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

Arman Zhao; Jie Shen; Yueyue Ding; Mao Sheng; Mengying Zuo; Haitao Lv; Jian Wang; Yiping Shen; Hongying Wang; Ling Sun

doi:10.1016/j.cca.2021.03.029

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

Clin Chim Acta. 2021 Aug:519:163-171. doi: 10.1016/j.cca.2021.03.029. Epub 2021 Apr 5.

Authors

Arman Zhao¹, Jie Shen², Yueyue Ding³, Mao Sheng⁴, Mengying Zuo⁵, Haitao Lv⁶, Jian Wang⁷, Yiping Shen⁸, Hongying Wang⁹, Ling Sun¹⁰

Affiliations

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].
² Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected].
³ Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected].
⁴ Department of Radiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected].
⁵ Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected].
⁶ Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected].
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].
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].
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].
¹⁰ Department of Cardiology, Children's Hospital of Soochow University, 92 Zhongnan Street, Suzhou Industrial Park, Suzhou 215025, Jiangsu, China. Electronic address: [email protected].

PMID: 33826954
DOI: 10.1016/j.cca.2021.03.029

Abstract

Background and aims: 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.

Materials and methods: 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.

Results: 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.

Conclusion: 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.

Keywords: De novo variant; Infantile sudden cardiac failure (SCFI); Long-read SMRT sequencing; Mitochondrial disease; PPA2 gene; Variant phasing.

MeSH terms

China
Codon, Nonsense
Exome Sequencing
Exome*
Heart Failure*
Humans
Infant
Pedigree

Substances

Codon, Nonsense