Polymeropoulos M H, Hurko O, Hsu F, Rubenstein J, Basnet S, Lane K, Dietz H, Spetzler R F, Rigamonti D
Laboratory of Genetic Disease Research, National Center for Human Genome Research, National Institutes of Health, Bethesda, MD 20892, USA.
Neurology. 1997 Mar;48(3):752-7. doi: 10.1212/wnl.48.3.752.
To determine with greater precision the map location of the locus associated with familial cavernous hemangiomas.
Cavernous malformations of the brain are a significant cause of seizures, progressive or apoplectic neurologic deficit, and headache. Prevalence estimates from autopsy series vary from 0.39 to 0.9%. This disorder (OMIM #116860) can be inherited as an autosomal dominant trait with variable penetrance. Linkage to markers on the long arm of chromosome 7 was recently reported in separate reports in three apparently unrelated Hispanic kindreds as well as in two kindreds of non-Hispanic descent.
DESIGN/METHODS: We examined clinically, by MRI scanning, and by pathologic examination of surgical specimens, members of four large Mexican-American families segregating cavernous hemangiomas of the brain. Linkage analysis was performed with use of blood specimens from morphologically proven cases. Two-point linkage analysis was performed with the MLINK program of the LINKAGE package. Multipoint analysis was performed between two markers and the disease locus with LINKMAP in the FASTLINKAGE package. Allele frequencies were set as described by the Genome Database (GDB). Maximum penetrance for the disease allele was set to 0.75.
The highest lod score was observed for marker D7S652 with Zmax = 6.66 at theta(max) = 0.00. Multipoint LOD score analysis placed the disease locus in the 11 cM interval between markers D7S630 and D7S527 with Zmax = 9.19. Haplotype analysis is in agreement with the placement of the disease gene between D7S630 and D7S527 and further shows a minimal shared region within this interval, indicating a founder effect in the establishment of the mutation in these families.
We confirmed the linkage of cavernous hemangioma to markers on the long arm of chromosome 7q, and the estimate of the map location has been refined to a region of shared haplotype between markers D7S630 and D7S527 in four Mexican-American families who may be descended from a common ancestor in Sonora County, Mexico.
更精确地确定与家族性海绵状血管瘤相关基因座的图谱位置。
脑海绵状畸形是癫痫、进行性或突发性神经功能缺损以及头痛的重要病因。尸检系列研究估计其患病率在0.39%至0.9%之间。这种疾病（OMIM #116860）可作为常染色体显性性状遗传，具有可变的外显率。最近在三份分别报道的、明显无亲缘关系的西班牙裔家族以及两份非西班牙裔血统家族的报告中，均报道了与7号染色体长臂上的标记物存在连锁关系。
设计/方法：我们对四个患有脑海绵状血管瘤的大型墨西哥裔美国家族的成员进行了临床检查、MRI扫描以及手术标本的病理检查。利用经形态学证实的病例的血液标本进行连锁分析。使用LINKAGE软件包中的MLINK程序进行两点连锁分析。使用FASTLINKAGE软件包中的LINKMAP在两个标记物与疾病基因座之间进行多点分析。等位基因频率按照基因组数据库（GDB）的描述设定。疾病等位基因的最大外显率设定为0.75。
标记物D7S652的最高对数优势分数为Zmax = 6.66，在theta(max) = 0.00时出现。多点对数优势分数分析将疾病基因座定位在标记物D7S630和D7S527之间11厘摩的区间内，Zmax = 9.19。单倍型分析与疾病基因位于D7S630和D7S527之间的定位结果一致，并且进一步显示出该区间内的一个最小共享区域，表明在这些家族中突变的建立存在奠基者效应。
我们证实了海绵状血管瘤与7号染色体长臂上的标记物存在连锁关系，并且在四个可能源自墨西哥索诺拉县共同祖先的墨西哥裔美国家族中，将图谱位置估计范围细化到了标记物D7S630和D7S527之间的共享单倍型区域。
