Combined PTPN11 and MYBPC3 Gene Mutations in an Adult Patient with Noonan Syndrome and Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.

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Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.33713 ◽

2010 ◽

Vol 152A (11) ◽

pp. 2768-2774 ◽

Cited By ~ 12

Author(s):

Murat Derbent ◽

Yekta Oncel ◽

Kürşad Tokel ◽

Birgül Varan ◽

Ayşegül Haberal ◽

...

Keyword(s):

Noonan Syndrome ◽

Gene Mutations ◽

Ptpn11 Gene

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Spectrum of MYBPC3 Gene Mutations in Patients with Hypertrophic Cardiomyopathy, Reporting Two Novel Mutations from North-West of Iran

Clinical Laboratory ◽

10.7754/clin.lab.2014.141134 ◽

2016 ◽

Vol 62 (05/2016) ◽

Cited By ~ 1

Author(s):

Leila Emrahi ◽

Mehrnoush Tabrizi ◽

Jalal Gharehsouran ◽

Seyyed Ardebili ◽

Mehrdad Estiar

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Gene Mutations ◽

Novel Mutations ◽

North West ◽

Mybpc3 Gene

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FREQUENCY OF METABOLIC GENE MUTATIONS IN PATIENTS REFERRED FOR HYPERTROPHIC CARDIOMYOPATHY GENETIC TESTING

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(14)60821-4 ◽

2014 ◽

Vol 63 (12) ◽

pp. A821

Author(s):

Thomas E. Callis ◽

Justin W. Leighton ◽

Sandra J. Gunselman ◽

Jeana T. DaRe

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Gene Mutations ◽

Metabolic Gene

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Hypertrophic cardiomyopathy: genetics

ESC CardioMed ◽

10.1093/med/9780198784906.003.0350_update_001 ◽

2018 ◽

pp. 1443-1450

Author(s):

Mohammed Majid Akhtar ◽

Luis Rocha Lopes

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Mapk Pathway ◽

Glycogen Storage ◽

Cellular Level ◽

Causative Mutation ◽

Clinical Role ◽

Genes Encoding ◽

Associated Proteins

Hypertrophic cardiomyopathy is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere and associated proteins. Knowledge of the genetic pathophysiology of the disease has advanced significantly since the initial identification of a point mutation in the beta-myosin heavy chain (MYH7) gene in 1990. Other genetic causes of the disease include mutations in genes coding for proteins implicated in calcium handling or which form part of the cytoskeleton. The recent emergence of next-generation sequencing allows quicker and less expensive identification of causative mutations. However, a causative mutation is not identified in up to 50% of probands. At present, the primary clinical role of genetic testing in hypertrophic cardiomyopathy is in the context of familial screening, allowing the identification of those at risk of developing the condition. Genetic testing can also be used to exclude genocopies, particularly in the presence of certain diagnostic ‘red flag’ features, where lysosomal, glycogen storage, neuromuscular or Ras-MAPK pathway disorders may be suspected. The role of individual mutations in predicting prognosis is limited at present. However, the higher incidence of sudden cardiac death in the presence of a family history of such, suggests that genetics play a significant role in determining outcome. With an increased understanding of the impact of these mutations on a cellular level and on longer-term clinical outcomes, the aim in future for gene and mutation specific prognosis or potential disease-modifying therapy is closer.

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ANGIOTENSIN-CONVERTING ENZYME INSERTION/DELETION POLYMORPHISMS CONTRIBUTES TO FAVORABLE CLINICAL COURSES OF HYPERTROPHIC CARDIOMYOPATHY CAUSED BY MYBPC3 GENE MUTATIONS

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(10)60263-x ◽

2010 ◽

Vol 55 (10) ◽

pp. A27.E262

Author(s):

Akira Funada ◽

Noboru Fujino ◽

Eiichi Masuta ◽

Hidekazu Ino ◽

Masakazu Yamagishi

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Angiotensin Converting Enzyme ◽

Gene Mutations ◽

Converting Enzyme ◽

Mybpc3 Gene

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Abstract 4845: Hypertrophic Cardiomyopathy due to Sarcomere Gene Mutations is Associated with More Severe Derangement of Microvascular Function Compared to Myofilament Negative Disease

Circulation ◽

10.1161/circ.118.suppl_18.s_948-d ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Iacopo Olivotto ◽

Francesca Girolami ◽

Michael J Ackerman ◽

Roberto Sciagra ◽

Stefano Nistri ◽

...

Keyword(s):

Genetic Testing ◽

Hypertrophic Cardiomyopathy ◽

Thin Filament ◽

Troponin I ◽

Genetic Test ◽

Troponin T ◽

Gene Mutations ◽

Thick Filament ◽

Microvascular Function ◽

Coronary Microvascular Dysfunction

Coronary microvascular dysfunction (CMD) is an important primary feature of hypertrophic cardiomyopathy (HCM), contributing to myocardial ischemia and ventricular remodelling, and is predictive of adverse outcome. Whether there is any association between presence/severity of CMD and HCM’s pathogenic substrate remains to be determined. To address this issue, we used positron emission tomography (PET) to assess CMD in an HCM cohort that received comprehensive genetic testing for sarcomeric/myofilament-HCM. We measured maximum (intravenous dipyridamole, 0.56 mg/kg) myocardial blood flow (Dip-MBF), using 13 N-labeled ammonia and PET in 46 HCM patients (age 38±14 years, 32 male). Genetic testing was performed by denaturing high performance liquid chromatography and automatic DNA sequencing of nine myofilament-encoding genes including both thick filament proteins (myosin binding protein C, beta-myosin heavy chain, regulatory and essential light chains); and thin filament proteins (troponin-T, troponin-I, troponin-C, alpha-tropomyosin and alpha-actin). Results . Thirty-four mutations were identified in 30/46 patients (myofilament-HCM; 65%), including 29 with thick filament and 6 with thin filament mutations, as well as 4 with complex genotype. Despite similar age and clinical features, patients with myofilament-HCM showed lower Dip-MBF values than the patients with a negative genetic test (1.6±0.7 versus 2.2±0.9 ml/min/g, respectively; p=0.03). Specifically, 13/30 (43%) patients with myofilament-HCM had a Dip-MBF below the lower tertile for the study group (≤1.38 ml/min/g), compared to 2/16 (12%) patients with a negative genetic test (p=0.034). No difference in Dip-MBF was evident with respect to the particular sarcomeric gene involved (ANOVA p=0.63). HCM due to sarcomere gene mutations is characterized by more severe impairment in microvascular function compared to myofilament negative disease, irrespective of the involved contractile protein. These findings suggest that sarcomeric mutations might be implicated in adverse remodelling of the microcirculation in patients with HCM, and account for the greater prevalence of ventricular dysfunction and failure in this subset.

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