Bayrak-Toydemir Pinar, McDonald Jamie, Akarsu Nurten, Toydemir Reha M, Calderon Fernanda, Tuncali Timur, Tang Wei, Miller Franklin, Mao Rong
Associated Regional and University Pathologists (ARUP), Institute of Clinical and Experimental Pathology, Salt Lake City, Utah 84108, USA.
Am J Med Genet A. 2006 Oct 15;140(20):2155-62. doi: 10.1002/ajmg.a.31450.
Hereditary hemorrhagic telangiectasia (HHT) is a genetically and clinically heterogeneous multisystem vascular dysplasia. Mutations of the endoglin and ACVRL1 genes are known to cause HHT. However, existence of HHT families in which linkage to these genes has been excluded has suggested that other gene(s) can cause HHT in some families. Recently, a family was reported to be linked to chromosome 5q, the HHT3 locus. Here we report on linkage results on a family with classic features of HHT, albeit a less severe phenotype with regards to epistaxis and telangiectases, in which linkage to HHT1, HHT2, and HHT3 is ruled out. Whole genome linkage analysis and fine mapping results suggested a 7 Mb region on the short arm of chromosome 7 (7p14) between STR markers D7S2252 and D7S510. We obtained a maximum two point LOD score of 3.60 with the STR marker D7S817. This region was further confirmed by haplotype analysis. These findings suggest the presence of another gene causing HHT (HHT4). The features in this family that strongly suggest the presence of a hereditary, multisystem vascular dysplasia would be easily missed during the typical evaluation and management of a patient with an AVM. This family helps emphasize the need to obtain a very detailed, targeted medical and family history for even mild, infrequent but recurring nosebleed, subtle telangiectases. Further studies of the candidate region and the identification of the gene responsible for the vascular anomalies in this family will add to our understanding of vascular morphogenesis and related disorders.
遗传性出血性毛细血管扩张症（HHT）是一种在遗传和临床方面具有异质性的多系统血管发育异常疾病。已知内皮糖蛋白和ACVRL1基因的突变会导致HHT。然而，有些HHT家族与这些基因并无连锁关系，这表明在某些家族中，其他基因也可能导致HHT。最近，有报道称一个家族与5号染色体q臂（HHT3位点）存在连锁关系。在此，我们报告一个具有HHT典型特征的家族的连锁分析结果，尽管该家族在鼻出血和毛细血管扩张方面的表型较轻，但已排除与HHT1、HHT2和HHT3的连锁关系。全基因组连锁分析和精细定位结果显示，在7号染色体短臂（7p14）上，STR标记D7S2252和D7S510之间存在一个7 Mb的区域。我们使用STR标记D7S817获得的最大两点LOD评分为3.60。通过单倍型分析进一步证实了该区域。这些发现表明存在另一个导致HHT的基因（HHT4）。在对患有动静脉畸形（AVM）的患者进行典型评估和管理时，这个家族中强烈提示存在遗传性多系统血管发育异常的特征很容易被忽视。这个家族有助于强调，即使是对于轻微、不频繁但反复出现的鼻出血和细微的毛细血管扩张，也需要获取非常详细、有针对性的医学和家族病史。对候选区域的进一步研究以及对该家族血管异常相关基因的鉴定，将增进我们对血管形态发生及相关疾病的理解。
