Phenotypic definition of Chiari type I malformation coupled with high-densi SNP genome screen ity shows significant evidence for linkage to regions on chromosomes 9 and 15
Phenotypic definition of Chiari type I malformation coupled with high-densi SNP genome screen ity shows significant evidence for linkage to regions on chromosomes 9 and 15
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DOI：
10.1002/ajmg.a.31546
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发表时间：
2006-12-15
影响因子：
2
通讯作者：
Speer, Marcy C.
中科院分区：
文献类型：
--
作者：
Boyles, Abee L.;Enterline, David S.;Speer, Marcy C.
基亚里I型畸形（CMI; OMIM 118420）是狭义的小脑扁桃体延伸到枕骨大孔以下，导致各种神经系统症状。人们普遍认为，相对于颅骨总体积，后颅窝（PF）体积较小会导致小脑痉挛和扁桃体疝入脊柱顶部。在一组受影响个体及其家庭成员的磁共振成像（MRI）中，我们测量了10种颅骨形态之间的相关性，并估计了这些家族的遗传性。骨骼之间的相关性描绘PF和PF体积的显着遗传力（0.955，P = 0.003）支持狭窄PF理论和这种情况的遗传基础。在23个家庭的71个受影响的个人，我们进行了一个基因组范围内的连锁筛选超过10,000个单核苷酸多态性的基因组，以确定区域的连锁CMI。15号染色体上的两点LOD得分达到3.3，在该区域的多点得分确定了LOD得分超过1的13 cM区域（15q21.1-22.3）。该区域包含一个生物学上可能的CMI基因，即Rhein-1，它是马凡氏综合征的主要基因，并与Shprintzen-Goldberg综合征有关，CMI是其中的一个显著特征。9号染色体上的多点LOD得分最大化为3.05，确定了LOD得分超过1的40 cM区域（9q21.33-33.1）和多点LOD得分超过2的更紧密区域，该区域仅为8.5 cM。这一连锁证据支持遗传作用的基亚里畸形，并证明进一步探索与精细定位和调查的候选基因在这些地区。(c)2006 Wiley-Liss，Inc.
Chiari type I malformation (CMI; OMIM 118420) is narrowly defined when the tonsils of the cerebellum extend below the foramen magnum, leading to a variety of neurological symptoms. It is widely thought that a small posterior fossa (PF) volume, relative to the total cranial volume leads to a cramped cerebellum and herniation of the tonsils into the top of the spinal column. in a collection of magnetic resonance imagings (MRIs) from affected individuals and their family members, we measured correlations between ten cranial morphologies and estimated their heritability in these families. Correlations between bones delineating the PF and significant heritability of PF volume (0.955, P = 0.003) support the cramped PF theory and a genetic basis for this condition. In a collection of 23 families with 71 affected individuals, we performed a genome wide linkage screen of over 10,000 SNPs across the genome to identify regions of linkage to CMI. Two-point LOD scores on chromosome 15 reached 3.3 and multipoint scores in this region identified a 13 cM region with LOD scores over 1 (15q21.1-22.3). This region contains a biologically plausible gene for CMI, fibrillin-1, which is a major gene in Marfan syndrome and has been linked to Shprintzen-Goldberg syndrome, of which CMI is a distinguishing characteristic. Multipoint LOD scores on chromosome 9 maximized at 3.05, identifying a 40 cM region with LOD scores over 1 (9q21.33-33.1) and a tighter region with multipoint LOD scores over 2 that was only 8.5 cM. This linkage evidence supports a genetic role in Chiari malformation and justifies further exploration with fine mapping and investigation of candidate genes in these regions. (c) 2006 Wiley-Liss, Inc.