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Long-read sequencing identified a novel nonsense and a de novo missense of PPA2 in trans in a Chinese patient with autosomal recessive infantile sudden cardiac failure.

Authors
  • Zhao, Arman1
  • Shen, Jie2
  • Ding, Yueyue3
  • Sheng, Mao4
  • Zuo, Mengying5
  • Lv, Haitao6
  • Wang, Jian7
  • Shen, Yiping8
  • Wang, Hongying9
  • Sun, Ling10
  • 1 Department of Clinical Laboratory, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected] , (China)
  • 2 Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected] , (China)
  • 3 Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected] , (China)
  • 4 Department of Radiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected] , (China)
  • 5 Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected] , (China)
  • 6 Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected] , (China)
  • 7 Department of Pediatric Surgery, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected] , (China)
  • 8 Department of Genetics and Metabolism, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, Guangxi, China; Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States; Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States. Electronic address: [email protected] , (China)
  • 9 Department of Clinical Laboratory, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China; Department of Clinical Laboratory, Children's Hospital of Wujiang District, Suzhou, 169 Park Road, Wujiang District, Suzhou 215234, Jiangsu, China. Electronic address: [email protected] , (China)
  • 10 Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Clinica chimica acta; international journal of clinical chemistry
Publication Date
Aug 01, 2021
Volume
519
Pages
163–171
Identifiers
DOI: 10.1016/j.cca.2021.03.029
PMID: 33826954
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Biallelic missense variants in PPA2 gene cause infantile sudden cardiac failure (SCFI; OMIM #617222) characterized by sudden cardiac failure, sudden cardiac death in infants. Here, we present an unusual survivor with one inherited plus one de novo variant in PPA2. Since next-generation sequencing (NGS) fails to resolve variant phasing, which require long-read sequencing to clarify the diagnosis. Whole exome and Sanger sequencing were initially performed to identify the causative variants. PCR-based short tandem repeats (STRs) analysis and long-read single molecule real-time (SMRT) sequencing were further implemented for paternity testing and variant phasing. Pathogenicity evaluation of the biallelic variants in PPA2 was conducted according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines based on VarSome. Whole exome and Sanger sequencing revealed two variants in PPA2, with one novel nonsense variant (c.524C > G; p.Ser175*) inherited from the mother and one de novo missense variant (c.379C > T; p.Arg127Cys). PCR-based STRs analysis verified the paternity. And long-read SMRT sequencing phased the two variants in trans and identified the paternal origin of the de novo variant. The genetic diagnosis clarified the genetic etiology of the proband and assisted in patient management and counseling. We identified a rare combination of one inherited plus one de novo variant of PPA2 in a patient with autosomal recessive SCFI, which expanded the mutation spectrum of PPA2 and demonstrated the power of target long-read sequencing to make up the diagnostic gap of prevailing NGS. Copyright © 2021. Published by Elsevier B.V.

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