Genome sequencing reveals novel noncoding variants in PLA2G6 and LMNB1 causing progressive neurologic disease.
Genome sequencing reveals novel noncoding variants in PLA2G6 and LMNB1 causing progressive neurologic disease.
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DOI：
10.1002/mgg3.1892
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发表时间：
2022-04
影响因子：
2
通讯作者：
中科院分区：
文献类型：
--
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神经退行性疾病和脑白质营养不良是在基因表达的复杂协调模式被破坏后可能发生的进行性神经病症。外显子组测序已被用作确定孟德尔神经系统疾病潜在遗传病因的有效诊断工具，然而基因组测序在识别和表征非编码区的拷贝数、结构和序列变体的能力方面具有优势。对两名病因不明的进行性神经系统疾病患者进行了外周血白细胞基因组测序，这些患者在包括外显子组测序在内的阴性遗传学检查后。对其中一名患者的外周血进行RNA测序，以确定其基因表达模式。潜在的致病变异与患者的临床表现相匹配。第一个先证者被发现是PLA 2G 6中可能的致病性错义变体（c.386T>C; p.Leu129Pro）的杂合子，并且在PLA 2G 6中具有额外的深内含子变体（c.2035 - 926 G>A）。RNA测序表明后一种变体产生了一个剪接受体位点，导致引入提前终止密码子的假外显子的掺入。第二个先证者是杂合子的261 kb缺失上游LMNB 1，包括增强子区域。先前报道的跨越顺式作用调控元件的该区域的拷贝数变体证实了其致病性。当结合临床表现时，这些发现分别导致常染色体隐性婴儿神经轴索营养不良和常染色体显性成人发作脱髓鞘性脑白质营养不良的明确诊断。在病因不明的进行性神经系统疾病患者中，应考虑在适当情况下增加RNA分析的基因组测序，以识别致病性非编码致病性变体。对两名病因不明的进行性神经系统疾病先证者进行基因组测序。第一个先证者被发现是PLA 2G 6中致病性错义变体（c.386T>C; p.Leu129Pro）的杂合型，并且在PLA 2G 6中具有额外的深度内含子变体（c.2035 - 926 G>A），产生RNA测序检测到的剪接受体位点。第二个先证者是杂合子的261 kb缺失上游LMNB 1，包括增强子区域。这些发现分别导致常染色体隐性婴儿神经轴索营养不良和常染色体显性成人发作脱髓鞘性脑白质营养不良的明确诊断。
Neurodegenerative disorders and leukodystrophies are progressive neurologic conditions that can occur following the disruption of intricately coordinated patterns of gene expression. Exome sequencing has been adopted as an effective diagnostic tool for determining the underlying genetic etiology of Mendelian neurologic disorders, however genome sequencing offer advantages in its ability to identify and characterize copy number, structural, and sequence variants in noncoding regions. Genome sequencing from peripheral leukocytes was performed on two patients with progressive neurologic disease of unknown etiology following negative genetic investigations including exome sequencing. RNA sequencing from peripheral blood was performed to determine gene expression patterns in one of the patients. Potential causative variants were matched to the patients’ clinical presentation. The first proband was found to be heterozygous for a likely pathogenic missense variant in PLA2G6 (c.386T>C; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6 (c.2035‐926G>A). RNA sequencing indicated this latter variant created a splice acceptor site leading to the incorporation of a pseudo‐exon introducing a premature termination codon. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. Previous reports of copy number variants spanning this region of cis‐acting regulatory elements corroborated its pathogenicity. When combined with clinical presentations, these findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult‐onset demyelinating leukodystrophy, respectively. In patients with progressive neurologic disease of unknown etiology, genome sequencing with the addition of RNA analysis where appropriate should be considered for the identification of causative noncoding pathogenic variants. Genome sequencing was performed on two probands with progressive neurologic disease of unknown etiology. The first proband was found to be heterozygous for a pathogenic missense variant in PLA2G6 (c.386T>C; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6, (c.2035‐926G>A) creating a splice acceptor site detected with RNA sequencing. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. These findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult‐onset demyelinating leukodystrophy, respectively.
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DOI：
10.1038/gim.2017.119
发表时间：
2018-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Lionel AC;Costain G;Monfared N;Walker S;Reuter MS;Hosseini SM;Thiruvahindrapuram B;Merico D;Jobling R;Nalpathamkalam T;Pellecchia G;Sung WWL;Wang Z;Bikangaga P;Boelman C;Carter MT;Cordeiro D;Cytrynbaum C;Dell SD;Dhir P;Dowling JJ;Heon E;Hewson S;Hiraki L;Inbar-Feigenberg M;Klatt R;Kronick J;Laxer RM;Licht C;MacDonald H;Mercimek-Andrews S;Mendoza-Londono R;Piscione T;Schneider R;Schulze A;Silverman E;Siriwardena K;Snead OC;Sondheimer N;Sutherland J;Vincent A;Wasserman JD;Weksberg R;Shuman C;Carew C;Szego MJ;Hayeems RZ;Basran R;Stavropoulos DJ;Ray PN;Bowdin S;Meyn MS;Cohn RD;Scherer SW;Marshall CR
通讯作者：
Marshall CR
影响因子：
3.1
作者：
Nmezi, Bruce;Giorgio, Elisa;Padiath, Quasar S.
通讯作者：
Padiath, Quasar S.
影响因子：
3.5
作者：
Giorgio, Elisa;Robyr, Daniel;Brusco, Alfredo
通讯作者：
Brusco, Alfredo
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.1002/ajmg.a.61558
发表时间：
2020-06
期刊：
American journal of medical genetics. Part A
影响因子：
--
作者：
Burdick KJ;Cogan JD;Rives LC;Robertson AK;Koziura ME;Brokamp E;Duncan L;Hannig V;Pfotenhauer J;Vanzo R;Paul MS;Bican A;Morgan T;Duis J;Newman JH;Hamid R;Phillips JA 3rd;Undiagnosed Diseases Network
通讯作者：
Undiagnosed Diseases Network