Yuan Bo, Harel Tamar, Gu Shen, Liu Pengfei, Burglen Lydie, Chantot-Bastaraud Sandra, Gelowani Violet, Beck Christine R, Carvalho Claudia M B, Cheung Sau Wai, Coe Andrew, Malan Valérie, Munnich Arnold, Magoulas Pilar L, Potocki Lorraine, Lupski James R
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
APHP, Service de génétique et embryologie médicales, CHU Paris Est - Hôpital d'Enfants Armand-Trousseau, Paris, 75571, France.
Am J Hum Genet. 2015 Nov 5;97(5):691-707. doi: 10.1016/j.ajhg.2015.10.003.
The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.
与波托茨基-卢普斯基综合征（PTLS）相关的基因组重复区域与1A型遗传性运动感觉神经病（CMT1A）相关的重复区域位置紧邻。PTLS的特征包括肌张力减退、生长发育迟缓、体重减轻、智力残疾和自闭症特征。CMT1A是一种常见的常染色体显性遗传性远端对称性周围神经病。关键的剂量敏感基因RAI1和PMP22分别与PTLS和CMT1A相关。导致大多数患有这些疾病的患者出现重复的原因是不同低拷贝重复序列（LCR）底物之间的非等位基因同源重组。围绕包含RAI1和PMP22的连续基因组区间两侧的LCR并不具有广泛的同源性；因此，包含这两个基因座的重复很少见，可能是由不同的突变机制产生的。我们通过高分辨率阵列比较基因组杂交和断点连接测序，对23名患者中同时重复PMP22和RAI1的基因组重排进行了特征分析，其中包括9种潜在的复杂基因组重排。在断点连接处发现了插入和微同源性，提示重排形成可能存在潜在的复制机制。在这些非重复性重排的断点连接处，观察到重复DNA序列的富集，表明它们可能易导致基因组不稳定和重排。临床评估显示出PTLS和CMT1A混合的表型，且神经病可能发病更早。此外，由于重排中包含额外的重复物质，可能会观察到其他临床发现。我们的基因组分析表明，复制机制是PMP22-RAI1相邻基因重复的主要机制，并为支持复杂基因组结构在基因组不稳定中的作用提供了进一步证据。
