Identification of genetic variants in two Vietnamese patients with hypertrophic cardiomyopathy by whole exome sequencing

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Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disease and a major cause of sudden death. It is also involved in increasing morbidity and mortality of various cardiovascular diseases. Genetic factors have been found to be important in determining the phenotypic manifestation of cardiac hypertrophy. However, only 50–60% of HCM patients have been identified as having pathogenic variants in known genes, suggesting that more studies are needed to find more disease genes. In this study, whole exome sequencing was performed on two patients from two unrelated families who were diagnosed with HCM to screen the associated mutations.

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Nội dung Text: Identification of genetic variants in two Vietnamese patients with hypertrophic cardiomyopathy by whole exome sequencing

Vietnam Journal of Biotechnology 22(2): 212-226, 2024. DOI: 10.15625/vjbt-19499 IDENTIFICATION OF GENETIC VARIANTS IN TWO VIETNAMESE PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY BY WHOLE EXOME SEQUENCING Nguyen Thi Kim Lien1,, Nguyen Van Tung 1, Le Trong Tu 2,3, Dang Thi Hai Van 2, Vu Quynh Nga3, Nguyen Ngoc Lan1, Nguyen Thanh Hien1, Le Tat Thanh1, Nguyen Minh Duc 1,4, Nguyen Huy Hoang1 1 Institute of Genome Research, Vietnam Academy of Science and Technology, Hanoi, Vietnam 2 Hanoi Medical University, Ministry of Health, Hanoi, Vietnam 3 Hanoi Heart Hospital, Ministry of Health, Hanoi, Vietnam 4 National Research Center for Medicinal Plant Germplasm and Breeding, National Institute of Medicinal Materials, Hanoi, Vietnam  To whom correspondence should be addressed. E-mail: ntkimlienibt@gmail.com Received: 27.11.2023 Accepted: 18.06.2024 ABSTRACT Hypertrophic cardiomyopathy (HCM) is a common genetic cardiovascular disease and a major cause of sudden death. It is also involved in increasing morbidity and mortality of various cardiovascular diseases. Genetic factors have been found to be important in determining the phenotypic manifestation of cardiac hypertrophy. However, only 50–60% of HCM patients have been identified as having pathogenic variants in known genes, suggesting that more studies are needed to find more disease genes. In this study, whole exome sequencing was performed on two patients from two unrelated families who were diagnosed with HCM to screen the associated mutations. Two heterozygous variants c.836A>C (p.Tyr279Ser) in the PTPN11 gene and c.83A>C, (p.His28Pro) in the PRKAG2 gene have been identified in patients 1 and 2, respectively. Assessment of the level of impact using prediction software shows that these are potentially harmful variants and may be the cause of disease in patients. Our results provided an understanding of the cause of the patient’s disease, helping clinicians diagnose and provide better genetic counseling to the patients’ family. Keywords: hypertrophic cardiomyopathy (HCM), PRKAG2, PTPN11, variant, Vietnamese patient, whole exome sequencing (WES). INTRODUCTION cardiac death (SCD) in adolescents (Marian, Braunwald, 2017). HCM is characterized by Hypertrophic cardiomyopathy (HCM) is hypertrophy of the ventricular myocardium, considered the leading cause of sudden which results from increased sensitivity to 212
Vietnam Journal of Biotechnology 22(2): 212-228, 2024. DOI: 10.15625/vjbt-19499 calcium. Cardiac hypertrophy is defined as Maron, 2018). The weak genotype- an increase in the mass of the heart muscle. phenotype correlation and wide phenotypic HCM is the most common genetic variability of the disease are the causes that cardiovascular disease, and the prevalence limit the ability to use genetics for definitive of HCM is approximately 1: 500 in young diagnosis (Mogensen et al., 2004; Tower- individuals (Marian, 2008). The prevalence Rader et al., 2017). may be higher in older people because the Genetic advances (next-generation penetrance of causative variants is age- sequencing) have improved knowledge dependent. The prevalence ranges from 0.02 about HCM at the molecular level and to 0.2% in Western countries (Maron et al., provided clinical genetic testing. Early 2016) and Asian countries (Moon et al., diagnosis of HCM is important for providing 2020; Bai et al., 2022). Heritability of the appropriate treatment and prevention diseases in the general population was strategies for patients as well as clinical estimated to be from 20 to 70% (Sharma et surveillance and genetic counseling for al., 2006). The clinical manifestations of family members (Elliott et al., 2014). Wang HCM include heart failure (HF) (Maron et et al. (2017) provided a list of 44 genes al., 2018), stroke (Fauchier et al., 2022), related to HCM. HCM is primarily inherited atrial fibrillation (AF) (Garg et al., 2019), as an autosomal dominant trait by variations arrhythmia, and SCD. SCD is the first and in the gene encoding the sarcomere protein most serious manifestation of the disease (Elliott et al., 2014). and usually occurs in otherwise healthy and asymptomatic young people (Elliott et al., Variants in the PTPN11 gene that encodes 2006). Of all SCD cases in people aged 5 to for the protein tyrosine phosphatase (PTP), 34 years, 14% were determined to be due to SHP2, nonreceptor type 11 (Shoji et al., HCM (Jayaraman et al., 2018). 2019; Caiazza et al., 2020), have been identified to be leading causes of HCM. So Diagnosis is made based on far, 162 variants in the PTPN11 gene echocardiography or cardiac magnetic associated with cardiovascular diseases have resonance imaging for identifying the wall been published in the HGMD database. thickness of the left ventricular (Maron, PTPN11 variants cause hypertyrosyl 2012; Fabris et al., 2013; Sternick et al., phosphorylation of the transmembrane 2014; Mavrogeni et al., 2015; Poyhonen et glycoprotein, protein zero-related (PZR), al., 2015; Yogasundaram et al., 2016; Maron, and increasing SHP2 binding. The catalytic Maron, 2016). HCM is a genetically activity of SHP2 is tightly regulated by heterogeneous myocardial disorder intramolecular conformational constraints. determined by unexplained left ventricular The “closed” conformation, which is hypertrophy (LVH), with histopathological mediated by the interaction between the SH2 findings including myocyte hypertrophy, and phosphatase domains, is destabilized myocyte disorders, and myocardial fibrosis due to the binding of the N-terminal SH2 (Elliott et al., 2014; Esposito et al., 2019). domain and phosphotyrosine peptides, HCM develops in childhood or adulthood resulting in an “open” conformation which (Bick et al., 2012; Maron et al., 2012), but makes the catalytic domain substrate has asymptomatic or mild symptoms accessible (Mohi et al., 2005). Studies in (Semsarian et al., 2015; Baxi et al., 2016; mouse models show that enhanced PZR 213
Nguyen Thi Kim Lien et al. tyrosyl phosphorylation in the hearts of mice (Cheung et al., 2000; Scott et al., 2004). induces myocardial fibrosis by engaging the Identifying PRKAG2 variants provides a Src/NF-κB pathway, leading to enhanced new insight into the molecular basis of left IL-6 activation. These results demonstrate ventricular hypertrophy (LVH) which is not that PTPN11 variants are responsible for explained by variants in genes encoding the PZR hypertyrosyl phosphorylation, which sarcomeric proteins. activates pathophysiological signaling that In our study, whole exome sequencing was leads to HCM and cardiac fibrosis. performed to identify HCM-associated In addition, PRKAG2 syndrome (PS) is a variants in two patients from two unrelated rare early-onset autosomal dominant genetic families. disorder that also presents with symptoms such as cardiac hypertrophy, ventricular MATERIALS AND METHODS preexcitation (VPE), and progressive abnormalities (Murphy et al., 2005). Subjects Murphy et al., (2005) estimated to be 1% in patients with both hypertrophy Patient 1 is a 7-year-old boy who was cardiomyopathy (HCM) and premature diagnosed with hypertrophic sinoatrial or atrioventricular conduction cardiomyopathy at the Hanoi Heart Hospital disease. To date, 63 variants in the PRKAG2 when he was two years old. The patient was gene associated with cardiovascular diseases admitted to the hospital with chest pain and have been identified (HGMD database). The difficulty in breathing due to exercise. Other PRKAG2 gene encodes the γ2 regulatory clinical symptoms include left chest pain, subunit of AMP-activated protein kinase 3/6 systolic murmur at the apex of the heart, (AMPK-γ2) (Scott et al., 2004). AMPK is regular heart rate of 110 beats/minute, SpO2 known as a ubiquitously expressed fuel 100%, and hepatomegaly 1 cm below the meter in eukaryotic cells that regulates right costal margin. Echocardiogram: left cellular energy homeostasis by turning on ventricular concentric thickening, mild left ATP-generating pathways and turning off ventricular outflow tract narrowing, mild anabolic pathways in response to cellular mitral regurgitation, left ventricular systolic stress (Hardie, 2015). The AMPK-γ2 subunit function, ejection fraction (EF) 75.8% is mainly expressed in the heart and has the (Figure 1). Electrocardiogram (ECG): sinus role of regulating AMPK activity by rhythm, rate 110 beats/minute, no competitively binding with ATP or AMP arrhythmia, increased biventricular load. 214
Vietnam Journal of Biotechnology 22(2): 212-228, 2024. DOI: 10.15625/vjbt-19499 Figure 1. Echocardiogram with images of left ventricular concentric hypertrophy of patient 1. Patient 2 is a 1-year-old girl who was TAPSE) of 11.8 mm, a mild mitral diagnosed with hypertrophic regurgitation, a moderate tricuspid valve, cardiomyopathy through postnatal screening and a PGmax (pressure gradient max) across echocardiography. The child was examined the tricuspid valve of 44 mmHg. and treated at the Hanoi Heart Hospital for Electrocardiogram showed increased left symptoms: difficulty in breathing, SpO2 and right ventricular loading; Blood test: 95%, pale skin, infrequent urination, moist NT-ProBNP 2,890 pg/ml, white blood cell rale lungs, liver 2 cm below the costal (WBC) 15,000/mm3, C-reactive protein margin, rapid breathing, frequency (45 (CRP) 15 mg/l. times/minute). The child has been prescribed Parents of patients provided written an echocardiogram with images of left informed consent under a research protocol ventricular concentric hypertrophy (Figure approved by the Institute of Genome 2), an ejection fraction (EF) of 42%, a mildly Research Institutional Review Board (No: dilated left heart chamber, decreased regular 02-2021/NCHG-HĐĐĐ). heart wall movement, a right ventricular (Tricuspid annular plane systolic excursion - 215
Nguyen Thi Kim Lien et al. Figure 2. Echocardiogram with images of left ventricular concentric hypertrophy of patient 2. Whole exome sequencing In silico analysis Genomic DNA was extracted from To predict the effect of the detected variants, peripheral blood white cells using the the different in silico tools: FATHMM QIAamp DNA blood mini kit manufactured (http://fathmm.biocompute.org.uk/inherited by QIAGEN (QIAGEN, Hilden, Germany). .html), MCAP (http://bejerano.stanford.edu/ The concentration and purity of the extracted mcap/), Mutation Assessor (http:// DNA were determined by NanoDrop One of mutationassessor.org/r3/), Mutation Taster Thermo Fisher. Whole exome sequencing (https://www.genecascade.org/MutationTas (WES) was performed on DNA samples ter2021/), PolyPhen-2 (http://genetics.bwh from the affected patients on the Illumina .harvard.edu/pph2/), PROVEAN (http:// system (Illumina, Inc., San Diego, CA). The provean.jcvi.org/seq_submit.php), SIFT Agilent SureSelect Human All Exon v7 (https://sift.bii.a-star.edu.sg/), and CADD capture kit (Agilent, Santa Clara, CA) was (https://cadd.gs.washington.edu/snv) were used for exome capture. Data were aligned used. To evaluate the effect of variants on to the hg19 reference genome and followed protein structure, the three-dimensional by creating indexes, marking, and removing structure of the wild type and mutant type repeated reads using the Picard tool was constructed using Swiss-PDB Viewer (http://broadinstitute.gith-ub.io/picard/). To v4.1 with PDB: Q9UGJ0 as a template. determine variants and minor allele frequencies the Genome Analysis Toolkit PCR and Sanger sequencing (GATK) (https://gatk.broadinstitute.org /hc/en-us) was used. Sanger sequencing was performed on DNA samples from the family trio to confirm 216
Vietnam Journal of Biotechnology 22(2): 212-228, 2024. DOI: 10.15625/vjbt-19499 variants identified by WES. The primer pairs RESULTS used for the polymerase chain reaction were designed based on the sequence transcripts Through whole-exome sequencing, a available on GenBank (accession number heterozygous single-base alteration at NM_002834.5 for the PTPN11 gene and position c.836A>C; p.Tyr279Ser NM_709450.1 for the PRKAG2 gene): (rs121918456) in the PTPN11 gene (Figure Forward primer 5’- 3A) in the patient 1 and a heterozygous ACGCCTGACCCAGATGAA-3’, Reverse single-base alteration at position c.83A>C primer 5’- (p.His28Pro) (rs138051386) in the PRKAG2 TAACAAGAGCACACGACCCT-3’ for gene (Figure 3B) in the patient 2 were found. the PTPN11 gene (PCR product size is The c.836A>C (p.Tyr279Ser) variant in the 344bp), Forward primer 5’- PTPN11 gene has been identified in the SNP TGCCATCAGCAAGGAAACAC-3’, database (https://www.ncbi.nlm.nih.gov/ Reverse primer 5’- snp/), ExAC database (http://exac ATGTTCACCTGTCGCCACTC-3’ for the .broadinstitute.org/), gnomAD database PRKAG2 gene (PCR product size is 306bp). (https://gnomad.broadinstitute.org/), and ClinVar database (https://www.ncbi.nlm The size and quality of the PCR products .nih.gov/clinvar). Meanwhile, the variant were then checked by using 1.5% agarose c.83A>C (p.His28Pro) in the PRKAG2 gene, gel electrophoresis. These products were although present in the SNP database, has subjected to purification using the Thermo not been evaluated for pathogenicity on the Fisher GeneJET PCR Purification Kit ClinVar database. The in silico prediction (Thermo Fisher Scientific Inc., USA). After results (Table 1) reported that these variants that, the purified PCR products were were likely to cause disease. These variants sequenced using the ABI PRISM 3500 were confirmed in patients and their parents Genetic Analyzer (Applied Biosystems, CA, using Sanger sequencing. The results USA), and the BigDye Terminator v3.1 showed that the variant in the PTPN11 gene Cycle Sequencing Kit. The sequencing in patient 1 was a de novo variant (Figure results were analyzed and compared to the 3A), and the variant in the PRKAG2 gene in reference sequence NM_002834.5 for the patient 2 was inherited from the father who PTPN11 gene and NM_709450.1 for the carried the variant but did not show the PRKAG2 gene to identify the variants using disease (Figure 3B). BioEdit 7.2.5 software. 217
Nguyen Thi Kim Lien et al. Figure 3. Genetic analysis identified the missense variants in the family of patients. (A). The missense variant c.836A>C; p.Tyr279Ser (rs121918456) in the PTPN11 gene in the family of patient 1. Genetic analysis shows that the patient 1 harbors a de novo variant in the PTPN11 gene. (B). The missense variant c.83A>C, p.His28Pro (rs138051386) in the PRKAG2 gene in the family of patient 2. Genetic analysis shows that the patient 2 harbors a heterozygous variant in the PRKAG2 gene, which is inherited from her father. Prediction results using prediction software patient 2, evaluation results using Meta and showed that the variant found in the PTPN11 PROVEAN software showed that the variant gene in patient 1 is the cause of the patient's had a neutral effect, but other software disease. This result is also consistent with (FATHMM, CADD, MCAP, Mutation the assessment in the ClinVar database that Taster, PolyPhen2, and SIFT) evaluated this this is a disease-causing variant. For the as a disease-causing variant. variant identified in the PRKAG2 gene in Table 1. Evaluation results using prediction tools for identified variants. The in silico prediction tools Patient 1 Patient 2 Gene PTPN11 (AD) PRKAG2 (AD) Mutation c.836A>C; p.Tyr279Ser c.83A>C; rs121918456 p.His28Pro 218
Vietnam Journal of Biotechnology 22(2): 212-228, 2024. DOI: 10.15625/vjbt-19499 rs138051386 FATHMM Damaging Damaging (Score: -5.90) (Score: -2.30) CADD Probably damaging Probably damaging (Score: 27.7) (Score: 19.3) MCAP Damaging Damaging (Score: 0.828) (Score: 0.061) Meta Damaging Tolerant (Score: 1.029) (Score: -0.639) Mutation Assessor Mutant (Score: 3.03) Mutation Taster Damaging Damaging (Score: 1.000) (Score: 1.000) PolyPhen2 Probably Damaging Probably (Score: 0.993) Damaging (Score: 0.997) PROVEAN Damaging Neutral (Score: -7.75) (Score: 0.76) SIFT Damaging Damaging (Score: 0.000) (Score: 0.044) To determine the evolutionary conservation patients were located in highly conservative of amino acids in the wild-type proteins at regions. Therefore, any change in amino the position of substitutions, the amino acid acids in this region will affect the structure sequences of PTPN11 and PRKAG2 protein and function of the protein. Results of the from different species were aligned using analysis once again confirmed that these Clustal X2 (Figure 4). Analysis results variants were the cause of the disease in the showed that the variants identified in the patients. PTPN11 and PRKAG2 genes in the two 219
Nguyen Thi Kim Lien et al. Figure 4. Multiple alignment of the proteins from human and other species by Clustal-X2. (A) Multiple alignment of the PTPN11 protein at the location where the variant occurred. Alignment of amino acid sequences of PTPN11 from different species, including Homo sapiens (NM_002834.5), Bos taurus (XM_002694590.6), Sus scrofa (XM_021073562.1), Canis lupus (XM_038436740.1), Mus musculus (NM_001109992.1), Rattus norvegicus (NM_001177593.1), Cricetulus griseus (XM_027414112.2), Equus caballus (XM_023647127.1), and Gallus gallus (NM_204968.2). (B) Multiple alignment of the PRKAG2 protein at the location where the variant occurred. Alignment of amino acid sequences of PRKAG2 from different species including Homo sapiens (KR709450.1), Cricetulus griseus (XM_027428416.2), Sus scrofa (XM_021078617.1), Canis lupus (XM_038559767.1), Equus quagga (XM_046669514.1), Bos indicus (XM_027538540.1), Mus musculus (NM_145401.2), Gallus gallus (XM_046910898.1), and Rattus norvegicus (XM_039107964.1). DISCUSSION unless symptoms are presented (Semsarian et al., 2015; Maron, 2018). Unclear clinical HCM is an autosomal dominant disorder manifestations and phenotypic variability of caused by pathogenic variants in genes the disease are the main challenges in encoding for sarcomeric proteins and definitively diagnosing HCM (Mogensen et proteins involved in many cardiomyocytes al., 2004; Tower-Rader et al., 2017). Only a signaling pathways that activate protein small number of HCM cases are diagnosed tyrosine kinases. HCM develops in by cardiovascular magnetic resonance childhood or adulthood (Bick et al., 2012; (CMR) (Fabris et al., 2013; Sternick et al., Maron et al., 2012), but is rarely identified 2014; Poyhonen et al., 2015; Yogasundaram 220
Vietnam Journal of Biotechnology 22(2): 212-228, 2024. DOI: 10.15625/vjbt-19499 et al., 2016). Therefore, many patients have that expresses knocked in PTPN11Y279C/+ subclinical disease and go undiagnosed until variant. These mice exhibit features of detected by genetic screening or incidentally human disease, including those of HCM during a physical examination, often (Marin et al., 2011; Lauriol et al., 2016). In performed after a family member was our study, patient 1 also carried a diagnosed. Understanding the molecular heterozygous variant (c.836A>C, mechanisms underlying specific gene p.Tyr279Ser, rs121918456) in the PTPN11 variants may provide opportunities for gene. This is a de novo variant, and it is personalized treatment of HCM patients. considered the cause of the disease in the patient. Pathogenic variants in the PTPN11 gene have been identified in most patients with In patient 2, we detected a heterozygous Noonan syndrome presenting with variant c.83A>C (p.His28Pro, rs138051386) hypertrophic cardiomyopathy. The PTPN11 in the PRKAG2 gene. The PRKAG2 gene gene encodes for the SH2 domain– encodes for the γ2 regulatory subunit of containing protein tyrosine phosphatase 2 AMP-activated protein kinase (AMPK) (SHP2) (a nonreceptor protein tyrosine (Scott et al., 2004). AMPK is an important phosphatase - PTP) (Tartaglia et al., 2001; energy-sensing enzyme that is activated by 2006; Carcavilla et al., 2013). SHP2 variants increases in the AMP/ATP ratio and is occurring in the PTP domain lead to reduced deeply involved in cellular ATP metabolism phosphatase activity and formation of the (Hardie, 2015). AMPK exists as a “open” conformation, leading to aberrant heterotrimeric complex composed of a signaling responsible for the pathogenesis of catabolic α subunit and regulatory β and γ HCM. Paardekooper Overman's study in subunits with multiple isoforms for each mouse models showed that PTPN11 variants subunit (Hardie, 2015). AMPK is activated cause hypertyrosyl phosphorylation of the by AMP binding to the γ subunit, causing a transmembrane glycoprotein, protein zero- conformational change in the α subunit, and related (PZR), resulting in increased SHP2 promoting phosphorylation (Hardie et al., binding (Paardekooper Overman et al., 2016). AMPK enzyme activity serves a 2014). PZR was identified as an SHP2 critical role in regulating cellular glucose binding partner, with the SH2 domains of and fatty acid metabolic pathways. Hence SHP2 binding phosphorylated tyrosine any alteration of these metabolic pathways residues (Zhao et al., 2000; Paardekooper by variants in the regulatory subunit of Overman et al., 2014; Yi et al., 2020). They AMPK will result in metabolic disorders in demonstrated that SHP2 mutations the heart. To evaluate the effect of variants (SHP2 Y279C ), which have an “open” on protein structure, the three-dimensional conformation, have increased PZR structure of the wild type and variant type association (Paardekooper Overman et al., was constructed using Swiss-PDB Viewer 2014). To understand the signaling v4.1 with PDB: Q9UGJ0 as a template mechanisms of congenital heart disease, (Figure 5). Marin et al. (2011) generated a mouse model 221
Nguyen Thi Kim Lien et al. Figure 5. Three-dimensional structure of the PRKAG2 protein predicted by Swiss-PdbViewer. (A) Wild type: forms a strong H-bond (in green color) between Leu24 and His28. (B) Variant type: forms a weak H-bond (in pink color) between Leu24 and Pro28. The variant identified in the present family 2016). The variant c.83A>C (p.His28Pro) is is located in the highly conserved region in considered to be the cause of the disease in the N terminal (Figure 4B). Although the patient 2. Additionally, HCM patients variant has not been evaluated by ClinVar or caused by PRKAG2 variant may have previously reported, but it has been assessed significant cardiovascular symptoms or have by prediction software as likely to cause asymptomatic or mild symptoms. Even in disease (Table 1). Variants in the PRKAG2 the same family, affected members sharing gene have been reported to cause of the same variant can have different hypertrophic cardiomyopathy in recent manifestations (Yang et al., 2017). Research studies (Porto et al., 2016; Calore, 2017; shows excessive cellular glycogen content Banankhah et al., 2018). Novel de novo alone is a unifying mechanism of variants in the PRKAG2 gene have been pathogenesis for variable phenotypes identified in patients with HCM and early- manifest in affected patients. This explains onset heart failure (Liu et al., 2013). Another the fact that the patient's father in our study novel variant in the PRKAG2 gene was also had the variant but did not show signs reported in a Chinese family with cardiac of the disease. Our results contributed to the hypertrophy (Yang et al., 2017). In our study, general understanding of disease etiology the variant c.83A>C (p.His28Pro, and showed that WES is an effective rs138051386) led to the formation of a weak analytical tool for identifying variants in hydrogen bond between Leu24 and Pro28, genetic diagnosis. which may affect the spatial structure of the PRKAG2 protein (Figure 5). Variants that CONCLUSION could potentially affect the three- dimensional structure of AMPK and lead to In this study, we identified two heterozygous altered enzyme activity have also been variants c.836A>C (p.Tyr279Ser, reported in previous studies (Porto et al., rs121918456) in the PTPN11 gene and 222
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