document: hypertrophic cardiomyopathy ( hcm ) is characterized by left and/or right ventricular hypertrophy , with predominant involvement of the interventricular septum in the absence of other causes of hypertrophy , such as hypertension , valvular heart disease , or metabolic disease [ 17 ] . 
   familial hcm is an autosomal dominant disorder caused by mutations in genes that encode sarcomere proteins . 
   it has been reported that at least 15 genes are implicated in 5570 % of hcm , and the major genes causing hcm include cardiac -myosin heavy chain ( myh7 ) , -tropomyosin , cardiac troponin t ( tnnt2 ) , cardiac myosin - binding protein c ( mybpc3 ) , cardiac troponin i ( tnni3 ) , cardiac myosin regulatory light chains ( myl2 ) , and cardiac myosin essential light chains ( myl3 ) [ 1 , 4 , 5 , 811 ] . 
   cardiac troponin t is a thin - filament protein that takes part in muscle contraction . 
   the troponin complex on the actin filament regulates the force and velocity of muscle contraction . 
   troponin c functions as a calcium receptor while troponin i inhibits adenosine triphosphatase ( atpase ) activity when bound to actin . 
   troponin t fixes the troponin group to tropomyosin . during relaxation , the troponin group is bound to actin and tropomyosin , blocking the interaction of myosin and actin . 
   mutations of tnnt2 were thought to account for approximately 15 % of familial hcm , with most missense mutations located in exons 816 , and were associated with a particularly severe form of the disease characterized by a poor overall prognosis with a high incidence of sudden death despite only mild left ventricular hypertrophy ( lvh ) [ 14 ] . 
   most tnnt2 mutations of familial hcm alter the contractile properties of cardiac muscle , especially the ca sensitivity of force development and atpase activity in vitro and in vivo [ 1317 ] . 
   previous reports have suggested that there is a more consistent relationship between certain genetic mutations and clinical outcome , allowing for the classification of  benign  and  malignant  mutations [ 1830 ] . 
   for example , a favorable prognosis has been reported in patients with a phe110ile mutation of the tnnt2 mutation ( in 16 individuals of 6 japanese families ) [ 19 , 20 ] . from these data , genetic analysis and determination of genotype 
   however , these findings were based on limited experience ; to date , only 30 different mutations have been identified in tnnt2 [ 911 , 18 ] . 
   in addition to this genetic diversity , the phenotypic expression of these mutations varies considerably , ranging from asymptomatic individuals with a normal life expectancy to those with sudden cardiac death or the need for an early heart transplant . 
   clinical parameters such as the degree of lvh , the presence or absence of a left ventricular outflow tract gradient , and electrophysiology testing have not been predictive markers of poor prognosis [ 15 ] . 
   more recently , it was reported that late gadolinium enhancement with cardiac magnetic resonance can be a predictive marker of the ventricular arrhythmia and poor prognosis in hcm . in recent years 
   , mutation - specific risk stratification was considered to be not possible , but genetic test - based risk stratification seemed to be clinically informative . 
   the tnnt2 mutation has the third - ranked incidence of familial hcm , and the genotype  phenotype correlation of this gene still remains insufficient in japanese familial hcm . 
   we genetically evaluated 173 patients ( 101 men and 72 women ; 079 years old , median age 20 years ) who were clinically diagnosed with familial hcm . 
   written informed consent was obtained from all study subjects in accordance with the declaration of helsinki . 
   if patients were younger than 16 years , informed consent was given by their guardians . 
   we assessed each patient by taking their history and performing a physical examination , and reviewed their medical records . 
   all assessments were done with the approval of the ethics committees of tokyo women s medical university . 
   the diagnosis of hcm was determined through clinical evaluation , chest radiography , electrocardiography , echocardiography , and cardiac catheterization based on current international consensus criteria . 
   diseases of the heart , hypertension , valvular heart disease , or metabolic disease attributable to hcm were excluded from this study by pediatric cardiologists . 
   genomic dna was prepared from peripheral blood lymphocytes or lymphoblast cell lines transformed by the epstein 
   tnnt2 coding regions and exon  intron boundaries , including regions approximately 30100 bp upstream and downstream from the exons , were amplified from genomic dna using primers , as described in previous reports [ 34 , 35 ] . 
   genomic dna ( 50 ng ) was amplified through the use of primers designed from flanking intron sequences ( table 1).table 1primers used for amplification of fragments from tnnt2 
   exonforward ( 53)reverse ( 53)2gagctcttctgaggaaggcactacccagaatccgagggac3 and 4cagggcagcgtggactccccccagggctcccaggattt5ccattctctgctctgggttcgtgcacatgggaaagctgttct6tagggcttatctgtggggaaggccttccctggaaagagcactg7gaaatggaaatccacagggatactgcaccccgttccatca8 and 9ctctaggaaggatcagggcccctcacaaaagggatggagga10gcgatgtcaccttctccctacaccgcacccggccaata11ggtttccaatcctttcccctaagctgcagtggacacctcattc12gcctttgtcttcctgccttctccagccagcccaatctcttcact13acagggagggggcaatctggcccccagagcagatgcgggcagtg14actgggtgctgccgtctggtcaagggggctgttggggaatagg15cactcagcccccttctccaagcttctccgccccacatttc16ggcaccccagtcctacccgtccccctcaacagcactttt primers used for amplification of fragments from tnnt2 
    amplified products were purified using a multiscreen polymerase chain reaction ( pcr ) plate ( millipore , billerica , ma , usa ) and directly sequenced using the abi - prism bigdye - terminator cycle sequencing reaction kit and abi 3130xl genetic analyzer ( applied biosystems , foster city , ca , usa ) . 
   when a mutation was detected , we confirmed that it was not presenting 363 japanese normal chromosomes by direct sequencing . 
   the pcr conditions of these genes were modified and fragments were analyzed by electrophoresis , as described previously [ 36 , 37 ] . 
   proband patients bearing tnnt2 mutations were additionally examined for reported hcm mutations , the coding regions of myh7 , mybpc3 , tnni3 , -tropomyosin , mly2 , mly3 , and all exons , and a promoter region of the -galactosidase a gene . 
   primer sequences and detailed pcr conditions for these additional analyses are available upon request . reference sequences and single - nucleotide polymorphism information were obtained from the national center for biotechnology information . 
   we genetically evaluated 173 patients ( 101 men and 72 women ; 079 years old , median age 20 years ) who were clinically diagnosed with familial hcm . 
   written informed consent was obtained from all study subjects in accordance with the declaration of helsinki . 
   if patients were younger than 16 years , informed consent was given by their guardians . 
   we assessed each patient by taking their history and performing a physical examination , and reviewed their medical records . 
   all assessments were done with the approval of the ethics committees of tokyo women s medical university . 
   the diagnosis of hcm was determined through clinical evaluation , chest radiography , electrocardiography , echocardiography , and cardiac catheterization based on current international consensus criteria . 
   diseases of the heart , hypertension , valvular heart disease , or metabolic disease attributable to hcm were excluded from this study by pediatric cardiologists . 
   genomic dna was prepared from peripheral blood lymphocytes or lymphoblast cell lines transformed by the epstein 
   tnnt2 coding regions and exon  intron boundaries , including regions approximately 30100 bp upstream and downstream from the exons , were amplified from genomic dna using primers , as described in previous reports [ 34 , 35 ] . 
   genomic dna ( 50 ng ) was amplified through the use of primers designed from flanking intron sequences ( table 1).table 1primers used for amplification of fragments from tnnt2 
   exonforward ( 53)reverse ( 53)2gagctcttctgaggaaggcactacccagaatccgagggac3 and 4cagggcagcgtggactccccccagggctcccaggattt5ccattctctgctctgggttcgtgcacatgggaaagctgttct6tagggcttatctgtggggaaggccttccctggaaagagcactg7gaaatggaaatccacagggatactgcaccccgttccatca8 and 9ctctaggaaggatcagggcccctcacaaaagggatggagga10gcgatgtcaccttctccctacaccgcacccggccaata11ggtttccaatcctttcccctaagctgcagtggacacctcattc12gcctttgtcttcctgccttctccagccagcccaatctcttcact13acagggagggggcaatctggcccccagagcagatgcgggcagtg14actgggtgctgccgtctggtcaagggggctgttggggaatagg15cactcagcccccttctccaagcttctccgccccacatttc16ggcaccccagtcctacccgtccccctcaacagcactttt primers used for amplification of fragments from tnnt2 
    amplified products were purified using a multiscreen polymerase chain reaction ( pcr ) plate ( millipore , billerica , ma , usa ) and directly sequenced using the abi - prism bigdye - terminator cycle sequencing reaction kit and abi 3130xl genetic analyzer ( applied biosystems , foster city , ca , usa ) . 
   when a mutation was detected , we confirmed that it was not presenting 363 japanese normal chromosomes by direct sequencing . 
   the pcr conditions of these genes were modified and fragments were analyzed by electrophoresis , as described previously [ 36 , 37 ] . 
   proband patients bearing tnnt2 mutations were additionally examined for reported hcm mutations , the coding regions of myh7 , mybpc3 , tnni3 , -tropomyosin , mly2 , mly3 , and all exons , and a promoter region of the -galactosidase a gene . 
   reference sequences and single - nucleotide polymorphism information were obtained from the national center for biotechnology information . 
   to investigate mutations of tnnt2 , we performed dna analysis in 173 unrelated japanese patients with familial hcm . 
   we identified three reported mutations and a new mutation of tnnt2 in 11 individuals from four families ( a , b , c , d ) ( table 2).table 2clinical features of patients with tnnt2 mutation in families a , b , c , and dhcm individualsa iii-2a iii-1a ii-6a ii-6 ( iii-2/mother)b iii-7b iii-2b iv-3c iv-3c iii-3c ii-3d iii-2exon9 and 109 and 109109991010108nucleotide substitutiont328a and c388tt328a and c388tt328ac388tc274c274c274c388c388c388t236camino substitutionp110i and r130cp110i and r130cp110ir130cr92wr92wr92wr92wr92wr92wi79tsexfmmffmmffffage ( years)121455463541242158025outcome ( years)12 , vf survivor14 , died suddenly24 , vf survivorclinical diagnosishcmhcmcavb , pminormaldhcm ( hcm)abnormal ecghcmhcmhcmhcmhcmelectrocardiogramsr + crbbbsr + crbbb , abnqpm rhythm ( cavb)wnlr - wave progressiondetails unknownrvh , deep qlvh , st depdetails unknowndetails unknownst dep , inv t2d echocardiogramlvh , ashlvh , ashlvhwnllvh , apical hypertrophydetails unknownlvhlvh , ashlvhdetails unknownlvh , ashcardiac catheterizationlv relaxation abnormalitieslv relaxation abnormalitieslv relaxation abnormalitiesndndndndndndndnd 
   hcm hypertrophic cardiomyopathy , hocm hypertrophic obstructive cardiomyopathy , dhcm dilated phase of hcm , lvh left ventricular hypertrophy , vf ventricular fibrillation , cavb complete atrioventricular block , sr sinus rhythm , crbbb complete right bundle branch block , abnq abnormal q wave , lvh left ventricular hypertrophy , rvh right ventricular hypertrophy , st dep st depression , inv t inversion t , pmi pacemaker implantation , ecg electrocardiogram , ash asymmetric septal hypertrophy , aph apical hypertrophy , nd not determined , wnl within normal limits clinical features of patients with tnnt2 mutation in families a , b , c , and d 
   hcm hypertrophic cardiomyopathy , hocm hypertrophic obstructive cardiomyopathy , dhcm dilated phase of hcm , lvh left ventricular hypertrophy , vf ventricular fibrillation , cavb complete atrioventricular block , sr sinus rhythm , crbbb complete right bundle branch block , abnq abnormal q wave , lvh left ventricular hypertrophy , rvh right ventricular hypertrophy , st dep st depression , inv t inversion t , pmi pacemaker implantation , ecg electrocardiogram , ash asymmetric septal hypertrophy , aph apical hypertrophy , nd not determined , wnl within normal limits in family a , all five members who carried or were suspected of having hcm also had arrhythmia . 
   four of them had blocks , including a complete atrioventricular block ( cavb ) and complete right bundle branch block ( crbbb ) ( fig . 1 ; ii-1 , 6 , iii-1 , 2 ) , and one had bradycardia . 
   two of them died suddenly ( fig . 1 ; i-2 , iii-1 ) , and one was a ventricular fibrillation ( vf ) survivor ( fig . 
   1 ; iii-2 ) . the proband ( fig . 1 ; iii-2 ) , aged 12 years , with sinus rhythm ( sr ) and a crbbb , had an episode of vf , and her elder brother ( fig . 1 ; iii-1 ) , 
   the proband and her brother and father ( fig . 1 ; iii-2 , iii-1 , i-2 ) showed mild lvh ( maximum wall thickness < 20 mm ) . 
   1pedigree and phenotype of family a. pedigree with three generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , cavb complete atrioventricular block , pmi pacemaker implantation , crbbb complete right bundle - branch block , vf ventricular fibrillation pedigree and phenotype of family a. pedigree with three generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , cavb complete atrioventricular block , pmi pacemaker implantation , crbbb complete right bundle - branch block , vf ventricular fibrillation dna analysis showed that the proband and her elder brother had the double reported mutations , arg130cys and phe110ile , of tnnt2 ( fig . 
   her father , who had arrhythmia and mild hcm , had the phe110ile mutation , and her mother ( ii-6 ) , who had no symptoms or abnormal findings , had the arg130cys mutation . in family b 
   , 3 of 10 members who carried or were suspected of having hcm were thought to have obstructive hypertrophic cardiomyopathy . 
   2 ; iii-7 ) showed apical hypertrophy and apical aneurysm at a comparatively young age . 
   her aunt ( fig . 2 ; ii-4 ) , who had a heart murmur , was thought to have hypertrophic obstructive cardiomyopathy ( hocm ) , and died when she was 19 years old . 
   2 ; iii-9 ) did not show obstructive hcm , but died suddenly when she was 21 years old . her grandmother ( fig . 
   iii-7 ) , her son ( fig . 2 ; iv-3 ) , and her cousin ( fig . 2 ; iii-2 ) , who carried hcm , had an arg92trp mutation of tnnt2.fig . 2pedigree and phenotype of family b. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , hocm hypertrophic obstructive cardiomyopathy , ecg electrocardiogram pedigree and phenotype of family b. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , hocm hypertrophic obstructive cardiomyopathy , ecg electrocardiogram in family c , the proband ( fig . 3 ; iv-3 ) , her mother ( fig . 3 
   ; iii-3 ) , and her grandmother ( fig . 3 ; ii-3 ) showed mild cardiac hypertrophy ( maximum wall thickness < 20 mm ) and asymmetric septal hypertrophy , and her myocardial hypertrophy had been gradually increasing . 
   her mother was suspected of having a shifting dilated phase by recent cardiac magnetic resonance imaging ( mri ) . 
   3 ; iv-3 ) had symptomatic west syndrome following perinatal brain damage , and was treated with corticotropin . 
   3 ; iv-3 ) and her mother ( fig . 3 ; iii-3 ) had the arg92trp mutation of tnnt2.fig . 
   3pedigree and phenotype of family c. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , wpw syndrome wolff - parkinson - white syndrome pedigree and phenotype of family c. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , wpw syndrome wolff - parkinson - white syndrome in family d , two of three members who carried or were suspected of having hcm died suddenly ( fig . 4 ; 
   4 ; iii-2 ) . the proband ( fig . 4 ; iii-2 ) had relatively strong cardiac hypertrophy ( maximum wall thickness > 20 mm ) , and cardiac standstill from ventricular fibrillation at the age of 24 years . 
   her cousin ( fig . 4 ; iii-3 ) died suddenly at a young age ( 13 years ) , and her granduncle also died at the age of 40 . 
   this transition was observed in codon 79 , and converted an isoleucine residue to a threonine residue ( fig . 
   ile79thr occurred in conserved residues found in tnnt2 orthologues of human , mouse , rat , cat , and ox ( fig . 
   iii-2 ) also had a 5-bp ( cttct ) deletion / deletion polymorphism of intron 3 of tnnt2 ( fig . 
   4pedigree and phenotype of family d. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   c the insertion / deletion ( i / d ) polymorphism pedigree and phenotype of family d. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , vf ventricular fibrillation 
   a the new ile79thr mutation of tnnt2 ( exon 8) . 
   this domain is well preserved in mammals 
   a the deletion / deletion ( d / d ) polymorphism . 
   c the insertion / deletion ( i / d ) polymorphism to clarify the clinical importance of this polymorphism , we performed genetic analysis in 47 hcm patients from 173 unrelated japanese patients with familial hcm . in these 47 patients , 
   24 had the deletion / deletion polymorphism ( 51 % , 14 men and 10 women ; 072 years old , median age 30 years old ) . 
   five of the 24 ( 21 % ) patients who had the deletion / deletion polymorphism were diagnosed with apical hcm or hocm . in 6 of the 10 ( 60 % ) with available data of echocardiography among these 24 patients , 
   on the other hand , in the 47 hcm patients , the remaining 23 did not have the deletion / deletion polymorphism , but had the deletion / insertion or insertion / insertion polymorphism ( 49 % , 15 men and 8 women ; 076 years old , median age 18 years ) . 
   two of the 23 ( 9 % ) patients were diagnosed with apical hcm , and there were no hocm patients . 
   two of the seven ( 29 % ) with available data of echocardiography among these 23 patients showed the maximum wall thickness of more than 30 mm . 
   to investigate mutations of tnnt2 , we performed dna analysis in 173 unrelated japanese patients with familial hcm . 
   we identified three reported mutations and a new mutation of tnnt2 in 11 individuals from four families ( a , b , c , d ) ( table 2).table 2clinical features of patients with tnnt2 mutation in families a , b , c , and dhcm individualsa iii-2a iii-1a ii-6a ii-6 ( iii-2/mother)b iii-7b iii-2b iv-3c iv-3c iii-3c ii-3d iii-2exon9 and 109 and 109109991010108nucleotide substitutiont328a and c388tt328a and c388tt328ac388tc274c274c274c388c388c388t236camino substitutionp110i and r130cp110i and r130cp110ir130cr92wr92wr92wr92wr92wr92wi79tsexfmmffmmffffage ( years)121455463541242158025outcome ( years)12 , vf survivor14 , died suddenly24 , vf survivorclinical diagnosishcmhcmcavb , pminormaldhcm ( hcm)abnormal ecghcmhcmhcmhcmhcmelectrocardiogramsr + crbbbsr + crbbb , abnqpm rhythm ( cavb)wnlr - wave progressiondetails unknownrvh , deep qlvh , st depdetails unknowndetails unknownst dep , inv t2d echocardiogramlvh , ashlvh , ashlvhwnllvh , apical hypertrophydetails unknownlvhlvh , ashlvhdetails unknownlvh , ashcardiac catheterizationlv relaxation abnormalitieslv relaxation abnormalitieslv relaxation abnormalitiesndndndndndndndnd 
   hcm hypertrophic cardiomyopathy , hocm hypertrophic obstructive cardiomyopathy , dhcm dilated phase of hcm , lvh left ventricular hypertrophy , vf ventricular fibrillation , cavb complete atrioventricular block , sr sinus rhythm , crbbb complete right bundle branch block , abnq abnormal q wave , lvh left ventricular hypertrophy , rvh right ventricular hypertrophy , st dep st depression , inv t inversion t , pmi pacemaker implantation , ecg electrocardiogram , ash asymmetric septal hypertrophy , aph apical hypertrophy , nd not determined , wnl within normal limits clinical features of patients with tnnt2 mutation in families a , b , c , and d 
   hcm hypertrophic cardiomyopathy , hocm hypertrophic obstructive cardiomyopathy , dhcm dilated phase of hcm , lvh left ventricular hypertrophy , vf ventricular fibrillation , cavb complete atrioventricular block , sr sinus rhythm , crbbb complete right bundle branch block , abnq abnormal q wave , lvh left ventricular hypertrophy , rvh right ventricular hypertrophy , st dep st depression , inv t inversion t , pmi pacemaker implantation , ecg electrocardiogram , ash asymmetric septal hypertrophy , aph apical hypertrophy , nd not determined , wnl within normal limits in family a , all five members who carried or were suspected of having hcm also had arrhythmia . 
   four of them had blocks , including a complete atrioventricular block ( cavb ) and complete right bundle branch block ( crbbb ) ( fig . 1 ; ii-1 , 6 , iii-1 , 2 ) , and one had bradycardia . 
   two of them died suddenly ( fig . 1 ; i-2 , iii-1 ) , and one was a ventricular fibrillation ( vf ) survivor ( fig . 
   1 ; iii-2 ) . the proband ( fig . 1 ; iii-2 ) , aged 12 years , with sinus rhythm ( sr ) and a crbbb , had an episode of vf , and her elder brother ( fig . 1 ; iii-1 ) , 
   the proband and her brother and father ( fig . 1 ; iii-2 , iii-1 , i-2 ) showed mild lvh ( maximum wall thickness < 20 mm ) . 
   1pedigree and phenotype of family a. pedigree with three generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , cavb complete atrioventricular block , pmi pacemaker implantation , crbbb complete right bundle - branch block , vf ventricular fibrillation pedigree and phenotype of family a. pedigree with three generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , cavb complete atrioventricular block , pmi pacemaker implantation , crbbb complete right bundle - branch block , vf ventricular fibrillation dna analysis showed that the proband and her elder brother had the double reported mutations , arg130cys and phe110ile , of tnnt2 ( fig . 
   her father , who had arrhythmia and mild hcm , had the phe110ile mutation , and her mother ( ii-6 ) , who had no symptoms or abnormal findings , had the arg130cys mutation . in family b 
   , 3 of 10 members who carried or were suspected of having hcm were thought to have obstructive hypertrophic cardiomyopathy . 
   2 ; iii-7 ) showed apical hypertrophy and apical aneurysm at a comparatively young age . 
   her aunt ( fig . 2 ; ii-4 ) , who had a heart murmur , was thought to have hypertrophic obstructive cardiomyopathy ( hocm ) , and died when she was 19 years old . 
   2 ; iii-9 ) did not show obstructive hcm , but died suddenly when she was 21 years old . her grandmother ( fig . 
   iii-7 ) , her son ( fig . 2 ; iv-3 ) , and her cousin ( fig . 2 ; iii-2 ) , who carried hcm , had an arg92trp mutation of tnnt2.fig . 2pedigree and phenotype of family b. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , hocm hypertrophic obstructive cardiomyopathy , ecg electrocardiogram pedigree and phenotype of family b. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , hocm hypertrophic obstructive cardiomyopathy , ecg electrocardiogram in family c , the proband ( fig . 3 ; iv-3 ) , her mother ( fig . 3 
   ; iii-3 ) , and her grandmother ( fig . 3 ; ii-3 ) showed mild cardiac hypertrophy ( maximum wall thickness < 20 mm ) and asymmetric septal hypertrophy , and her myocardial hypertrophy had been gradually increasing . 
   her mother was suspected of having a shifting dilated phase by recent cardiac magnetic resonance imaging ( mri ) . 
   3 ; iv-3 ) had symptomatic west syndrome following perinatal brain damage , and was treated with corticotropin . 
   3 ; iv-3 ) and her mother ( fig . 3 ; iii-3 ) had the arg92trp mutation of tnnt2.fig . 
   3pedigree and phenotype of family c. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , wpw syndrome wolff - parkinson - white syndrome pedigree and phenotype of family c. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , wpw syndrome wolff - parkinson - white syndrome in family d , two of three members who carried or were suspected of having hcm died suddenly ( fig . 4 ; 
   4 ; iii-2 ) . the proband ( fig . 4 ; iii-2 ) had relatively strong cardiac hypertrophy ( maximum wall thickness > 20 mm ) , and cardiac standstill from ventricular fibrillation at the age of 24 years . 
   her cousin ( fig . 4 ; iii-3 ) died suddenly at a young age ( 13 years ) , and her granduncle also died at the age of 40 . 
   this transition was observed in codon 79 , and converted an isoleucine residue to a threonine residue ( fig . 
   ile79thr occurred in conserved residues found in tnnt2 orthologues of human , mouse , rat , cat , and ox ( fig . 
   iii-2 ) also had a 5-bp ( cttct ) deletion / deletion polymorphism of intron 3 of tnnt2 ( fig . 
   4pedigree and phenotype of family d. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   c the insertion / deletion ( i / d ) polymorphism pedigree and phenotype of family d. pedigree with four generations ( roman numerals ) , the propositus is denoted by an arrow . 
   hcm hypertrophic cardiomyopathy , vf ventricular fibrillation 
   a the new ile79thr mutation of tnnt2 ( exon 8) . 
   this domain is well preserved in mammals 
   a the deletion / deletion ( d / d ) polymorphism . 
   c the insertion / deletion ( i / d ) polymorphism to clarify the clinical importance of this polymorphism , we performed genetic analysis in 47 hcm patients from 173 unrelated japanese patients with familial hcm . in these 47 patients , 
   24 had the deletion / deletion polymorphism ( 51 % , 14 men and 10 women ; 072 years old , median age 30 years old ) . 
   five of the 24 ( 21 % ) patients who had the deletion / deletion polymorphism were diagnosed with apical hcm or hocm . in 6 of the 10 ( 60 % ) with available data of echocardiography among these 24 patients , 
   on the other hand , in the 47 hcm patients , the remaining 23 did not have the deletion / deletion polymorphism , but had the deletion / insertion or insertion / insertion polymorphism ( 49 % , 15 men and 8 women ; 076 years old , median age 18 years ) . 
   two of the 23 ( 9 % ) patients were diagnosed with apical hcm , and there were no hocm patients . 
   two of the seven ( 29 % ) with available data of echocardiography among these 23 patients showed the maximum wall thickness of more than 30 mm . 
   previous studies have reported familial hcm cases where a consistent relationship between certain genetic mutations and clinical outcome was observed , allowing for the classification of  benign  and  malignant  mutations [ 1830 ] . however , in recent years it was considered that the specific gene mutation can not be the sole factor that dictates clinical phenotype . 
   mutation , mutation type was not seen to be clinically useful in predicting prognosis in hcm given this very low incidence rate [ 32 , 3840 ] . 
   in addition , it was reported that mutation of a sarcomeric protein gene can cause rcm , hcm , and dcm within the same family , and patients with a benign mutation experienced a very serious clinical course [ 41 , 42 ] . in the present study , 
   the phenotype of each family was often different from reported cases , even if they had the same genetic mutation . 
   in addition , families with the same genetic mutation showed a similar trend in the phenotype , but it was not exactly the same . 
   however , sudden death in youth was observed in all of these families . on the other hand 
   mutation , which did not show the phenotype of hcm or a family history of sudden death . 
   for example , in family a , two tnnt2 mutations were found , the arg130 cys and phe110ile mutations . 
   the arg130 cys mutation has been reported by a chinese research group , whose clinical features had an early onset , syncope , sudden death in youth , heart failure , and arrhythmia as atrial fibrillation . 
   the phe110ile mutation has been reported to show a favorable prognosis , and have comparatively slight hypertrophy or apical hypertrophy ( in 16 individuals of 6 japanese families ) [ 19 , 20 ] . 
   a , whereas the proband and her elder brother , who carried these two mutations , showed similar reported phenotypes of the arg130 cys mutation , her mother and mother s family members , who had the arg130cys mutation , showed no abnormal clinical features such as cardiac hypertrophy , sudden death , or abnormal electrocardiograms . 
   furthermore , her father and father s family members , who had the phe110ile mutation , showed atrioventricular blocks , and these phenotypes have not been reported . in family b , 
   the mutation showed comparatively slight cardiac hypertrophy or a high incidence of sudden death in males ( 19 individuals of two mixed racial families ) [ 2224 ] . 
   however , the proband and her family , who carried hcm , showed relatively severe cardiac hypertrophy , with a high incidence of sudden death in females . in family c , an arg92trp mutation was also found . 
   the proband and her family , who carried hcm , showed mild cardiac hypertrophy and asymmetric septal hypertrophy . 
   the proband s myocardial hypertrophy had been gradually increasing , and her mother had a suspected shift to the dilated phase . 
   she survived following an episode of vf , and her cousin died suddenly at the age of 13 years . 
   previously , a mutation of the 79 residue , the ile79asn mutation , had been reported [ 24 , 25 ] , and this mutation also showed a poor prognosis . in our mutated case , even if the amino acid mutation ( ile79thr ) was different from the reported case ( ile79asn ) , the patient showed a malignant prognosis . in family d , a 5-base - pair ( cttct ) deletion / deletion ( d / d ) polymorphism in intron 3 of the tnnt2 was also found . 
   it has been reported that this polymorphism had caused skipping of exon 4 of tnnt2 , and that the deletion allele could be associated with a predisposition for prominent lvh . although it was in a very limited range , from our genetic study on this polymorphism we gained the impression that a patient carrying the tnnt2 deletion / deletion polymorphism had a stronger tendency toward hypertrophy . to conduct further analysis , further examination including new cases is required . 
   we considered that , at least in japanese familial hcm , only the type of genetic mutation of tnnt2 did not seem useful in distinguishing the prognosis . 
   however , if mutations were found , there was a risk of sudden death in youth . 
   therefore , regardless of the type of genetic mutation , it would be more important to observe the patient in detail from birth in each lineage . 
   the development of a  case - based  method would be useful to treat and help each individual , and more attention needs to be paid toward searching for the modifier and environmental factors including diet , lifestyle , exercise , and the modification gene and polymorphism .
summary: hypertrophic cardiomyopathy ( hcm ) is an autosomal dominant disorder resulting from mutations in genes for at least 15 various sarcomere - related proteins including cardiac -myosin heavy chain , cardiac myosin - binding protein c , and cardiac troponin t. the troponin t gene ( tnnt2 ) mutation has the third incidence of familial hcm , and the genotype  phenotype correlation of this gene still remains insufficient in japanese familial hcm . 
   therefore , in the present study , we focused on screening the tnnt2 mutation in 173 unrelated japanese patients with familial hcm , and found three reported mutations and a new mutation of tnnt2 in 11 individuals from four families . in these families , two individuals from one family had double mutations , arg130cys and phe110ile , six individuals from two other families had an arg92trp mutation , and one individual of another family had a new mutation , ile79thr , of tnnt2 . 
   the phenotype of each family was often different from reported cases , even if they had the same genetic mutation . 
   in addition , families with the same genetic mutation showed a similar trend in the phenotype , but it was not exactly the same . 
   however , sudden death in youth was observed in all of these families . 
   although the type of genetic mutation is not useful for predicting prognosis in hcm , the possibility of sudden cardiac death remains . 
   therefore , the prognosis of individuals bearing the tnnt2 mutation with familial hcm should be more carefully observed from birth .