Ek Marlene, Kvarnung Malin, Pettersson Maria, Soller Maria Johansson, Anderlid Britt-Marie, Thonberg Håkan, Eisfeldt Jesper, Lindstrand Anna
Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden.
Department of Clinical Genetics and Genomics, Karolinska University Hospital, 171 76, Stockholm, Sweden.
Sci Rep. 2024 Dec 5;14(1):30343. doi: 10.1038/s41598-024-81507-7.
Inversions are balanced structural variants that often remain undetected in genetic diagnostics. We present a female proband with a de novo Chromosome 15 paracentric inversion, disrupting MEIS2 and NUSAP1. The inversion was detected by short-read genome sequencing and confirmed with adaptive long-read sequencing. The breakpoint junction analysis revealed a 96 bp (bp) deletion and an 18 bp insertion in the two junctions, suggesting that the rearrangement arose through a replicative error. Transcriptome sequencing of cultured fibroblasts revealed normal MEIS2 levels and 0.61-fold decreased expression of NUSAP1. Furthermore, three fusion transcripts were detected and confirmed by Sanger sequencing. Heterozygous loss of MEIS2 (MIM# 600987) is associated with a cleft palate, heart malformations, and intellectual impairment, which overlap with the clinical symptoms observed in the proband. The observed fusion transcripts are likely non-functional, and MEIS2 haploinsufficiency is the likely disease causative mechanism. Altogether, this study's findings illustrate the importance of including inversions in rare disease diagnostic testing and highlight the value of long read sequencing for the validation and characterization of such variants.
倒位是一种平衡的结构变异，在基因诊断中常常难以被检测到。我们报告了一名女性先证者，其发生了15号染色体的新发臂间倒位，破坏了MEIS2和NUSAP1基因。该倒位通过短读长基因组测序检测到，并经适应性长读长测序得以证实。断点连接分析显示，两个连接处分别有96个碱基对（bp）的缺失和18个碱基对的插入，提示该重排是由复制错误引起的。对培养的成纤维细胞进行转录组测序，结果显示MEIS2水平正常，而NUSAP1的表达下降了0.61倍。此外，检测到三个融合转录本，并经桑格测序证实。MEIS2（MIM# 600987）杂合性缺失与腭裂、心脏畸形和智力障碍有关，这些与在先证者中观察到的临床症状相符。所观察到的融合转录本可能无功能，MEIS2单倍剂量不足可能是致病机制。总之，本研究结果说明了在罕见病诊断检测中纳入倒位检测的重要性，并突出了长读长测序对于此类变异的验证和特征描述的价值。
