Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy

Almomani, Rowida; Verhagen, Judith M.A.; Herkert, Johanna C.; Brosens, Erwin; Spaendonck‐Zwarts, Karin Y. van; Asimaki, Angeliki; Zwaag, Paul A. van der; Frohn-Mulder, Ingrid M.E.; Bertoli‐Avella, Aida M.; Boven, Ludolf G.; Slegtenhorst, Marjon A. van; Smagt, Jasper J. van der; IJcken, Wilfred F. J. van; Timmer, Bert; Stuijvenberg, Margriet van; Verdijk, Robert M.; Saffitz, Jeffrey E.; Plessis, Frederik A. du; Michels, Michelle; Hofstra, Robert M.W.; Sinke, Richard J.; Tintelen, J. Peter van; Wessels, Marja W.; Jongbloed, Jan D. H.; Laar, Ingrid M.B.H. van de

doi:10.1016/j.jacc.2015.10.093

Cited by 81 publications

(93 citation statements)

References 28 publications

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“…While much of the existing literature on the clinical experience using genomic sequencing in inherited cardiomyopathies consists of case reports describing the use of WES for gene discovery in a proband 39 or small collections of families with severe complex cardiomyopathies of unknown etiology, 27,40 data from small cardiomyopathy cohorts have also been reported. Seidelmann et al 41 reported their experience with WES in a variety of inherited cardiovascular conditions, including HCM.…”

Section: Discussionmentioning

confidence: 99%

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

Cirino

Lakdawala

McDonough

et al. 2017

Circ Cardiovasc Genet

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Background As DNA sequencing costs decline, genetic testing options have expanded. Whole exome and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multi-gene panels that have been the cornerstone of genetic testing. Methods and Results Forty-one patients with hypertrophic cardiomyopathy (HCM) who had undergone targeted HCM genetic testing (either multi-gene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS. Results from panel genetic testing and WGS were compared. In 20 of 41 participants panel genetic testing identified variants classified as pathogenic, likely pathogenic or uncertain significance (VUS). WGS identified 19 of these 20 variants but the variant detection algorithm missed a pathogenic 18-base pair duplication in MYBPC3 due to low coverage. In 3 individuals, WGS identified variants in genes implicated in cardiomyopathy but not included in panel testing: a pathogenic PTPN11 variant and VUSs in ILK and FLNC. WGS also identified 84 secondary findings (mean=2/person, range= 0–6), which mostly defined carrier status for recessive conditions. Conclusions WGS detected nearly all variants identified on panel testing, provided one new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical utility and numerous secondary genetic findings were also identified. While panel testing and WGS provided similar diagnostic yield, WGS offered the advantage of re-analysis over time to incorporate advances in knowledge, but necessitated expertise in genomic interpretation to appropriately incorporate WGS into clinical care.

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Section: Discussionmentioning

confidence: 99%

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

Cirino

Lakdawala

McDonough

et al. 2017

Circ Cardiovasc Genet

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show abstract

“…For example, premature termination codons (PTC) in the ALPK3 gene were recently found in neonates who succumbed to precocious cardiomyopathy. 82 It may prove informative to generate similar alleles of Alpk3 in mice to understand the nature of this new genetic form of human cardiomyopathy.…”

Section: Two-component Crisprmentioning

confidence: 99%

“…In addition, exome sequencing will continue to disclose rare mutations associated with defects in the cardiovascular system that will be amenable for study in the mouse. 82 Since the desired edit will generally involve only one nucleotide substitution, single-strand oligonucleotide donors of 120–140 nucleotides length will be sufficient as HDR templates. A challenge in correcting or modeling a human variant in protein-coding sequence is the constrained sequence space for designing an optimal sgRNA; if the desired edit is too far removed from the DSB, integration of the edit may not occur or will do so inefficiently.…”

Section: Three Component Crisprmentioning

confidence: 99%

A CRISPR Path to Engineering New Genetic Mouse Models for Cardiovascular Research

Miano

Zhu

Lowenstein

2016

ATVB

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Previous efforts to target the mouse genome for the addition, subtraction, or substitution of biologically informative sequences required complex vector design and a series of arduous steps only a handful of labs could master. The facile and inexpensive clustered regularly interspaced short palindromic repeats (CRISPR) method has now superseded traditional means of genome modification such that virtually any lab can quickly assemble reagents for developing new mouse models for cardiovascular research. Here we briefly review the history of CRISPR in prokaryotes, highlighting major discoveries leading to its formulation for genome modification in the animal kingdom. Core components of CRISPR technology are reviewed and updated. Practical pointers for two-component and three-component CRISPR editing are summarized with a number of applications in mice including frameshift mutations, deletion of enhancers and non-coding genes, nucleotide substitution of protein-coding and gene regulatory sequences, incorporation of loxP sites for conditional gene inactivation, and epitope tag integration. Genotyping strategies are presented and topics of genetic mosaicism and inadvertent targeting discussed. Finally, clinical applications and ethical considerations are addressed as the biomedical community eagerly embraces this astonishing innovation in genome editing to tackle previously intractable questions.

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“…Intercalated discs comprise adherens junctions, gap junctions, and desmosomes, which are collectively important for electromechanical coupling. Remodeling of intercellular junctions is a well-studied area of heart disease and heart failure; the absence of desmosomal proteins at the cell membrane, as shown by Almomani et al (3) with reduced plakoglobin, has been previously reported in arrhythmogenic cardiomyopathy (AC) (6). Plakoglobin, in particular, plays a dual role as both a structural protein of the desmosome and a signaling molecule in the Wnt/β-catenin pathway.…”

mentioning

confidence: 98%

“…In this issue of the Journal , Almomani et al (3) report ALPK3 as a novel gene in human pediatric cardiomyopathy. Using a combination of homozygosity mapping, whole exome sequencing, and candidate gene screening, the group identified homozygous premature stop codon mutations in ALPK3 and, from immunohistological observations of heart tissue, suggest potential mechanisms for further exploration.…”

mentioning

confidence: 99%

Pediatric Cardiomyopathy

Mestroni

Sweet

Taylor

2016

Journal of the American College of Cardiology

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Biallelic Truncating Mutations in ALPK3 Cause Severe Pediatric Cardiomyopathy

Abstract: Biallelic truncating mutations in the newly identified gene ALPK3 give rise to severe, early-onset cardiomyopathy in humans. Our findings highlight the importance of transcription factor pathways in the molecular mechanisms underlying human cardiomyopathies.

Cited by 81 publications

References 28 publications

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

A CRISPR Path to Engineering New Genetic Mouse Models for Cardiovascular Research

Pediatric Cardiomyopathy

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