Markunas Christina A, Enterline David S, Dunlap Kaitlyn, Soldano Karen, Cope Heidi, Stajich Jeffrey, Grant Gerald, Fuchs Herbert, Gregory Simon G, Ashley-Koch Allison E
Center for Human Genetics, Duke University Medical Center, Durham, NC, USA.
Ann Hum Genet. 2014 Jan;78(1):1-12. doi: 10.1111/ahg.12041. Epub 2013 Oct 6.
Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the base of the skull. Although cerebellar tonsillar herniation (CTH) is hypothesized to result from an underdeveloped posterior cranial fossa (PF), patients are frequently diagnosed by the extent of CTH without cranial morphometric assessment. We recently completed the largest CMI whole genome qualitative linkage screen to date. Despite an initial lack of statistical evidence, stratified analyses using clinical criteria to reduce heterogeneity resulted in a striking increase in evidence for linkage. The present study focused on the use of cranial base morphometrics to further dissect this heterogeneity and increase power to identify disease genes. We characterized the genetic contribution for a series of PF traits and evaluated the use of heritable, disease-relevant PF traits in ordered subset analysis (OSA). Consistent with a genetic hypothesis for CMI, much of the PF morphology was found to be heritable and multiple genomic regions were strongly implicated from OSA, including regions on Chromosomes 1 (LOD = 3.07, p = 3 × 10(-3) ) and 22 (LOD = 3.45, p = 6 × 10(-5) ) containing several candidates warranting further investigation. This study underscores the genetic heterogeneity of CMI and the utility of PF traits in CMI genetic studies.
Chiari I型畸形（CMI）的特征是小脑扁桃体通过颅底疝出。尽管推测小脑扁桃体疝（CTH）是由后颅窝（PF）发育不全引起的，但患者常根据CTH的程度进行诊断，而未进行颅骨形态测量评估。我们最近完成了迄今为止最大规模的CMI全基因组定性连锁筛查。尽管最初缺乏统计学证据，但使用临床标准进行分层分析以减少异质性，显著增加了连锁证据。本研究重点在于利用颅底形态测量学进一步剖析这种异质性，并提高识别疾病基因的能力。我们对一系列PF特征的遗传贡献进行了表征，并评估了在有序子集分析（OSA）中使用可遗传的、与疾病相关的PF特征的情况。与CMI的遗传假说一致，发现许多PF形态是可遗传的，并且OSA强烈提示了多个基因组区域，包括1号染色体（LOD = 3.07，p = 3 × 10⁻³）和22号染色体（LOD = 3.45，p = 6 × 10⁻⁵）上包含几个有待进一步研究的候选基因的区域。这项研究强调了CMI的遗传异质性以及PF特征在CMI遗传研究中的实用性。
