Ali S Alzahrani, Abdulghani Bin Nafisah, Meshael Alswailem, Balgees Alghamdi, Burair Alsaihati, Hussain Aljafar, Batoul Baz, Hindi Alhindi, Yosra Moria, Muhammad Imran Butt, Abdulrahman Ghiatheddin Alkabbani, Omalkhaire M Alshaikh, Anhar Alnassar, Ahmed Bin Afeef, Reem AlQuraa, Rawan Alsuhaibani, Omar Alhadlaq, Fayha Abothenain, Yasser A Altwaijry
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None of these patients had family history of PA or a known PA-associated syndrome. Peripheral blood DNA was isolated and whole-exome sequenced. We used American College of Medical Genetics and Genomics (ACMG) criteria and a number of in silico analysis tools to characterize genetic variant pathogenicity levels and focused on previously reported PA-associated genes.</p><p><strong>Results: </strong>We identified 35 variants of unknown significance (VUS) in 17 PA-associated genes occurring in 40 patients (29.8%). Although designated VUS by the strict ACGM criteria, they are predicted to be pathogenic by in silico analyses and their extremely low frequencies in 1000 genome, gnomAD, and the Saudi Genome Project databases. Further analysis of these variants by the Alpha Missense analysis tool yielded 8 likely pathogenic variants in 9 patients in the following genes: <i>AIP</i>:c.767C>T (p.S256F), <i>CDH23</i>:c.906G>C (p.E302D), <i>CDH23</i>:c.1096G>A (p.A366T), <i>DICER1</i>:c.620C>T (p.A207V), <i>MLH1</i>:c.955G>A (p.E319K), <i>MSH2</i>:c.148G>A (p.A50T), <i>SDHA</i>:c.869T>C (p.L290P) and <i>USP48</i> (2 patients): c.2233G>A (p.V745M).</p><p><strong>Conclusion: </strong>This study suggests that about 6.7% of patients with apparently sporadic PAs carry likely pathogenic variants in PA-associated genes. 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Their median age was 34 years (range, 11-85 years) and 31 patients had microadenomas (23.0%) and 103 macroadenomas (77%). None of these patients had family history of PA or a known PA-associated syndrome. Peripheral blood DNA was isolated and whole-exome sequenced. We used American College of Medical Genetics and Genomics (ACMG) criteria and a number of in silico analysis tools to characterize genetic variant pathogenicity levels and focused on previously reported PA-associated genes.</p><p><strong>Results: </strong>We identified 35 variants of unknown significance (VUS) in 17 PA-associated genes occurring in 40 patients (29.8%). Although designated VUS by the strict ACGM criteria, they are predicted to be pathogenic by in silico analyses and their extremely low frequencies in 1000 genome, gnomAD, and the Saudi Genome Project databases. Further analysis of these variants by the Alpha Missense analysis tool yielded 8 likely pathogenic variants in 9 patients in the following genes: <i>AIP</i>:c.767C>T (p.S256F), <i>CDH23</i>:c.906G>C (p.E302D), <i>CDH23</i>:c.1096G>A (p.A366T), <i>DICER1</i>:c.620C>T (p.A207V), <i>MLH1</i>:c.955G>A (p.E319K), <i>MSH2</i>:c.148G>A (p.A50T), <i>SDHA</i>:c.869T>C (p.L290P) and <i>USP48</i> (2 patients): c.2233G>A (p.V745M).</p><p><strong>Conclusion: </strong>This study suggests that about 6.7% of patients with apparently sporadic PAs carry likely pathogenic variants in PA-associated genes. 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引用次数: 0
摘要
背景：利用全外显子组测序（WES）研究垂体腺瘤（PAs）种系遗传学的数据十分有限：本研究利用 WES 调查了 PA 患者的种系遗传变异：我们研究了 134 例连续的功能性（80.6%）和非功能性（19.4%）PA，其中女性患者 61 例（45.5%），男性患者 73 例（54.5%）。他们的中位年龄为34岁（11-85岁），31名患者患有微腺瘤（23.0%），103名患者患有大腺瘤（77%）。这些患者均无 PA 家族史或已知的 PA 相关综合征。我们分离了外周血DNA并进行了全外显子组测序。我们采用了美国医学遗传学和基因组学学会（ACMG）的标准和一些硅学分析工具来确定遗传变异的致病性水平，并重点研究了之前报道的 PA 相关基因：我们在 40 名患者（29.8%）的 17 个 PA 相关基因中发现了 35 个意义不明的变异（VUS）。尽管根据严格的 ACGM 标准，这些变异被指定为 VUS，但根据硅学分析及其在 1000 基因组、gnomAD 和沙特基因组计划数据库中极低的频率，这些变异被预测为致病基因。通过阿尔法错义分析工具对这些变异进行进一步分析，在 9 名患者中发现了 8 个可能致病的变异，它们分别位于以下基因中：AIP:c.767C>T（p.S256F）、CDH23:c.906G>C（p.E302D）、CDH23:c.1096G>A（p.A366T）、DICER1:c.620C>T（p.A207V）、MLH1:c.955G>A（p.E319K）、MSH2:c.148G>A（p.A50T）、SDHA:c.869T>C（p.L290P）和 USP48（2 名患者）：c.2233G>A（p.V745M）：本研究表明，约有 6.7% 的明显散发性 PA 患者可能携带 PA 相关基因的致病变异。这些发现需要进一步的研究来证实。
Context: Data on germline genetics of pituitary adenomas (PAs) using whole-exome sequencing (WES) are limited.
Objective: This study investigated the germline genetic variants in patients with PAs using WES.
Methods: We studied 134 consecutive functioning (80.6%) and nonfunctioning (19.4%) PAs in 61 female (45.5%) and 73 male patients (54.5%). Their median age was 34 years (range, 11-85 years) and 31 patients had microadenomas (23.0%) and 103 macroadenomas (77%). None of these patients had family history of PA or a known PA-associated syndrome. Peripheral blood DNA was isolated and whole-exome sequenced. We used American College of Medical Genetics and Genomics (ACMG) criteria and a number of in silico analysis tools to characterize genetic variant pathogenicity levels and focused on previously reported PA-associated genes.
Results: We identified 35 variants of unknown significance (VUS) in 17 PA-associated genes occurring in 40 patients (29.8%). Although designated VUS by the strict ACGM criteria, they are predicted to be pathogenic by in silico analyses and their extremely low frequencies in 1000 genome, gnomAD, and the Saudi Genome Project databases. Further analysis of these variants by the Alpha Missense analysis tool yielded 8 likely pathogenic variants in 9 patients in the following genes: AIP:c.767C>T (p.S256F), CDH23:c.906G>C (p.E302D), CDH23:c.1096G>A (p.A366T), DICER1:c.620C>T (p.A207V), MLH1:c.955G>A (p.E319K), MSH2:c.148G>A (p.A50T), SDHA:c.869T>C (p.L290P) and USP48 (2 patients): c.2233G>A (p.V745M).
Conclusion: This study suggests that about 6.7% of patients with apparently sporadic PAs carry likely pathogenic variants in PA-associated genes. These findings need further studies to confirm them.
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