Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1.,Genetics in Medicine

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Constitutional mismatch repair deficiency is the diagnosis in 0.41% of pathogenic NF1/SPRED1 variant negative children suspected of sporadic neurofibromatosis type 1.
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-08-10 , DOI: 10.1038/s41436-020-0925-z
Juan A Perez-Valencia ₁ , Richard Gallon ₂ , Yunjia Chen ₃ , Jakob Koch ₁ , Markus Keller ₁ , Klaus Oberhuber ₁ , Alicia Gomes ₃ , Johannes Zschocke ₁ , John Burn ₂ , Michael S Jackson ₂ , Mauro Santibanez-Koref ₂ , Ludwine Messiaen ₃ , Katharina Wimmer ₁

Affiliation

Purpose

Biallelic germline mismatch repair (MMR) gene pathogenic variants (PVs) cause constitutional MMR deficiency (CMMRD), a highly penetrant childhood cancer syndrome phenotypically overlapping with neurofibromatosis type 1 (NF1). CMMRD testing in suspected NF1 children without NF1/SPRED1 PVs enables inclusion of CMMRD positives into monitoring programs prior to tumor onset. However, testing is associated with potential harms and the prevalence of CMMRD among these children is unknown.

Methods

Using a simple and scalable microsatellite instability (MSI) assay of non-neoplastic leukocyte DNA to detect CMMRD, we retrospectively screened >700 children suspected of sporadic NF1 but lacking NF1/SPRED1 PVs.

Results

For three of seven MSI-positive patients germline MMR gene PVs confirmed the diagnosis of CMMRD. Founder variants NM_000535.5(PMS2):c.736_741delinsTGTGTGTGAAG, prevalent in Europe and North America, and NM_000179.2(MSH6):c.10C>G, affecting 1:400 French Canadians, represented two of five PVs. The prevalence of CMMRD was 3/735 (0.41%, 95% confidence interval [CI]: 0.08–1.19%).

Conclusion

Our empirical data provide reliable numbers for genetic counseling and confirm previous prevalence estimations, on which Care for CMMRD consortium guidelines are based. These advocate CMMRD testing of preselected patients rather than offering reflex testing to all suspected sporadic NF1 children lacking NF1/SPRED1 PVs. The possibility of founder effects should be considered alongside these testing guidelines.

中文翻译：

0.41% 的致病性 NF1/SPRED1 变异阴性疑似散发性神经纤维瘤病 1 型儿童被诊断为体质性错配修复缺陷。

目的

双等位基因种系错配修复 (MMR) 基因致病变异 (PV) 导致体质性 MMR 缺陷 (CMMRD)，这是一种高度渗透的儿童癌症综合征，表型与 1 型神经纤维瘤病 (NF1) 重叠。在没有NF1 / SPRED1 PV的疑似 NF1 儿童中进行 CMMRD 检测，可以在肿瘤发作前将 CMMRD 阳性纳入监测计划。然而，检测与潜在危害相关，这些儿童中 CMMRD 的患病率尚不清楚。

方法

我们使用一种简单且可扩展的非肿瘤性白细胞 DNA 微卫星不稳定性 (MSI) 检测方法来检测 CMMRD，我们回顾性筛查了 700 多名疑似散发性 NF1 但缺乏NF1 / SPRED1 PV 的儿童。

结果

对于七名 MSI 阳性患者中的三名，种系 MMR 基因 PV 证实了 CMMRD 的诊断。Founder 变体 NM_000535.5(PMS2):c.736_741delinsTGTGTGTGAAG，在欧洲和北美流行，NM_000179.2(MSH6):c.10C>G，影响 1:400 法裔加拿大人，代表了五个 PV 中的两个。CMMRD 的患病率为 3/735（0.41%，95% 置信区间 [CI]：0.08–1.19%）。