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Targeted deep-intronic sequencing in a cohort of unexplained cases of suspected Lynch syndrome.
European Journal of Human Genetics ( IF 3.7 ) Pub Date : 2019-12-10 , DOI: 10.1038/s41431-019-0536-9 Anke Marie Arnold 1, 2 , Monika Morak 1, 3 , Anna Benet-Pagès 1 , Andreas Laner 1 , Dimitrij Frishman 2, 4 , Elke Holinski-Feder 1, 3
European Journal of Human Genetics ( IF 3.7 ) Pub Date : 2019-12-10 , DOI: 10.1038/s41431-019-0536-9 Anke Marie Arnold 1, 2 , Monika Morak 1, 3 , Anna Benet-Pagès 1 , Andreas Laner 1 , Dimitrij Frishman 2, 4 , Elke Holinski-Feder 1, 3
Affiliation
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Lynch syndrome (LS) is caused by germline defects in DNA mismatch repair (MMR) pathway, resulting in microsatellite instability (MSI-H) and loss of immunohistochemical staining (IHC) of the respective protein in tumor tissue. However, not in all clinically suspected LS patients with MSI-H tumors and IHC-loss, causative germline alterations in the MMR genes can be detected. Here, we investigated 128 of these patients to possibly define new pathomechanisms. A search for large genomic rearrangements and deep-intronic regulatory variants was performed via targeted next-generation sequencing (NGS) of exonic, intronic, and chromosomal regions upstream and downstream of MLH1, MSH2, MSH6, PMS2, MLH3, MSH3, PMS1, and EPCAM. Within this cohort, two different large rearrangements causative for LS were detected in three cases, belonging to two families (2.3%). The sensitivity to detect large rearrangements or copy number variations (CNV) was evaluated to be 50%. In 9 of the 128 patients (7%), previously overlooked pathogenic single-nucleotide variants (SNV) and two variants of uncertain significance (VUS) were identified in MLH1, MSH2, and MSH6. Pathogenic aberrations were not found in MLH3, MSH3, and PMS1. A potential effect on regulation was exerted for 19% of deep-intronic SNVs, predominantly located in chromosomal regions where the modification of histone proteins suggests an enhancer function. In conclusion, conventional variation analysis of coding regions is missing rare genomic rearrangements, nevertheless they should be analyzed. Assessment of deep-intronic SNVs is so far non-conclusive for medical questioning.
中文翻译：
在一群无法解释的林奇综合征疑似病例中进行了靶向的深度内含子测序。
林奇综合征（LS）由DNA错配修复（MMR）途径中的种系缺陷引起，导致微卫星不稳定性（MSI-H）和肿瘤组织中相应蛋白质的免疫组织化学染色（IHC）丢失。然而，并非在所有具有MSI-H肿瘤和IHC丢失的临床可疑LS患者中，都可以检测到MMR基因的致病种系改变。在这里，我们调查了这些患者中的128位，以可能定义新的病理机制。通过MLH1，MSH2，MSH6，PMS2，MLH3，MSH3，PMS1和EPCAM。在这个队列中，在三个案例中检测到两个不同的导致LS的大型重排，属于两个家族（2.3％）。检测大的重排或拷贝数变异（CNV）的灵敏度评估为50％。在128名患者中的9名（7％）中，在MLH1，MSH2和MSH6中发现了先前被忽略的病原性单核苷酸变异（SNV）和两个不确定性显着变异（VUS）。在MLH3，MSH3和PMS1中未发现致病性像差。19％的深度内含子SNV发挥了潜在的调节作用，主要位于染色体区域，在该区域中，组蛋白的修饰暗示了增强子的功能。总之，编码区的常规变异分析缺少罕见的基因组重排，但仍应进行分析。迄今为止，对深度内含性SNV的评估对于医学质询尚无定论。
更新日期：2019-12-11
中文翻译：
在一群无法解释的林奇综合征疑似病例中进行了靶向的深度内含子测序。
林奇综合征（LS）由DNA错配修复（MMR）途径中的种系缺陷引起，导致微卫星不稳定性（MSI-H）和肿瘤组织中相应蛋白质的免疫组织化学染色（IHC）丢失。然而，并非在所有具有MSI-H肿瘤和IHC丢失的临床可疑LS患者中，都可以检测到MMR基因的致病种系改变。在这里，我们调查了这些患者中的128位，以可能定义新的病理机制。通过MLH1，MSH2，MSH6，PMS2，MLH3，MSH3，PMS1和EPCAM。在这个队列中，在三个案例中检测到两个不同的导致LS的大型重排，属于两个家族（2.3％）。检测大的重排或拷贝数变异（CNV）的灵敏度评估为50％。在128名患者中的9名（7％）中，在MLH1，MSH2和MSH6中发现了先前被忽略的病原性单核苷酸变异（SNV）和两个不确定性显着变异（VUS）。在MLH3，MSH3和PMS1中未发现致病性像差。19％的深度内含子SNV发挥了潜在的调节作用，主要位于染色体区域，在该区域中，组蛋白的修饰暗示了增强子的功能。总之，编码区的常规变异分析缺少罕见的基因组重排，但仍应进行分析。迄今为止，对深度内含性SNV的评估对于医学质询尚无定论。
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