Genetic Testing For Hypertrophic Cardiomyopathy Research Articles

Genotype-Phenotype Correlations in Apical Variant Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy is underscored by profound phenotypic and genotypic heterogeneity. Echocardiographically, hypertrophic cardiomyopathy can be categorized into four morphological subtypes: reverse curve, sigmoidal, neutral contour, and apical variant. Previous studies indicate that reverse curve hypertrophic cardiomyopathy is the strongest predictor of a positive genetic test. Little is known about the spectrum and prevalence of mutations and genotype-phenotype correlations in apical hypertrophic cardiomyopathy. Between 1999 and 2007, 1053 patients with the diagnosis of hypertrophic cardiomyopathy (60% male, age at diagnosis 44.4 ± 19 years) underwent sarcomeric genetic testing. Blinded to the genetic test results, each echocardiogram was scored for septal morphology and phenotyping was performed using the patient's medical record. Subset analysis was performed to elucidate the genotype, phenotype, and outcome of apical hypertrophic cardiomyopathy. Overall, 71 patients (7%) had apical hypertrophic cardiomyopathy on echocardiography (63% male, mean age 47.8 ± 15 years, mean left ventricular wall thickness 19.8 ± 6 mm). Left ventricular outflow tract obstruction was uncommon (seven patients; 10%). Eighteen patients (25%) had a positive genetic test, with the majority of mutations found in MYBPC3 (six; 35%) and MYH7 (six; 35%). Follow-up was available on 68 patients (96%) with a median age of 57.3 years (range 19.3-82 years). Mean follow-up was 5.5 years (range 0.1-18.2 years). There was no statistical difference between the occurrence rates of adverse events between genotype-positive and genotype-negative groups. In this largest cohort of patients with genetic testing for hypertrophic cardiomyopathy, <10% exhibited apical disease. This least common subtype was associated with a negative genetic test result 75% of the time. In contrast to prior publications suggesting a predilection for ACTC1/TPM1 mutations in patients with apical hypertrophic cardiomyopathy, the two most common genotypes (MYBPC3-HCM and MYH7-HCM) remained most common among patients who had a positive genetic test.

Shaping the future and living in the present: Living a ‘good’ life with a familial heart disease

In genetic counselling practices, individuals are explicitly encouraged to take an active stance towards their future. The premise is that, by considering their genetic risks and taking preventive measures, they have some control over their future life and health. However, it is unclear how families engaged in genetic testing actually deal with the promises of genetic test results, and how they perceive their future. This qualitative study aims to provide insight into the way in which families shape and live their lives with genetic risks. How do they navigate life with a familial heart disease? We followed six extended families involved in genetic testing for hypertrophic cardiomyopathy in the Netherlands for 4 years. The present analysis of four of these families reveals how they make sense of the future in various ways and perceive the opportunities for control. Whereas some families strongly believe the future can be shaped in some way, others are reluctant, do not believe in or even protest against the notion that genetic testing will help them to shape their future lives. We conclude that in the pursuit of Nussbaum’s notion of the ‘good’ life, ‘shaping the future’ and ‘living in the present’ are not opposing or mutually exclusive repertoires; instead, traces of both are apparent in all four case studies.

Characterization of a Phenotype-Based Genetic Test Prediction Score for Unrelated Patients With Hypertrophic Cardiomyopathy

ObjectivesTo determine the prevalence and spectrum of mutations and genotype-phenotype relationships in the largest hypertrophic cardiomyopathy (HCM) cohort to date and to provide an easy, clinically applicable phenotype-derived score that provides a pretest probability for a positive HCM genetic test result. Patients and MethodsBetween April 1, 1997, and February 1, 2007, 1053 unrelated patients with the clinical diagnosis of HCM (60% male; mean ± SD age at diagnosis, 44.4±19 years) had HCM genetic testing for the 9 HCM-associated myofilament genes. Phenotyping was performed by review of electronic medical records. ResultsOverall, 359 patients (34%) were genotype positive for a putative HCM-associated mutation in 1 or more HCM-associated genes. Univariate and multivariate analyses identified the echocardiographic reverse curve morphological subtype, an age at diagnosis younger than 45 years, a maximum left ventricular wall thickness of 20 mm or greater, a family history of HCM, and a family history of sudden cardiac death as positive predictors of positive genetic test results, whereas hypertension was a negative predictor. A score, based on the number of predictors of a positive genetic test result, predicted a positive genetic test result ranging from 6% when only hypertension was present to 80% when all 5 positive predictor markers were present. ConclusionIn this largest HCM cohort published to date, the overall yield of genetic testing was 34%. Although all the patients were diagnosed clinically as having HCM, the presence or absence of 6 simple clinical/echocardiographic markers predicted the likelihood of mutation-positive HCM. Phenotype-guided genetic testing using the Mayo HCM Genotype Predictor score provides an easy tool for an effective genetic counseling session.

Gene database for the development of genetic testing for hypertrophic cardiomyopathy

Background Hypertrophic cardiomyopathy (HCM) is a disease characterised by hypertrophy of the left ventricle of the heart. HCM has a prevalence of ~1 in 500 in the general population and is the leading cause of sudden cardiac death (SCD). Mutations in 30 genes have been found to be associated with HCM and accounting for 50-60% genetic causes [1]; etiologies of a larger percentage of HCM still remain unknown. These observations prompted us to create a gene database on genes implicated in HCM and to predict the function of the mutated genes. The findings of more new genes directly or indirectly implicated in HCM will be more helpful in developing comprehensive genetic tests for HCM.

Distinguishing Hypertrophic Cardiomyopathy-Associated Mutations from Background Genetic Noise

Despite the significant progress that has been made in identifying disease-associated mutations, the utility of the hypertrophic cardiomyopathy (HCM) genetic test is limited by a lack of understanding of the background genetic variation inherent to these sarcomeric genes in seemingly healthy subjects. This study represents the first comprehensive analysis of genetic variation in 427 ostensibly healthy individuals for the HCM genetic test using the "gold standard" Sanger sequencing method validating the background rate identified in the publically available exomes. While mutations are clearly overrepresented in disease, a background rate as high as ∼5% among healthy individuals prevents diagnostic certainty. To this end, we have identified a number of estimated predictive value-based associations including gene-specific, topology, and conservation methods generating an algorithm aiding in the probabilistic interpretation of an HCM genetic test.

Genetics of hypertrophic cardiomyopathy in Norway

Genetic testing for hypertrophic cardiomyopathy (HCM) became available in Norway in 2003. Here, we describe the results of this testing in probands with HCM referred until the end of 2012. The translated exons of MYBPC3, MYH7, TNNI3, TNNT2, MYL2 and MYL3 were analyzed in two groups of probands. In Group 1, comprising 696 probands above 1 year of age, a mutation was found in 203 patients (29.2%). Of those, 5.9% were carriers of two mutations. Mean age in double mutation carriers, single mutation carriers and mutation negative probands was 44 years (± 19 years), 50 years (± 5 years) and 55 years (± 6 years), respectively. In Group 2, comprising 26 infants below the age of 1, a mutation was found in 15.4%. A total of 120 different mutations were found of which 51 (42.5%) were novel.

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current population-based allele frequencies. From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.

The G263X MYBPC3 mutation is a common and low-penetrant mutation for hypertrophic cardiomyopathy in the region of Asturias (Northern Spain)

Hypertrophic cardiomyopathy (HCM) is characterised by wide disease manifestations, ranging from severe left ventricular septum (LVS) size and incapacitating symptoms to normal LVS and no symptoms at all. In addition to life style and other non-genetic factors, the phenotype variability could be explained in part by the heterogeneous genetic background of MCH [ 1 Keren A. Syrris P. McKenna W.J. Hypertrophic cardiomyopathy: the genetic determinants of clinical disease expression. Nat Clin Pract Cardiovasc Med. 2008; 5: 158-168 Crossref PubMed Scopus (161) Google Scholar , 2 Bos J.M. Towbin J.A. Ackerman M.J. Diagnostic, prognostic, and therapeutic implications of genetic testing for hypertrophic cardiomyopathy. J Am Coll Cardiol. 2009; 54: 201-211 Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar , 3 Richard P. Charron P. Carrier L. et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003; 107: 2227-2232 Crossref PubMed Scopus (983) Google Scholar ]. Moreover, the mutated gene and the type of mutation could also influence disease severity. The myosin binding protein C3 (MYBPC3) is the most frequently mutated gene and has been linked to a delayed expression of HCM. In the other hand, cardiac beta-myosin heavy chain (MYH7) mutations are commonly found among patients with early onset symptoms and severe disease manifestations [ 3 Richard P. Charron P. Carrier L. et al. Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003; 107: 2227-2232 Crossref PubMed Scopus (983) Google Scholar , 4 García-Castro M. Coto E. Reguero J.R. et al. Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy. Rev Esp Cardiol. 2009; 62: 48-56 Crossref PubMed Scopus (55) Google Scholar ].

Clinical predictors of genetic testing outcomes in hypertrophic cardiomyopathy

Genetic testing for hypertrophic cardiomyopathy has been commercially available for almost a decade; however, low mutation detection rate and cost have hindered uptake. This study sought to identify clinical variables that can predict probands with hypertrophic cardiomyopathy in whom a pathogenic mutation will be identified. Probands attending specialized cardiac genetic clinics across Australia over a 10-year period (2002-2011), who met clinical diagnostic criteria for hypertrophic cardiomyopathy and who underwent genetic testing for hypertrophic cardiomyopathy were included. Clinical, family history, and genotype information were collected. A total of 265 unrelated individuals with hypertrophic cardiomyopathy were included, with 138 (52%) having at least one mutation identified. The mutation detection rate was significantly higher in the probands with hypertrophic cardiomyopathy with an established family history of disease (72 vs. 29%, P < 0.0001), and a positive family history of sudden cardiac death further increased the detection rate (89 vs. 59%, P < 0.0001). Multivariate analysis identified female gender, increased left-ventricular wall thickness, family history of hypertrophic cardiomyopathy, and family history of sudden cardiac death as being associated with greatest chance of identifying a gene mutation. Multiple mutation carriers (n = 16, 6%) were more likely to have suffered an out-of-hospital cardiac arrest or sudden cardiac death (31 vs. 7%, P = 0.012). Family history is a key clinical predictor of a positive genetic diagnosis and has direct clinical relevance, particularly in the pretest genetic counseling setting.

Clinical Implication of Genetic Testing for Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is caused by a dominant mutation of the sarcomere protein gene in approximately 60% of cases. Genetic testing of HCM has several benefits. Diagnosis can be confirmed if the sarcomere protein gene mutation is identified. Genetic testing enables to follow-up blood relatives who are mutationpositive only, and can identify asymptomatic and non-onset patients. Relatives with negative results of genetic testing could be freed from anguish. On the other hand, genetic testing has some disadvantages. Treatment often does not change after testing. Forty percent of cases has unknown causative genes. Relationship between gene mutation and clinical findings or treatment responsiveness is little known, and so on. Many issues need to be resolved to incorporate genetic diagnosis into daily practice for HCM. However, genetic testing for HCM cannot be regarded as unnecessary and expensive debauchery, but rather represents a valuable measure in the medical facilities. Although there still remain questions about genetic diagnosis of HCM, accumulated knowledge to date is fairly enough to establish the genetic testing as a useful tool for individualized management of HCM patients and their families.

A variant of unknown significance in the GLA gene causing diagnostic uncertainty in a young female with isolated hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is genetically heterogeneous, and largely caused by mutations in genes encoding sarcomere proteins. However, GLA mutations causing Fabry disease, an X-linked lysosomal storage disorder, may also present with isolated HCM. As HCM genetic testing panels are increasingly being used clinically, variants of unknown significance (VUS) are encountered, leading to challenges in interpretation. We present an illustrative case: a 10-year-old girl with isolated HCM who, on testing with a HCM multi-gene panel, was found to carry a maternally inherited p.W24R variant in GLA. Attempts to evaluate the significance of this variant, by direct biochemical testing of patient specimens, gave inconclusive results. Subsequent in vitro protein expression studies suggested that the variant is unlikely to be pathogenic. This case highlights diagnostic dilemmas that can be provoked by VUS in general, and specifically raises a question whether GLA sequencing should be included in first-line diagnostic testing for female children with isolated hypertrophic cardiomyopathy.

Utility of Genetic Testing in Hypertrophic Cardiomyopathy in a Statewide Service

Utility of Genetic Testing in Hypertrophic Cardiomyopathy in a Statewide Service

The Key Role of Family History in Predicting Genetic Testing Outcomes in Hypertrophic Cardiomyopathy

Introduction: Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous condition. Proband genetic testing is important in elucidating the genetic status of asymptomatic relatives. Currently, the mutation detection rate is less than ideal (50%) and the prohibitive cost means there is limited access. Prediction of genetic testing outcomes based on simple clinical variables would allow clinicians to make a more informed decision before ordering a genetic test.Methods: HCM patients enrolled in the Australian National Genetic Heart Disease Registry, or attended 2 major HCM centres, and had HCM genetic testing (10 gene panel) were included. Demographics, family history, clinical and genetic data were recorded.Results: There were 166 unrelated HCM probands, and a genetic diagnosis was made in 109 (66%; sarcomere positive). Patients with a family history of disease (more than 1 affected) had an 82% pick-up rate, while those with no family history had a 41% pick-up rate (p<0.0001) (Table). Subgroup analysis of the family history group found those with a positive history of sudden death had a pick-up rate of 92% compared to 69% in the group with no history of sudden death (p=0.004) (Table). In comparison, the sarcomere negative group were significantly older (54 ± 2 yrs vs 47 ± 2 yrs, p=0.02), more likely to be male (70% vs 46%, p=0.0032) & had a reduced maximal LV wall thickness (19 ± 1 mm vs 22 ± 1 mm, p=0.026).Conclusions: Family history, specifically an established history of disease & sudden death, predicts a greater chance of making a genetic diagnosis in HCM probands. This has important implications for pre-test counseling and identifying those most likely to have a positive outcome.

Clinical relevance of genetic testing in hypertrophic cardiomyopathy

More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed, and become an important tool in clinical practice for diagnosis and prognosis overall in the Western countries. However its practical benefits are still understimated and clinicians often question about cost-effectiveness of genic testing in HCM patients and their families. This resistance is in contrast with considerable evidence supporting the role of genetics in tailoring management for HCM patients. Several current clinical uses of genetic testing in HCM, ranging from diagnosis in ambiguous situations, identification of disease phenocopies and HCM complex genotypes and confirmation of inherited disease in family members are reviewed. In the near future it is hoped that next generation sequencing will provide further diffusion of genetic testing in HCM and improvement in care.

Constructing “best interests”: Genetic testing of children in families with hypertrophic cardiomyopathy

Professional guidelines on genetic testing of children have recently shifted their focus from protecting the child's autonomous choice to professionals, together with parents, striving to work in the child's "best interest." This notion of "best interest" allows room for therapeutical as well as psychological and social considerations, and gives rise to the question how parents and professionals weigh up the child's best interest in practice. In this qualitative study, we followed six extended families involved in genetic testing for hypertrophic cardiomyopathy in the Netherlands for 3½ years. In total 57 members of these families were interviewed in depth; many of them more than once. Our empirical analysis shows that the best interest of a child is constructed via long-term processes in the broader context of family and kin. In this context, "best interests" are considered and reconsidered. We conclude that a child's best interest should not be framed as the result of an instantaneous agreement between parents and professionals. In dealing with genetic testing of children, parents as well as professionals reflect on and learn from the processes of generating new meanings of "best interest." To enable professionals to deal with the variety in family life, these learning processes should be documented closely.

Genetic Testing for Hypertrophic Cardiomyopathy: Ongoing Voyage from Exploration to Clinical Exploitation

More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed and expanded, and is now widely available as a potential clinical service in the Western countries. In the meantime, however, the cross-talk between geneticists and clinicians has developed slowly, and still remains unstandardized, with modalities of interaction and degree of mutual comprehension that vary wildly in various settings. In addition, clinicians often question the clinical utility of genetic testing in HCM patients and their families. The apparent lack of practical benefit, in the face of considerable costs, has long hindered large-scale diffusion of genetic testing, particularly in developing countries, and still accounts for understandable (but not always justifiable) resistance on the part of the physicians. However, such resistance is in contrast with considerable evidence supporting a role for molecular diagnosis in tailoring management for HCM patients. We here review several sound clinical reasons in favour of systematic genetic testing in HCM, ranging from identification of complex genotypes, heralding severe disease expression and outcome, to the added benefit of multidisciplinary genetic teamwork, enhancing awareness towards inheritable diseases in the cardiology community. We hope to show that to underestimate the clinical potential of genetic testing in HCM, and to defer its implementation until more advanced knowledge becomes available, is to lose an important opportunity for present improvement in care.

PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: Summary of the literature and implications for genetic testing

hypertrophic cardiomyopathy (HCM) is a major cause of sudden death in young athletes and one of the most common inherited cardiovascular diseases, affecting 1 in 500 individuals. Often viewed as a disease of the cardiac sarcomere, mutations in genes encoding myofilament proteins are associated with disease pathogenesis. Despite a clinically available genetic test, a significant portion of HCM patients remain genetically unexplained. We sought to determine the spectrum and prevalence of mutations in PLN-encoded phospholamban in a large cohort of HCM cases as a potential cause of mutation-negative HCM. comprehensive genetic interrogation of the promoter and coding region of PLN was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and direct DNA sequencing. one L39X nonsense mutation was identified in 1 of 1,064 HCM proband cases with a family history of HCM, previously found to be negative for the current HCM genetic test panel. This mutation cosegregated with incidence of HCM in a multigenerational family. Compared with similar studies, we identified an overall yield of PLN-HCM mutations of 0.65%, similar to 3 genes that are part of current HCM genetic test panels. We did not observe any PLN coding sequence genetic variation in 600 reference alleles. overall, mutations in PLN are rare in frequency, yet the small size of the genetic locus may make it amenable to inclusion on HCM gene test panels, especially because the frequency of background genetic variation among otherwise healthy subjects appears negligible. The exact role of mutations in PLN and other calcium-handling proteins in the development of HCM warrants further investigation.

Genetics and Clinical Destiny: Improving Care in Hypertrophic Cardiomyopathy

The greatest opportunity afforded by discovering the genetic basis of human heart disease is accurate prediction and prevention of illness. Hypertrophic cardiomyopathy (HCM) provides a paradigm to fulfill this opportunity. Human genetics research has identified many gene mutations that result in cardiac hypertrophy, of which HCM is the most common and well-characterized. Sarcomere gene mutations in HCM result in left ventricular hypertrophy (LVH), myocardial fibrosis and disarray, diastolic dysfunction, and increased risk for arrhythmias, sudden death, and heart failure. Making the clinical diagnosis of HCM currently hinges on identifying unexplained hypertrophy, but LVH is a sign of established disease only. This finding cannot identify at-risk mutation carriers and cannot discriminate HCM from other forms of cardiac hypertrophy, either genetic or acquired. Response by Landstrom on p 2440 In contrast, gene-based diagnosis is not constrained in this manner. Defining the mutation that causes LVH in an individual provides an accurate diagnosis for that patient and, therefore, considerable information about their prognosis. Moreover, unlike clinical diagnosis which only identifies overt disease, genetic diagnosis can also identify patients at risk for developing disease. There are certainly many challenges to realizing the full potential of genetics, but such information provides unprecedented promise. Continued efforts to refine and clinically implement genetic testing in HCM will bring important payoffs in the future, and will serve as a model for other genetic cardiovascular diseases. By identifying at-risk individuals prior to clinical diagnosis, characterizing disease pathogenesis, and fostering development of novel therapies to delay or prevent phenotypic expression, genetic discoveries will improve the lives of our patients with HCM. ### Genetics of HCM The familial, autosomal-dominant nature of HCM has long been recognized, but the precise genetic etiology was discovered through genome-wide linkage studies in the 1980s. This seminal work identified pathogenic mutations in genes encoding contractile proteins and established the paradigm …

Parental Knowledge and Attitudes Toward Hypertrophic Cardiomyopathy Genetic Testing

Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant condition with an increased risk of sudden cardiac death. Although clinical genetic testing can be used for confirmation of a clinical diagnosis as well as a predictive test, based on our clinical experience it is underutilized. Therefore, we developed and administered a questionnaire to assess potential determinants of parental interest in this testing. Of the 30 adult caregivers who participated, 80% had heard of genetic testing, whereas only 30% knew about genetic testing specifically for HCM. Once informed of the availability, 62% said they would consider testing in the future and 28% would consider it in the next year. Participants' younger age, higher education level, knowledge of carrier testing, and positive view of genetic testing were significantly associated with the participant considering HCM genetic testing for their child (p <or= 0.05). Based on a logistic regression model, age, education level, and knowing that HCM is an inherited disease were the best predictors of who would consider genetic testing. This study provides healthcare providers with a framework to understand caregivers' knowledge and views of genetic testing, which can be used to improve clinical care for pediatric HCM patients.

A New Era in Clinical Genetic Testing for Hypertrophic Cardiomyopathy

Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.