Department of Genetics, CHEO, Ottawa, Ontario, Canada.
Department of Pathology and Laboratory Medicine University of Ottawa, Ottawa, Ontario, Canada.
Am J Med Genet C Semin Med Genet. 2018 Dec;178(4):447-457. doi: 10.1002/ajmg.c.31660.
Nablus syndrome was first described by the late Ahmad Teebi in 2000, and 13 individuals have been reported to date. Nablus syndrome can be clinically diagnosed based on striking facial features, including tight glistening skin with reduced facial expression, blepharophimosis, telecanthus, bulky nasal tip, abnormal external ear architecture, upswept frontal hairline, and sparse eyebrows. However, the precise genetic etiology for this rare condition remains elusive. Comparative microarray analyses of individuals with Nablus syndrome (including two mother-son pairs) reveal an overlapping 8q22.1 microdeletion, with a minimal critical region of 1.84 Mb (94.43-96.27 Mb). Whereas this deletion is present in all affected individuals, 13 individuals without Nablus syndrome (including two mother-child pairs) also have the 8q22.1 microdeletion that partially or fully overlaps the minimal critical region. Thus, the 8q22.1 microdeletion is necessary but not sufficient to cause the clinical features characteristic of Nablus syndrome. We discuss possible explanations for Nablus syndrome, including one-locus, two-locus, epigenetic, and environmental mechanisms. We performed exome sequencing for five individuals with Nablus syndrome. Although we failed to identify any deleterious rare coding variants in the critical region that were shared between individuals, we did identify one common SNP in an intronic region that was shared. Clearly, unraveling the genetic mechanism(s) of Nablus syndrome will require additional investigation, including genomic and RNA sequencing of a larger cohort of affected individuals. If successful, it will provide important insights into fundamental concepts such as variable expressivity, incomplete penetrance, and complex disease relevant to both Mendelian and non-Mendelian disorders.
纳布卢斯综合征由已故的艾哈迈德·提比（Ahmad Teebi）于 2000 年首次描述，迄今为止已报告了 13 例。纳布卢斯综合征可以根据显著的面部特征进行临床诊断，包括皮肤紧绷、表情减少、睑裂狭小、内眦赘皮、宽大的鼻尖、外耳结构异常、额发上翘和稀疏的眉毛。然而，这种罕见疾病的确切遗传病因仍难以捉摸。对纳布卢斯综合征患者（包括两对母子）的比较微阵列分析显示，存在重叠的 8q22.1 微缺失，最小关键区域为 1.84 Mb（94.43-96.27 Mb）。虽然所有受影响的个体都存在该缺失，但 13 名没有纳布卢斯综合征的个体（包括两对母子）也存在部分或完全重叠最小关键区域的 8q22.1 微缺失。因此，8q22.1 微缺失是导致纳布卢斯综合征特征性临床特征的必要但非充分条件。我们讨论了纳布卢斯综合征的可能解释，包括单基因座、双基因座、表观遗传和环境机制。我们对五名纳布卢斯综合征患者进行了外显子组测序。尽管我们未能在个体之间共享的关键区域中发现任何有害的罕见编码变异，但我们确实在一个共享的内含子区域中发现了一个常见的 SNP。显然，阐明纳布卢斯综合征的遗传机制需要进一步研究，包括对更大的受影响个体群体进行基因组和 RNA 测序。如果成功，它将为可变表达、不完全外显率和与孟德尔和非孟德尔疾病相关的复杂疾病等基本概念提供重要的见解。
