Supplementary Material for: Complete Penetrance and Absence of Intrafamilial Variability in a Large Family with Hereditary Leiomyomatosis and Renal Cell Carcinoma

<b><i>Background:</i></b> Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial disorder due to <i>FH</i> mutation. Despite a considerable increase in information about the genetic background, inter- and intrafamilial phenotypic variability/penetrance are not well documented. <b><i>Objective:</i></b> To describe a large French HLRCC family and provide new data on penetrance and intrafamilial variability. <b><i>Materials and Methods:</i></b> The whole family was contacted for clinical examination, skin biopsy, uterine and kidney imagery and molecular analysis. <b><i>Results:</i></b> The family included 22 members in 3 generations. The second generation consisted of 13 members who were older than the expected age of onset of disease manifestations. Of the 12 available members of this second generation, 6 (1 man and 5 women, aged 44-57 years) had a novel <i>FH</i> mutation. All had the same mild phenotype with cutaneous asymptomatic leiomyomas, uterine fibroids (if women) and no kidney tumor. The other 6 members not bearing the familial mutation had normal clinical and radiological findings. In this second generation, the penetrance was therefore complete, and there was no intrafamilial variability in the clinical expression of the mutation. <b><i>Conclusion:</i></b> This study provides additional data on genotype/phenotype correlation, intrafamilial variability and penetrance that should help to improve prognosis and genetic counseling.

<b><i>背景：</i></b> 遗传性平滑肌瘤病和肾细胞癌（Hereditary leiomyomatosis and renal cell carcinoma，HLRCC）是一种由<i>FH</i>基因突变导致的常染色体显性遗传性家族性疾病。尽管目前对其遗传背景的认知已显著提升，但家族间及家族内的表型异质性/外显率尚未得到充分阐释。
<b><i>目的：</i></b> 本研究旨在描述一个大型法国HLRCC家系，并为该疾病的外显率及家族内表型异质性提供全新数据。
<b><i>材料与方法：</i></b> 对该家系全体成员进行临床检查、皮肤活检、子宫及肾脏影像学检查，以及分子遗传学分析。
<b><i>结果：</i></b> 该家系共包含3代22名成员。第二代共计13名成员，其年龄均超过该病的预期发病年龄。在该代可评估的12名成员中，6名（1名男性、5名女性，年龄44~57岁）携带一种新型<i>FH</i>基因突变。所有携带者均表现为一致的轻度表型：皮肤无症状性平滑肌瘤、女性患者伴发子宫肌瘤，无肾脏肿瘤。其余6名未携带家系特异性突变的成员，其临床及影像学检查结果均正常。因此，在该家系第二代中，该突变的外显率为完全外显，且突变的临床表型无家族内异质性。
<b><i>结论：</i></b> 本研究为基因型/表型相关性、家族内表型异质性及外显率的相关研究提供了补充数据，有望助力改善该病的预后评估与遗传咨询工作。