PPA2 Deficiency in 2 Sisters :  A Rare Cause of Sudden Cardiac Death

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Abstract

Inorganic pyrophosphatase 2 (PPA2) deficiency is a genetic cause of sudden cardiac death, often triggered by viral infection or alcohol consumption. Literature on management is limited because most cases are diagnosed post mortem. We report lethal and nonlethal cardiac presentations of PPA2 deficiency in 2 adolescent sisters that resulted from a novel pathogenic PPA2 variant. ( Level of Difficulty: Advanced.)

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Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards, Nazneen Aziz, Sherri Bale … (2015)

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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The mutational constraint spectrum quantified from variation in 141,456 humans

Konrad J. Karczewski, Laurent C. Francioli, Grace Tiao … (2021)

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes 1 . Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases.

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Genetic Basis of Severe Childhood-Onset Cardiomyopathies

Catalina Vasilescu, Tiina H Ojala, Virginia Brilhante … (2018)

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Author and article information

Contributors

Veronica Fettig

Journal

Journal ID (nlm-ta): JACC Case Rep

Journal ID (iso-abbrev): JACC Case Rep

Title: JACC Case Reports

Publisher: Elsevier

ISSN (Electronic): 2666-0849

Publication date PMC-release: 20 September 2023

Publication date Collection: 18 October 2023

Publication date (Electronic): 20 September 2023

Volume: 24

Electronic Location Identifier: 102024

Affiliations

[a ]Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA

[b ]Department of Pediatric Cardiology, Icahn School of Medicine at Mount Sinai, Children’s Heart Center, Mount Sinai Hospital, New York, New York, USA

[c ]The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

[d ]Department of Pediatric Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

[e ]Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

Author notes

[∗ ] Address for correspondence: Ms Veronica M. Fettig, Mount Sinai Hospital, One Gustave L. Levy Place, Box 1030, New York, New York 10029, USA. veronica.fettig@ 123456mssm.edu

Article

Publisher Item ID: S2666-0849(23)00358-3 Publisher ID: 102024

DOI: 10.1016/j.jaccas.2023.102024

PMC ID: 10589443

PubMed ID: 37869221

SO-VID: 2afc5025-445c-4c06-89e1-d60dae0b0a64

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 5 May 2023

Date revision received : 22 August 2023

Date accepted : 23 August 2023

PPA2 Deficiency in 2 Sisters : A Rare Cause of Sudden Cardiac Death

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Abstract

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G3: Genes|Genomes|Genetics

Most cited references 13

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

The mutational constraint spectrum quantified from variation in 141,456 humans

Genetic Basis of Severe Childhood-Onset Cardiomyopathies

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