hypertrophic cardiomyopathy ( hcm ) is one of the most common cardiomyopathies , which induces sudden cardiac death . a 10-month female infant who experienced cough , fever , aggressive exertional dyspnea , and recurrent cyanosis was admitted to our hospital . the patient was first diagnosed with type i respiratory failure , dysfunction of heart , severe pneumonia , and also some cardiac disorders were suspected . the echocardiography , cardiac computed tomography scan , cardiac magnetic resonance imaging scan , and also electrocardiogram were performed to confirm a diagnosis of hcm . based on the sequencing analysis , a new heterozygous mutant of raf1 at c. 770c > t had been identified in absence of the same mutant in both her parents . besides , the existence of normal karyotypes was confirmed among 3 samples . so we first reported a single mutant of raf1 770c > t with idiopathic hcm in a very early age . this patient would have suffered significant cardiac ventricular hypertrophy with more severe clinical manifestation in an extremely younger age compared with other identified mutations . however , we could only take limited advantages of deoxyribonucleic acid sequencing in hcm diagnosis and therapy . reporting additional observations of well designed cohorts with a long - term follow - up would be very helpful to accelerate the transition of genetic molecular research on hcm . hypertrophic cardiomyopathy ( hcm ) is one of the most common cardiomyopathies , which would induce sudden cardiac death among children and young individuals . typically , hcm is defined as a kind of primary disorder of the myocardium characterized by hypertrophy , usually affecting the left ventricle , in the absence of other loading conditions such as hypertension and aortic valve stenosis . in addition , it is also referred to as a  tumor of the heart  under modern definition which might demonstrate diverse clinical cardiac disorders . most of them , heart failure or arrhythmias would usually be the common complains , while some individuals might experience a benign and asymptomatic physiopathological course . until now , the diagnosis of hcm has mainly been based on the echocardiographic manifestation of unexplained cardiac hypertrophy , which can be subtle or massive . however , with the rapid development of genetic and molecular technologies , we have the opportunities to pursue further understanding of the deoxyribonucleic acid ( dna ) and molecular basis of cardiac diseases . during the past decades , a series of mutant genes have been identified , which focused on the functional impact of sarcomere , while new mutations are obtained at the same time . today , molecular genetics have already redefined etiology and diagnostic criteria for numerous diseases . moreover , these new insights provide targeted and individual treatment for particular diseases . on the contrary , there are limited insights that the genetic diagnoses of hcm could provide , and a lack of precision genetic management and therapy still exists , although functional experiments have approved several core roles of mutations . here , we would like to report a case of early - onset hcm case with a recently identified mutation of raf1 without any known syndromes . besides , a predicament between the basic genetic researches and clinical practice is a serious concern . this study was approved by the ethics committee of west china second university hospital of sichuan university . a 10-month female infant was admitted to our hospital after experiencing cough and fever with a highest temperature of about 40  c for 5 days on january 21 , 2016 . moreover , she suffered an aggressive exertional dyspnea and underwent recurrent cyanosis since her birth , with an adverse growth and development in the previous 2 days . the physical examination at admission observed a heartbeat rate of > 160 per minute , with > 70 respirations / min , blood pressure 88/44  mm hg , edema of lower lips , 3 depression signs , rough breath sounds , enlargement of liver ( 4  cm below costal margin ) but without splenomegaly , and a systolic murmur at the apical zone of heart . the artery blood gas analysis revealed that partial pressure of oxygen was under 40  mm hg . besides , levels of cardiac troponin i and brain natriuretic peptide were extremely high as 0.890  g / l and 273.0  ng / l , respectively . so the patient was first diagnosed with type i respiratory failure , dysfunction of heart , severe pneumonia , and some kinds of disorder of the heart were suspected as well . the echocardiography , cardiac computed tomography ( ct ) scan , cardiac magnetic resonance imaging ( mri ) scan , and also electrocardiogram were performed following the mechanical ventilation . the echocardiography detected the hypertrophic myocardium both in left and right ventricles , especially for the right ventricular wall that indicated a poor prognosis ( fig . in addition , the stenosis of left outflow tract was identified with the accelerated blood flow . however , it revealed a persisted left ventricular systolic function , but with a failure of a normal diastolic function . a similar manifestation had been confirmed both in ct and mri scan and the data of the left ventricular ejection fraction as 73.8% , end systolic volume ( esv ) as 3.0  ml , and end diastolic volume ( edv ) as 11.4  ml were obtained , while the right ventricular esv was 2.8  ml , and edv was 8.6  ml ( fig . 1b ) . the images of echocardiography and mri for this patient : ( a ) presents the echocardiographic image indicating the severe hypertrophic ventricular walls , ( b ) presents the mri images for cardiac hypertrophy . mri  =  magnetic resonance imaging . as mentioned above , the strong antibiotics treatment had been applied with meropenem ( dainippon sumitomo , osaka , japan ) ( 0.8  g / d ) and cefoperazone ( pfizer , la jolla , ca , usa ) ( 0.6 g / d ) . the mechanical ventilation has also been applied after intubation as she suffered respiratory failure , and budesonide ( astrazeneca , london , uk ) ( 1  g / d ) was also given to improve the oxygen transfusion . typically , only diuretics of spirolactone ( minsheng , hangzhou , china ) and hydrochlorothiazide ( fangqiang , jiangsu , china ) were provided for treating heart failure with a dosage of 8  mg / d . however , as obstruction of outflow tract was suspected , no positive inotropic medication was applied . after 3 days of treatment , the patient was still depending on the mechanical ventilation and suffering heart failure , but in a lighter condition . on the contrary , the parents refused to take any medical treatment due to financial issues as well as negative prognosis . in addition , there were no opportunities for our doctors to administer any medication or treatment such as -blocker or angiotensin - converting enzyme inhibitor to improve her prognosis . besides , as the hcm was mostly accompanied with a kind of genetic variations or secondary to some syndromes , the whole - genome sequencing and chromatin analysis have been suggested . we obtained the blood sample from her parents and herself with informed consent from parents . biosystems foster city , ca , usa ) and capillary electrophoresed on an abi3130xl bioanalyser ( applied biosystems foster city , ca , usa ) using standard methodologies . based on the sequencing analysis , a new heterozygous mutant of raf1 at c. 770c > t had been identified ( fig . 2 ) . besides , the existence of normal karyotypes was confirmed among 3 samples . as raf1 mutant was usually associated with noonan syndrome and leopard syndrome , we reviewed the clinical manifestations and related examinations and excluded the possibilities of these 2 syndromes . to rule out noonan syndrome , the chromatin analysis was appropriate without any special face . and for leopard syndrome , it had been excluded by the absence of various sized lentigines , pulmonary stenosis , skeletal malformation , disorders of heart conduction , and deafness . here , we first reported an idiopathic hcm case with a single mutant of raf1 770c > t in a very early age . the results of genetic sequencing that indicate a single mutant of raf1 770c > t in absence of parents finding . following the diagnosis and management procedure , the same mutation is absent between her parents , and it is not necessary to perform any follow - up , examination , or warrant risk of next offspring for such parents . however , it is also embarrassing that we could launch little things for this infant based on the genetic result . the management , treatment , and prognosis are mainly approached according to her clinical and echocardiographic manifestation , not refereeing to the genetic background . although the genetic testing is important in hcm , and great milestones have been achieved with basic researches , the usefulness of mutation results is really limited , failing to conduct the precision management and therapy for affected cases . however , we also performed a follow - up after the discharge , and the infant demised within 10 days due to uncontrolled heart failure . hcm is a common type of cardiomyopathy , and the clinical diagnosis is the most essential criterion for such disease . however , starting from the early 1990s , genetic linkage studies of hcm have been published . since then , major advances have been made to get a better understanding of genetic and molecular basis of hcm . hcm is partly caused by an autosomal dominant mutation in genes that encode sarcomere proteins or sarcomere associated proteins . among them , 8 genes are known to definitively cause hcm , which are associated with the motor molecules of myocardium including the -myosin heavy chain ( myh7 , 3035% ) , myosin - binding protein c ( mybpc3 , 2030% ) , troponin t ( tnnt2 , 1015% ) , troponin i ( tnni3 , < 5% ) , -tropomyosin ( tpm1 , < 5% ) , actin ( actc , < 1% ) , regulatory light chain ( myl2 , < 1% ) , and essential light chain ( myl3 , < 1% ) . abovementioned mutations could affect the cardiac muscle force generations , velocities , atpase supplementations , contractile kinetics , duty ratio , and the concentration of calcium . moreover , functional experiments on cells and transgenic animal models have also been carried out to demonstrate a similar physiological procedure , which provide pioneer results on genetic and molecular mechanism of cardiomyopathy . given that , great contributions have been made to reveal the facts of hcm at genetic and molecular levels . however , in this case , we have not identified a single mutation of idiopathic hcm reported . besides , a new mutant on raf1 770c > so , the raf1 770c > t mutation is recognized as a potential hcm dna variant that was previously unknown as a cause of hcm but has molecular characteristics in myocardial development , which are similar to recognized hcm mutations . moreover , raf1 mutations that affect the raf1 's kinase activity were found to cause noonan and leopard syndromes with a high prevalence of hcm . those hcm - associated mutations exhibited high kinase activities and increased extracellular regulated kinase activation in phosphorylation , particularly as it pertains to cardiac hypertrophy . besides , it has also been confirmed to be involved in dilated cardiomyopathy . several intracellular signaling pathways regulate the procedure of cardiac hypertrophy including the ras / mitogen - activated protein kinase cascades and calcineurin / nuclear factor of activated t cells ( nfat ) . evidence showed that raf1 encoded a downstream ras effector and induced hypertrophy signaling via nfat . as mentioned above , we seriously considered that the nonsarcomere - related mutation of raf1 770c > t could be a genetic cause of this early - onset hcm case , which also supplied ideas on the differences of the prognosis and pathological cause between this early - onset cases and ordinary patients with sarcomere gene related mutations who shall experience clinical manifestation around a later age . the raf1 mutation might induce significant ventricular hypertrophy in a very young age , and especially for the right ventricular and outflow tract obstruction . so that there was a possibility to suffer heart failure during their infant period , which should be the main difference from other mutations - related cardiomyopathy . nowadays , with the incredible development of dna - sequencing technology , we get more and more understandings of diseases , not only limited in cardiovascular diseases . taking the advantages of genetic sequencing , several types of targeted drugs have been developed and made into practice in a clinical procedure . however , to cardiovascular diseases , hundreds of publications have been reported with hundreds of mutations , along with a series of transgenic cell and animal investigations revealing that how such mutations exactly affected myocardial function . but there is still no high - quality and convinced clinical research to provide suggestions on how to use the genetic background into clinical practice , especially for the affected cases of precision management and therapy . the latest guideline also pointed out that information from genetic sequencing about risk of sudden cardiac death or prognosis is still limited . so it brought us a situation that great milestones had been achieved with basic researches , but the usefulness of mutation results was really limited and failed to conduct the precision management and therapy . after a numerous mutations have been published , researchers and doctors seem still to have a long way to approach the facts of cardiomyopathy . a decade ago , researchers strongly used to believe understanding how mutations perturb biophysical events of muscle contraction and cell - signaling pathways will inevitably allow advances in future management , treatment , and interventions . however , we are still seeking a way on how to approach the facts between the genetic mutations and clinical practice , so that investigations on the following objectives should be recalled to help guideline updating by genetic revolution : how to define the risk stages and prognosis of disease based on genetic results , large sample size observation study should be performed to find out whether particular genotypes are correlated with the survival ratio , whether separated therapeutic strategies should be carried out according to individual genomic sequencing not only based on their clinical and echocardiographic manifestations , and the treatment of hcm , as well as all kinds of cardiomyopathy calls for targeted medication , which should be the ultimate purpose of genetic research . there are still many efforts should be done to make the innovation of genetic investigation to benefit the patients with hcm . in general , this is the very first report of idiopathic hcm with newly identified mutant of raf1 c.770c > t in absence of noonan and leopard syndromes that were previously reported to be associated with raf1 variants . the mutation of raf1 would induce significant cardiac ventricular hypertrophy with severe clinical manifestation in a young age . however , this case also brought us to review the current role of genetic screening in the diagnosis and therapy of hcm , although genetic - related researches have made great advances . it indicated that there were limited contributions which the information based on genetic background could make in defining risk stages , predict prognosis and individuals treatment , as well as little consults that physician could provide . reporting additional observations of well designed cohorts with a long - term follow - up would be of great help to accelerate the transition of genetic molecular research on hcm .
abstractintroduction : hypertrophic cardiomyopathy ( hcm ) is one of the most common cardiomyopathies , which induces sudden cardiac death . 
 several mutants have been identified among hcm cases.methods and results : a 10-month female infant who experienced cough , fever , aggressive exertional dyspnea , and recurrent cyanosis was admitted to our hospital . 
 the patient was first diagnosed with type i respiratory failure , dysfunction of heart , severe pneumonia , and also some cardiac disorders were suspected . 
 the echocardiography , cardiac computed tomography scan , cardiac magnetic resonance imaging scan , and also electrocardiogram were performed to confirm a diagnosis of hcm . 
 moreover , the whole - genome sequencing and chromatin analysis have been suggested . 
 based on the sequencing analysis , a new heterozygous mutant of raf1 at c. 770c > t had been identified in absence of the same mutant in both her parents . besides , the existence of normal karyotypes was confirmed among 3 samples.conclusion:so we first reported a single mutant of raf1 770c > t with idiopathic hcm in a very early age . 
 this patient would have suffered significant cardiac ventricular hypertrophy with more severe clinical manifestation in an extremely younger age compared with other identified mutations . 
 however , we could only take limited advantages of deoxyribonucleic acid sequencing in hcm diagnosis and therapy . 
 reporting additional observations of well designed cohorts with a long - term follow - up would be very helpful to accelerate the transition of genetic molecular research on hcm .