Branchio-Otic Syndrome Caused by a Genomic Rearrangement: Clinical Findings and Molecular Cytogenetic Studies in a Patient with a Pericentric Inversion of Chromosome 8
Branchio-Otic Syndrome Caused by a Genomic Rearrangement: Clinical Findings and Molecular Cytogenetic Studies in a Patient with a Pericentric Inversion of Chromosome 8
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DOI：
10.1159/000355436
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发表时间：
2014-01-01
影响因子：
1.7
通讯作者：
Kutsche, K.
中科院分区：
文献类型：
--
作者：
Schmidt, T.;Bierhals, T.;Kutsche, K.
鳃-耳-肾（BOR）综合征是一种常染色体显性遗传性发育障碍，其特征是耳朵、鳃弓和肾脏的异常。它是由 EYA1、SIX1 和 SIX5 基因突变引起的。影响 EYA1 基因的 8 号染色体的基因组重排也已被描述。鉴于此，多重连接依赖性探针扩增 (MLPA) 等异常拷贝数识别方法已被引入作为 BOR 综合征分子诊断的常规实验室技术。与标准细胞遗传学和阵列方法以及 Southern blot 相比，这些技术的优点是显而易见的。 MLPA 可检测部分或整个感兴趣基因的缺失或重复，但不能检测平衡的结构畸变，例如倒位和易位。因此，基因组重排对基因的破坏可能会逃避分子遗传学分析的检测，尽管这种基因破坏会导致单倍体不足，从而导致疾病。对于一名具有 BOR 综合征临床特征（例如听力丧失、耳前瘘管和面部畸形，但没有肾脏异常）的患者，与 BOR 综合征相关的 3 个基因的测序以及阵列比较基因组杂交和 MLPA 均无法发现致病突变。通过常规细胞遗传学分析，我们最终在受影响的女性中发现了 8 号染色体的中心倒位。高分辨率多色显带证实了 8 号染色体倒位，并将核型范围缩小到 46,XX,inv(8)(p22q13)。通过荧光原位杂交，我们缩小了8号染色体上的两个断点范围，发现q13.3中的EYA1基因被直接破坏。我们的结论是，在 BOR 综合征或其他孟德尔疾病的遗传诊断中，标准核型分析不应被忽视，特别是当分子检测未能检测到具有令人信服的表型的患者的任何致病性改变时。 (C) 2013 S. Karger AG，巴塞尔
Branchio-oto-renal (BOR) syndrome is an autosomal dominantly inherited developmental disorder, which is characterized by anomalies of the ears, the branchial arches and the kidneys. It is caused by mutations in the genes EYA1, SIX1 and SIX5. Genomic rearrangements of chromosome 8 affecting the EYA1 gene have also been described. Owing to this fact, methods for the identification of abnormal copy numbers such as multiplex ligation-dependent probe amplification (MLPA) have been introduced as routine laboratory techniques for molecular diagnostics of BOR syndrome. The advantages of these techniques are clear compared to standard cytogenetic and array approaches as well as Southern blot. MLPA detects deletions or duplications of a part or the entire gene of interest, but not balanced structural aberrations such as inversions and translocations. Consequently, disruption of a gene by a genomic rearrangement may escape detection by a molecular genetic analysis, although this gene interruption results in haploinsufficiency and, therefore, causes the disease. In a patient with clinical features of BOR syndrome, such as hearing loss, preauricular fistulas and facial dysmorphisms, but no renal anomalies, neither sequencing of the 3 genes linked to BOR syndrome nor array comparative genomic hybridization and MLPA were able to uncover a causative mutation. By routine cytogenetic analysis, we finally identified a pericentric inversion of chromosome 8 in the affected female. High-resolution multicolor banding confirmed the chromosome 8 inversion and narrowed down the karyotype to 46,XX,inv(8)(p22q13). By applying fluorescence in situ hybridization, we narrowed down both breakpoints on chromosome 8 and found the EYA1 gene in q13.3 to be directly disrupted. We conclude that standard karyotyping should not be neglected in the genetic diagnostics of BOR syndrome or other Mendelian disorders, particularly when molecular testing failed to detect any causative alteration in patients with a convincing phenotype. (C) 2013 S. Karger AG, Basel