Damla Eker, Hakan Gurkan, Yasemin Karal, Sinem Yalcintepe, Selma Demir, Engin Atli, Serap T Karasalihoglu
{"title":"利用下一代测序方法研究小儿外周性张力低下的遗传病因。","authors":"Damla Eker, Hakan Gurkan, Yasemin Karal, Sinem Yalcintepe, Selma Demir, Engin Atli, Serap T Karasalihoglu","doi":"10.1055/s-0042-1745873","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background</b> Hypotonia occurs as a result of neurological dysfunction in the brain, brainstem, spinal cord, motor neurons, anterior horn cells, peripheral nerves, and muscles. Although the genotype-phenotype correlation can be established in 15 to 30% of patients, it is difficult to obtain a correlation in most cases. <b>Aims</b> This study was aimed to investigate the genetic etiology in cases of peripheral hypotonia that could not be diagnosed using conventional methods. <b>Methods</b> A total of 18 pediatric patients with peripheral hypotonia were included. They were referred to our genetic disorders diagnosis center from the Pediatric Neurology Department with a prediagnosis of hypotonia. A custom designed multigene panel, including <i>ACTA1</i> , <i>CCDC78</i> , <i>DYNC1H1</i> , <i>GARS</i> , <i>RYR1</i> , <i>COL6A1</i> , <i>COL6A2</i> , <i>COL6A3</i> , <i>FKRP</i> , <i>FKTN</i> , <i>IGHMBP2</i> , <i>LMNA</i> , <i>LAMA2</i> , <i>LARGE1</i> , <i>MTM1</i> , <i>NEM</i> , <i>POMGnT1</i> , <i>POMT1</i> , <i>POMT2</i> , and <i>SEPN1</i> , was used for genetic analysis using next-generation sequencing (NGS). <b>Results</b> In our study, we found 13 variants including pathogenic (two variants in LAMA2) and likely pathogenic variants (three variants in RYR1 and POMGnT1) and variants of uncertain clinical significance (eight variants in RYR1, COL6A3, COL6A2, POMGnT1 and POMT1) in 11 (61%) out of 18 patients. In one of our patients, a homozygous, likely pathogenic c.1649G > A, p.(Ser550Asn) variant was defined in the <i>POMGnT1</i> gene which was associated with a muscle-eye-brain disease phenotype. <b>Conclusion</b> The contribution of an in-house designed gene panel in the etiology of peripheral hypotonia with a clinical diagnosis was 5.5%. An important contribution with the clinical diagnosis can be made using the targeted multigene panels in larger samples.</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":null,"pages":null},"PeriodicalIF":1.2000,"publicationDate":"2022-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9286875/pdf/","citationCount":"0","resultStr":"{\"title\":\"Investigating the Genetic Etiology of Pediatric Patients with Peripheral Hypotonia Using the Next-Generation Sequencing Method.\",\"authors\":\"Damla Eker, Hakan Gurkan, Yasemin Karal, Sinem Yalcintepe, Selma Demir, Engin Atli, Serap T Karasalihoglu\",\"doi\":\"10.1055/s-0042-1745873\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background</b> Hypotonia occurs as a result of neurological dysfunction in the brain, brainstem, spinal cord, motor neurons, anterior horn cells, peripheral nerves, and muscles. Although the genotype-phenotype correlation can be established in 15 to 30% of patients, it is difficult to obtain a correlation in most cases. <b>Aims</b> This study was aimed to investigate the genetic etiology in cases of peripheral hypotonia that could not be diagnosed using conventional methods. <b>Methods</b> A total of 18 pediatric patients with peripheral hypotonia were included. They were referred to our genetic disorders diagnosis center from the Pediatric Neurology Department with a prediagnosis of hypotonia. A custom designed multigene panel, including <i>ACTA1</i> , <i>CCDC78</i> , <i>DYNC1H1</i> , <i>GARS</i> , <i>RYR1</i> , <i>COL6A1</i> , <i>COL6A2</i> , <i>COL6A3</i> , <i>FKRP</i> , <i>FKTN</i> , <i>IGHMBP2</i> , <i>LMNA</i> , <i>LAMA2</i> , <i>LARGE1</i> , <i>MTM1</i> , <i>NEM</i> , <i>POMGnT1</i> , <i>POMT1</i> , <i>POMT2</i> , and <i>SEPN1</i> , was used for genetic analysis using next-generation sequencing (NGS). <b>Results</b> In our study, we found 13 variants including pathogenic (two variants in LAMA2) and likely pathogenic variants (three variants in RYR1 and POMGnT1) and variants of uncertain clinical significance (eight variants in RYR1, COL6A3, COL6A2, POMGnT1 and POMT1) in 11 (61%) out of 18 patients. In one of our patients, a homozygous, likely pathogenic c.1649G > A, p.(Ser550Asn) variant was defined in the <i>POMGnT1</i> gene which was associated with a muscle-eye-brain disease phenotype. <b>Conclusion</b> The contribution of an in-house designed gene panel in the etiology of peripheral hypotonia with a clinical diagnosis was 5.5%. An important contribution with the clinical diagnosis can be made using the targeted multigene panels in larger samples.</p>\",\"PeriodicalId\":40142,\"journal\":{\"name\":\"Global Medical Genetics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.2000,\"publicationDate\":\"2022-07-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9286875/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Global Medical Genetics\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1055/s-0042-1745873\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2022/9/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q4\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Global Medical Genetics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1055/s-0042-1745873","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/9/1 0:00:00","PubModel":"eCollection","JCR":"Q4","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
摘要
背景:张力低下是脑、脑干、脊髓、运动神经元、前角细胞、周围神经和肌肉神经功能障碍的结果。虽然15 - 30%的患者可以建立基因型-表型相关性,但在大多数情况下很难获得相关性。目的探讨常规方法无法诊断的外周性张力低下的遗传病因。方法对18例周围性张力低下患儿进行分析。他们从小儿神经科转介到我们的遗传疾病诊断中心,预先诊断为张力过低。使用定制设计的多基因面板,包括ACTA1、CCDC78、DYNC1H1、GARS、RYR1、COL6A1、COL6A2、COL6A3、FKRP、FKTN、IGHMBP2、LMNA、LAMA2、LARGE1、MTM1、NEM、POMGnT1、POMT1、POMT2和SEPN1,使用下一代测序(NGS)进行遗传分析。结果在我们的研究中,我们在18例患者中的11例(61%)中发现了13种变异,包括致病性变异(LAMA2中2种变异)和可能致病性变异(RYR1和POMGnT1中3种变异)以及临床意义不确定的变异(RYR1、COL6A3、COL6A2、POMGnT1和POMT1中8种变异)。在我们的一位患者中,在POMGnT1基因中定义了一种纯合子,可能是致病性的c.1649G > a, p.(Ser550Asn)变异,该变异与肌肉-眼-脑疾病表型相关。结论自行设计的基因面板对外周性张力低下病因学和临床诊断的贡献率为5.5%。在更大的样本中使用靶向多基因面板可以对临床诊断做出重要贡献。
Investigating the Genetic Etiology of Pediatric Patients with Peripheral Hypotonia Using the Next-Generation Sequencing Method.
Background Hypotonia occurs as a result of neurological dysfunction in the brain, brainstem, spinal cord, motor neurons, anterior horn cells, peripheral nerves, and muscles. Although the genotype-phenotype correlation can be established in 15 to 30% of patients, it is difficult to obtain a correlation in most cases. Aims This study was aimed to investigate the genetic etiology in cases of peripheral hypotonia that could not be diagnosed using conventional methods. Methods A total of 18 pediatric patients with peripheral hypotonia were included. They were referred to our genetic disorders diagnosis center from the Pediatric Neurology Department with a prediagnosis of hypotonia. A custom designed multigene panel, including ACTA1 , CCDC78 , DYNC1H1 , GARS , RYR1 , COL6A1 , COL6A2 , COL6A3 , FKRP , FKTN , IGHMBP2 , LMNA , LAMA2 , LARGE1 , MTM1 , NEM , POMGnT1 , POMT1 , POMT2 , and SEPN1 , was used for genetic analysis using next-generation sequencing (NGS). Results In our study, we found 13 variants including pathogenic (two variants in LAMA2) and likely pathogenic variants (three variants in RYR1 and POMGnT1) and variants of uncertain clinical significance (eight variants in RYR1, COL6A3, COL6A2, POMGnT1 and POMT1) in 11 (61%) out of 18 patients. In one of our patients, a homozygous, likely pathogenic c.1649G > A, p.(Ser550Asn) variant was defined in the POMGnT1 gene which was associated with a muscle-eye-brain disease phenotype. Conclusion The contribution of an in-house designed gene panel in the etiology of peripheral hypotonia with a clinical diagnosis was 5.5%. An important contribution with the clinical diagnosis can be made using the targeted multigene panels in larger samples.