial and shoulder muscles. The recognition of asymptomatic mutation carriers is essential for selection of participants for future trials, and the likelihood estimates are helpful in counseling.

研究目的：本研究在全国面肩肱型肌营养不良症（facioscapulohumeral muscular dystrophy, FSHD）专科诊疗中心开展一项观察性横断面研究，旨在评估FSHD1型的外显率，并分析表型-基因型相关性。
研究方法：本研究纳入10例携带4~9个D4Z4重复等位基因的FSHD1型先证者及140名家系亲属，共150名受试者。所有受试者均完成基因分型检测，包括突变携带者的D4Z4甲基化水平测定。将突变携带者分为三类：① 有症状组：病史提示存在肌无力症状，查体可见FSHD相关肌体征；② 无症状组：无肌无力病史，但查体可见FSHD相关肌体征；③ 非外显组：无肌无力病史，且查体无FSHD相关肌体征。本研究分析了校正年龄后的临床严重程度评分与重复序列数目、性别及D4Z4甲基化水平之间的相关性。
研究结果：有症状FSHD患者以及有症状合并无症状FSHD患者的最大似然估计结果显示，外显率与重复序列数目相关，且在成年晚期仍呈上升趋势。本研究观察到多例存在隐匿性面肌无力、伴或不伴轻度肩带肌无力的无症状携带者（占比25%[17/69]）。非外显病例的检出率低于近期人群研究（17%[12/69]），且多数无症状携带者自述存在肩部疼痛。携带7或9个重复序列的中重度受累突变携带者，其D4Z4甲基化水平普遍偏低。
讨论：本项基于家系的研究发现总体非外显率低于既往报道，这可能得益于通过细致查体对面部及肩部肌肉的检查，从而识别出大量无症状突变携带者。识别无症状突变携带者对于未来临床试验的受试者筛选至关重要，而外显率的似然估计结果可为遗传咨询提供有力参考。