Fu Wenqing, Ligabue Alessio, Rogers Kai J, Akey Joshua M, Monnat Raymond J
Department of Genome Sciences, University of Washington, Seattle, Washington.
Department of Pathology, University of Washington, Seattle, Washington.
Hum Mutat. 2017 Feb;38(2):193-203. doi: 10.1002/humu.23148. Epub 2016 Dec 9.
Heritable loss of function mutations in the human RECQ helicase genes BLM, WRN, and RECQL4 cause Bloom, Werner, and Rothmund-Thomson syndromes, cancer predispositions with additional developmental or progeroid features. In order to better understand RECQ pathogenic and population variation, we systematically analyzed genetic variation in all five human RECQ helicase genes. A total of 3,741 unique base pair-level variants were identified, across 17,605 potential mutation sites. Direct counting of BLM, RECQL4, and WRN pathogenic variants was used to determine aggregate and disease-specific carrier frequencies. The use of biochemical and model organism data, together with computational prediction, identified over 300 potentially pathogenic population variants in RECQL and RECQL5, the two RECQ helicases that are not yet linked to a heritable deficiency syndrome. Despite the presence of these predicted pathogenic variants in the human population, we identified no individuals homozygous for any biochemically verified or predicted pathogenic RECQL or RECQL5 variant. Nor did we find any individual heterozygous for known pathogenic variants in two or more of the disease-associated RECQ helicase genes BLM, RECQL4, or WRN. Several postulated RECQ helicase deficiency syndromes-RECQL or RECQL5 loss of function, or compound haploinsufficiency for the disease-associated RECQ helicases-may remain missing, as they likely incompatible with life.
人类RECQ解旋酶基因BLM、WRN和RECQ4的功能丧失性突变可导致布卢姆综合征、沃纳综合征和罗思蒙德-汤姆森综合征，这些综合征具有癌症易感性，并伴有其他发育或早衰特征。为了更好地理解RECQ的致病性和群体变异，我们系统分析了人类所有五个RECQ解旋酶基因的遗传变异。在17,605个潜在突变位点中，共鉴定出3,741个独特的碱基对水平变异。通过直接计数BLM、RECQ4和WRN的致病性变异来确定总体和疾病特异性携带者频率。结合生化和模式生物数据以及计算预测，在尚未与遗传性缺陷综合征相关联的两个RECQ解旋酶RECQ1和RECQ5中，鉴定出300多个潜在致病性群体变异。尽管人群中存在这些预测的致病性变异，但我们未发现任何个体对任何经生化验证或预测的致病性RECQ1或RECQ5变异呈纯合状态。我们也未发现任何个体在两个或更多与疾病相关的RECQ解旋酶基因BLM、RECQ4或WRN中对已知致病性变异呈杂合状态。几种假定的RECQ解旋酶缺陷综合征——RECQ1或RECQ5功能丧失，或与疾病相关的RECQ解旋酶的复合单倍剂量不足——可能仍然未被发现，因为它们可能与生命不相容。
