Sanggaard Kirsten Marie, Rendtorff Nanna Dahl, Kjaer Klaus Wilbrandt, Eiberg Hans, Johnsen Torsten, Gimsing Steen, Dyrmose Jørgen, Nielsen Kristian Otto, Lage Kasper, Tranebjaerg Lisbeth
Wilhelm Johannsen Centre for Functional Genome Research, Section of Genetics, Institute of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Eur J Hum Genet. 2007 Nov;15(11):1121-31. doi: 10.1038/sj.ejhg.5201900. Epub 2007 Jul 18.
The branchio-oto-renal (BOR) syndrome is an autosomal-dominant disorder characterized by hearing loss, branchial and renal anomalies. BOR is genetically heterogeneous and caused by mutations in EYA1 (8q13.3), SIX1 (14q23.1), SIX5 (19q13.3) and in an unidentified gene on 1q31. We examined six Danish families with BOR syndrome by assessing linkage to BOR loci, by performing EYA1 multiplex ligation-dependent probe amplification (MLPA) analysis for deletions and duplications and by sequencing of EYA1, SIX1 and SIX5. We identified four EYA1 mutations (c.920delG, IVS10-1G>A, IVS12+4A>G and p.Y591X) and one SIX1 mutation (p.W122R), providing a molecular diagnosis in five out of the six families (83%). The present, yet preliminary, observation that renal and temporal bone malformations are less frequent in SIX1-related disease suggests a slightly different clinical profile compared to EYA1-related disease. Unidentified mutations impairing mRNA expression or further genetic heterogeneity may explain the lack of mutation finding in one family despite LOD score indications of EYA1 involvement.
鳃耳肾（BOR）综合征是一种常染色体显性疾病，其特征为听力丧失、鳃部和肾脏异常。BOR具有遗传异质性，由EYA1（8q13.3）、SIX1（14q23.1）、SIX5（19q13.3）以及1q31上一个未明确的基因发生突变所致。我们通过评估与BOR基因座的连锁关系、对EYA1进行多重连接依赖探针扩增（MLPA）分析以检测缺失和重复，以及对EYA1、SIX1和SIX5进行测序，对六个患有BOR综合征的丹麦家庭进行了研究。我们鉴定出四个EYA1突变（c.920delG、IVS10 - 1G>A、IVS12 + 4A>G和p.Y591X）以及一个SIX1突变（p.W122R），在六个家庭中的五个家庭（83%）中做出了分子诊断。目前虽属初步的观察结果显示，与EYA1相关疾病相比，SIX1相关疾病中肾脏和颞骨畸形的发生率较低，这表明其临床特征略有不同。尽管LOD评分表明EYA1有牵连，但未鉴定出的影响mRNA表达的突变或进一步的遗传异质性可能解释了在一个家庭中未发现突变的原因。
