Lohmann Katja, Redin Claire, Tönnies Holger, Bressman Susan B, Subero Jose Ignacio Martin, Wiegers Karin, Hinrichs Frauke, Hellenbroich Yorck, Rakovic Aleksandar, Raymond Deborah, Ozelius Laurie J, Schwinger Eberhard, Siebert Reiner, Talkowski Michael E, Saunders-Pullman Rachel, Klein Christine
Institute of Neurogenetics, University Lübeck, Lübeck, Germany.
Center for Genomic Medicine, Massachusetts General Hospital, Boston.
JAMA Neurol. 2017 Jul 1;74(7):806-812. doi: 10.1001/jamaneurol.2017.0666.
Chromosomal rearrangements are increasingly recognized to underlie neurologic disorders and are often accompanied by additional clinical signs beyond the gene-specific phenotypic spectrum.
To elucidate the causal genetic variant in a large US family with co-occurrence of dopa-responsive dystonia as well as skeletal and eye abnormalities (ie, ptosis, myopia, and retina detachment).
DESIGN, SETTING, AND PARTICIPANTS: We examined 10 members of a family, including 5 patients with dopa-responsive dystonia and skeletal and/or eye abnormalities, from a US tertiary referral center for neurological diseases using multiple conventional molecular methods, including fluorescence in situ hybridization and array comparative genomic hybridization as well as large-insert whole-genome sequencing to survey multiple classes of genomic variations. Of note, there was a seemingly implausible transmission pattern in this family due to a mutation-negative obligate mutation carrier.
Genetic diagnosis in affected family members and insight into the formation of large deletions.
Four members were diagnosed with definite and 1 with probable dopa-responsive dystonia. All 5 affected individuals carried a large heterozygous deletion encompassing all 6 exons of GCH1. Additionally, all mutation carriers had congenital ptosis requiring surgery, 4 had myopia, 2 had retinal detachment, and 2 showed skeletal abnormalities of the hands, ie, polydactyly or syndactyly or missing a hand digit. Two individuals were reported to be free of any disease. Analyses revealed complex chromosomal rearrangements on chromosome 14q21-22 in unaffected individuals that triggered the expansion to a larger deletion segregating with affection status. The expansion occurred recurrently, explaining the seemingly non-mendelian inheritance pattern. These rearrangements included a deletion of GCH1, which likely contributes to the dopa-responsive dystonia, as well as a deletion of BMP4 as a potential cause of digital and eye abnormalities.
Our findings alert neurologists to the importance of clinical red flags, ie, unexpected co-occurrence of clinical features that may point to the presence of chromosomal rearrangements as the primary disease cause. The clinical management and diagnostics of such patients requires an interdisciplinary approach in modern clinical-diagnostic care.
越来越多的人认识到染色体重排是神经系统疾病的基础，并且通常伴随着超出基因特异性表型谱的其他临床体征。
在一个美大家族中阐明因果遗传变异，该家族同时出现多巴反应性肌张力障碍以及骨骼和眼部异常（即上睑下垂、近视和视网膜脱离）。
设计、地点和参与者：我们使用多种传统分子方法，包括荧光原位杂交、阵列比较基因组杂交以及大插入片段全基因组测序，对一家美国三级神经疾病转诊中心的10名家庭成员进行了检查，其中包括5名患有多巴反应性肌张力障碍以及骨骼和/或眼部异常的患者，以检测多种类型的基因组变异。值得注意的是，由于一名突变阴性的必然突变携带者，这个家族存在看似不合理的遗传模式。
对受影响家庭成员进行基因诊断，并深入了解大缺失的形成。
4名成员被诊断为确诊的多巴反应性肌张力障碍，1名成员可能患有该疾病。所有5名受影响个体均携带一个大的杂合缺失，该缺失涵盖GCH1的所有6个外显子。此外，所有突变携带者都有需要手术治疗的先天性上睑下垂，4人患有近视，2人患有视网膜脱离，2人表现出手部骨骼异常，即多指畸形、并指畸形或缺少一个手指。据报告有2人未患任何疾病。分析显示，未受影响个体的14号染色体q21-22区域存在复杂的染色体重排，这些重排引发了向与患病状态分离的更大缺失的扩展。这种扩展反复发生，解释了看似不符合孟德尔遗传模式的现象。这些重排包括GCH1的缺失，这可能导致多巴反应性肌张力障碍，以及BMP4的缺失，这可能是手指和眼部异常的潜在原因。
我们的研究结果提醒神经科医生注意临床警示信号的重要性，即临床特征的意外同时出现可能表明染色体重排是主要病因。对此类患者的临床管理和诊断需要现代临床诊断护理中的多学科方法。
