1 The First Dongguan Affiliated Hospital, Guangdong Medical University, 523710 Dongguan, Guangdong, China
2 Department of Endocrinology and Metabolism, Zhuhai Hospital Affiliated to Jinan University; The First Hospital Affiliated to Medical College of Macao University of Science and Technology, 519000 Zhuhai, Guangdong, China
3 The Second Department of Cardiology, The Second People's Hospital of Guangdong Province, 510310 Guangzhou, Guangdong, China
Academic Editor: John Lynn Jefferies
Abstract
Restrictive cardiomyopathy (RCM) is an uncommon cardiac muscle disease characterized by impaired ventricular filling and severe diastolic dysfunction with or without systolic dysfunction. The patients with RCM present poor prognosis and high prevalence of sudden cardiac death, especially in the young. The etiology of RCM may be idiopathic, familial or acquired predispositions from various systemic diseases. The genetic background of familial RCM is often caused by mutations in genes encoding proteins of sarcomeres and a significant minority by mutations in non-sarcomeric proteins and transthyretin proteins. It is important to identify the associations between genotype and phenotype to guide clinical diagnosis and treatment. Here, we have summarized the reported index cases with RCM involving genetic etiology to date and highlighted the most significant phenotype results.
Keywords
- restrictive cardiomyopathy
- mutations
- sarcomeres
- phenotype
- genotype
Restrictive cardiomyopathy (RCM) is the least frequently encountered form of cardiac muscle disease, which increases myocardial stiffness and results in impaired ventricular filling [1, 2]. RCM should be classified as either primary or secondary according to underlying etiology [3]. The hallmark of RCM is diastolic dysfunction in the presence of normal or near-normal systolic function, ventricular volumes and wall thickness, at least at the beginning of disease [4]. Consequently, the systolic function might deteriorate at later stages of the disease [5]. Patients with RCM may present signs of left or right heart failure. Right-sided symptoms often predominate, such as peripheral edema and ascites. However, there is a worse prognosis when the left ventricle is affected or ventricular arrhythmias and conduction disturbances are encountered [4, 6]. Pharmacological therapy and heart failure management for RCM show limited efficacy to improve ventricular filling or prolong survival [7]. Although therapy is unsatisfactory, early and accurate diagnosis can significantly improve symptom and survival [4, 7]. The correct diagnosis depends on the distinction between RCM and constrictive pericarditis, which share similar clinical presentations and physical findings [8, 9]. But their pathophysiological mechanism and prognosis differ significantly [10].
RCM may be idiopathic, familial, acquired predispositions from various systemic
diseases or a combination of them [2]. Some familial cases presenting genetically
determined etiology are often associated with autosomal dominant inheritance or
X-linked inheritance [11]. Although familial RCM caused by a single genetic
defect is rare in clinical practice, mapping several specific disease-causing
genetic mutations resulting in RCM has been recognized [12]. The genetic
mutations associated with the occurrence and progression of RCM involve sarcomere
proteins, such as troponin I (TNNI3), troponin T (TNNT2),
This article focuses on heritable genetic mutations and genotype-phenotype associations with familial RCM, as shown in Table 1 (Ref. [11, 13, 14, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48]). The risk stratification and clinical treatment of RCM patients could be affected and improved depending on the systematic databases of genetic alterations.
| Genes | Mutation | Sex | Age | Phenotypes | Complications | Refs | ||
| HCM | DCM | HF | ||||||
| Sarcomeric Genes | ||||||||
| TNNI3 | p.D190H | M | 11 y | – | – | + | Marked atrial enlargement | [17] |
| p.R192H | M | 19 y | + | – | + | Paroxysmal AF, involvement in worst clinical phenotypes | ||
| p.K178E | F | 6 y | – | – | + | Dyspnea, involvement in worst clinical phenotypes | ||
| p.R145W | M/F | 70/68 y | – | – | + | Dyspnea, angina | ||
| p.A171T | M | 63 y | – | – | – | An embolic stroke | ||
| p.L144Q | F | 31 y | – | – | + | – | ||
| TNNI3 | p.R204H | F | 16 y | + | – | + | – | [20] |
| TNNI3 | p.L144H | F | 27 y | – | – | + | Died of pulmonary embolism at 30-year old | [21] |
| p.R170Q | M | 15 y | – | – | + | Marked atrial enlargement | ||
| TNNI3 | p.P150S | M | – | – | – | + | AF | [22] |
| TNNI3 | g.4789_4790delAA | F | 6.4 y | – | – | + | – | [23] |
| TNNI3 | g.4762delG | F | 23 y | + | – | + | Died of congestive HF | [24] |
| TNNT2 | p.96delE | F | 12 m | – | – | + | Involvement in infantile RCM | [25] |
| TNNT2 | p.100-101delNE | F | 11 y | + | – | + | Overlap of RCM and HCM phenotypes | [26] |
| TNNT2 | p.I79N | F | 53 y | – | – | + | A malignant form of HCM involved | [13] |
| TNNT2 | p.E136K | M | 3.5 y | – | – | + | Dysplastic coronaries | [23, 27] |
| TNNC1 | p.A8V and p.D145E | F | 8 m | + | – | + | Involvement in young-onset and fatal restrictivephysiology | [28] |
| MYH7 | p.P838L | M | 2 m | + | – | + | Early onset, mild hypertrophy, evolution to death quickly | [14] |
| MYH7 | p.G768R | M | 15 m | + | – | + | Involvement in restrictive physiology in childhood and HCM in adults | [29] |
| MYH7 | p.R721K | F | – | – | – | + | – | [30] |
| MYH7 | p.Y386C | F | 9 m | – | – | + | Myocardial bridging | [31] |
| MYL3 | p.E143K | F | 22 y | – | – | + | Severe biatrial enlargement | [32] |
| MYL2 | p.G57E | |||||||
| TPM1 | p.N279H | F | 36 y | + | – | + | – | [32] |
| TPM1 | p.E62Q and p.M281T | F | 6 y | + | – | + | – | [33] |
| ACTC | p.D313H | F | 8.2 y | – | + | + | A mixed RCM/DCM phenotype | [23] |
| MYBPC3 | p.Q463X | F | 34 y | + | + | + | Persistent AF | [34] |
| p.E334K | M | 45 y | + | + | + | – | ||
| Nonsarcomeric Genes | ||||||||
| DES | p. R16C | M | 30 y | – | – | + | AVB, involvement in a recessive phenotype of restrictive physiology | [35] |
| p.T453I | M | 17 y | – | – | – | AVB | ||
| p.R406W | M | 27 y | – | – | + | AVB, early onset severe cardiac and skeletal myopathy | ||
| IVS3.del+2_11 TATACCTTGG | F | 48 y | – | – | + | AVB | ||
| DES | p.Y122H | M | 19 y | – | – | – | AVB | [36] |
| DES | p.E413K | M | 30 y | – | – | + | AVB, severe skeletal myopathy | [37] |
| DES | c.735G |
M | 41 y | – | – | + | AF, right HF, skeletal myopathy | [38] |
| MYPN | p.Q529X | M | – | + | – | + | – | [19] |
| TTN | p.Y7621C | F | 35 y | – | – | + | AF, thromboembolism | [11] |
| FLNC | p.S1624L | F | 14 y | – | – | + | Intestinal lymphangiectasia | [39] |
| p.I2160F | F | 15 y | – | – | + | – | ||
| BAG3 | p.P209L | F | 15 y | – | – | – | Severe myopathy, neuropathy, long QT syndrome, late-onset RCM | [40, 41] |
| Infiltrative RCM Pathogenic Mutations | ||||||||
| TTR | p.V122I | – | – | – | – | + | Late-onset RCM, prevalent in African Americans | [42] |
| p.I68L | – | – | + | – | + | Male predominance, age-dependent penetrance | [43] | |
| p.L111M | – | – | – | – | + | Young-onset and manifest RCM, carpal tunnel syndrome | [44] | |
| p.T60A | – | – | – | – | + | A major determinant of poor prognosis | [45] | |
| p.H88R | M | 65 y | – | – | + | Late-onset cardiomyopathy | [46] | |
| p.A65G | F | 72 y | – | – | + | Hereditary amyloidosis | [47] | |
| p.S23N | F | 46 y | – | – | + | Manifest cardiac and peripheral, ATTR amyloidosis | [48] | |
| M, male; F, female; y, years; m, months; RCM, restricted cardiomyopathy; HCM, hypertrophic cardiomyopathy; DCM, dilated cardiomyopathy; HF, heart failure; AF, atrial fibrillation; AVB, atrioventricular block; –, not mentioned in the previous reports; +, mentioned/occurred in previous reports. | ||||||||
Cardiac muscle cells (cardiomyocytes), as the structure of myocardium tissue,
are composed of parallel bundles of myofibrils with a diameter of about 1
The sarcomeres are defined as regions residing between the Z-lines (also known
as Z-disks or Z-bands) based on the electron-optical properties and structural
components [51]. The sarcomeres consist of an A-band flanked by two half I-bands
as the central region. The A-band is anisotropic due to parallel aligned thick
filaments composed of myosin. The myosin is a hexameric protein including two
heavy chains and four light chains. Each myosin molecule contains two myosin
“heads”, which are associated with two light chains, respectively, and make a
total of four light chains [52]. The myosin “heads” are recognized to reveal
the active site for ATP hydrolysis, with which myosin motor proteins produce a
force on actin filaments [53]. The I-band on each side of the A-band is nearly
isotropic composed of actin and its associated proteins due to thinner and less
well-aligned filaments (called thin filaments) [54, 55]. It is well known that
the interaction of filamentous actin with myosin is the basis of muscle
contraction [56]. The actin, with monomeric (G-actin) polymerized and filamentous
(F-actin) states, is the most abundant and highly conserved protein in most
eukaryotic cells [57, 58]. G-actin proteins polymerize into long F-actin in the
presence of Mg
The cardiomyocyte cytoskeleton mainly consists of highly ordered sarcomeres
referring to myosin-actin and titin filaments (also described as connectin) [70].
The cytoskeleton acts as a sensitive and dynamic cellular organizer and effector
rather than a static skeleton responding to extracellular signals. The titin
filament, a giant molecular spring and scaffold in cardiomyocytes, spans from the
Z-line with NH2 terminus over the half I-band and thick filament to M-line, the
centre of sarcomere [71]. Titin protein is potentially expressed in millions of
various isoforms of different lengths due to differential splicing within the
region of titin located in the I-band from the transcript [72, 73]. Cardiac titin
consists of an N2-B segment between the proximal and distal immunoglobulin (Ig)
domains and might not match a complementary N2-A component. Therefore, the
cardiac titin isoforms are mainly classified as N2-B (3000 kDa in the absence of
N2-A) or N2-BA (
Cardiomyopathies are defined as diseases of the myocardium related to cardiac dysfunction [80], ranging from lifelong symptomless conditions to life-threatening symptoms, including progressive heart failure, different arrhythmias and even sudden cardiac death. Some cardiomyopathies may be idiopathic or familial/genetic/inherited etiology. The genetic studies involving disease-causing mutations suggested that pathological variations in the sarcomere gene played a central role in inherited cardiomyopathies [81]. Several lines of evidence supported that the so-called “disease of the sarcomere” is highly associated with initiation and even different clinical phenotypes of RCM [3]. The observation that the familial occurrence of RCM had long been established firstly attracted attention to its genetic background [82].
The genetic basis of RCM is largely attributed to mutations in the sarcomeric complex. The main mutations are summarized as follows.
TnI has evolved into three isoforms in higher vertebrates, encoded by three
related genes: TNNI1, TNNI2 and TNNI3. Cardiac TnI
(cTnI) in the adult is specifically expressed and regulated by TNNI3,
slow and fast skeletal muscle cells by TNNI1 and TNNI2,
respectively [83]. In the human chromosomal genome, TNNI3 is located at
19q13.4, encoding approximately 210 amino acids residues with a molecular weight
of 24.0 kDa [84]. The functional domain in cTnI between residues from 61 to 112
binds TnT. The inhibitory domain, including residues from 147 to 163, bind
strongly to actin and the N-terminal of TnC. It is necessary for regulating the
connection of Ca
Most RCM-associated mutations in TNNI3 are generally missense rather
than frameshift or splice mutations. It has been described that a c.87A
Besides missense mutations, deletion mutations in TNNI3 are also responsible for the development of RCM in a tiny percentage of patients. A novel deletion mutation of two nucleotides g.4789_4790delAA in exon 7 of TNNI3 was identified in RCM individual [23]. This mutation contributed to a frameshift and the presence of a premature termination codon at amino acid site 209 (E177fsX209). Another index patient diagnosed with RCM at the age of 23 and died due to progression of congestive heart failure at the age of 28 indicated a deletion of one nucleotide g.4762delG in exon 7 of TNNI3. This deletion also induced a frameshift in residue 168 and the introduction of a premature termination codon at site 176 (D168fsX176) [24]. According to laboratory tests, this mutation resulted in the truncation of the C-terminal part of cTnI and an approximate 50% decrease in total cTnI, likely leading to a nearly total deficiency of the second actin TnC binding domain. The damage of the inhibitory effect of the Tn-Tm complex on thin filaments could cause impaired myocardium relaxation and restrictive filling [24].
Collectively, the integrity of the cTnI is essential for conformation of the Tn complex in myofilament and the inhibition of actomyosin ATPase activity. To dissect the pathogenic cellular mechanisms resulting from TNNI3 mutations to identify the cause of RCM is scientifically and clinically important.
TNNT2 gene encodes the Tm-binding subunit of the Tn complex in the
heart, which acts as a regulator of striated muscle contraction in response to
differential intracellular Ca
The first case of RCM caused by a de novo mutation of TNNT2
was reported in a 12-month-old girl [97]. This infantile case had experienced
recurrent episodes of sinus bradycardia and tachycardia, malignant ventricular
arrhythmias and hemodynamic instability. She received extracorporeal membrane
oxygenation therapy, followed by a biventricular assist device insertion and
subsequently underwent heart transplantation [97]. Genetic testing revealed a
novel deletion mutation c.285_287GGA in exon 9 of TNNT2, resulting in
deletion of glutamine in 96 amino acid residual (p.96delE). The p.96delE mutation
is located in the highly conserved domain. It induces the deficiency of a
negative charge in the coiled-coil region, affecting the TnT-Tm-actin complex’s
interactions [98]. Following experimental results demonstrated that p.96delE
mutation significantly increased the Ca
Some missense mutations proved to be associated with RCM. In a large family with
autosomal dominant cardiomyopathy, the c.236T
Therefore, the identified TNNT2 mutations, such as p.100-101delNE and p.I79N, associated with RCM often occur in a TnT binding fragment corresponding to residues 70–170 in the N-terminal domain. This finding suggests the existence of a mutational hotspot region in TNNT2 where mutations may result in impaired Tm-dependent functions of cTnT [102].
Cardiac troponin C (cTnC) consists of two globular EF-hand (the most common
calcium-binding motif) domains and a flexible linker. The calcium-sensing part of
the Tn complex is troponin C encoded by TNNC1 in both cardiac muscle and
slow skeletal muscle. There are two high-affinity calcium-binding sites in the
C-domain of cTnC where are often occupied by Ca
Previously, mutations in TNNC1 have been associated with HCM or DCM.
Nowadays, the evidence indicated that a compound heterozygous mutation p.A8V
(c.C23T) and p.D145E (c.C435A) in TNNC1 inducing fatal RCM was described
in a pediatric proband who inherited the mutation from her unaffected paternal
grandmother and maternal grandfather, respectively [28]. The younger sister of
this proband, who carried the same genetic background, initially showed
congenital HCM, evolved to RCM, subsequently occurred with heart failure and
death. This phenomenon suggests that RCM induced by the compound heterozygosity
p.A8V and p.D145E is combined with a young-onset marked restrictive physiology,
familial history of sudden cardiac death and gradually evolves into septal
hypertrophy. The p.A8V mutation alone caused a more open cTnC N-domain
conformation, presumably increasing interactions with the switch region of cTnI
[104], while the p.D145E mutation altered Ca
As described above, myosin is a hexameric contractile protein containing two
heavy chains (MHC, encoded by MYH7 in the heart) associated with four
light chains (MLC). The four MLCs are classified as two regulatory light chains
(encoded by MYL2 in the heart) and two essential light chains (encoded
by MYL3 in the heart). The C-terminal part of each MHC is
A de novo heterozygous mutation p.P838L was firstly identified in MYH7 in an infantile RCM case. The clinical presentation of this proband was characterized by early-onset, mild hypertrophy of the left ventricle and a very short evolution to death [14]. The p.P838L mutation is located in an extremely conserved hinge segment between the rod region and the globular head region of myosin protein. The marked restrictive physiology might result from the myosin head region’s impaired flexion during the relaxation cycle. However, in a p.P838L myosin transgenic Drosophila melanogaster model, the heart morphology and cardiac function was normal, although the p.P838L mutant myosin increased basal ATPase, actin sliding velocity, rotational flexibility and the average angle of two heads in vitro [110]. On the one hand, the seemingly different findings might result from the possibility that Drosophila myosin protein is less sensitive to the p.P838L perturbation than humans. On the other hand, the identification of the human pathogenic mutations involved sequencing of select candidate genes. Hence, it is possible that a mutation in another genetic locus, alone or in conjunction with P838L myosin, is responsible for the severe phenotype observed in the human patients [110]. Another missense mutation, p.G768R in exon 21 of MYH7, also was found in a pediatric RCM case [29]. The p.G768R locates in a highly conserved region across species and has previously been reported as a disease-causing mutation associated in adults with HCM [111]. It suggests that the phenotypic manifestations of MYH7 mutations in children, especially young ones, are different from adult ones. Further investigations are needed to determine whether other untested genetic mutations or sensitive indicators functioned as potential contributors to the severity and age of onset. A novel MYH7 p.R721K mutation was found in an RCM proband, who died at 47-year old due to progressive congestive heart failure, and her young son both showed biatrial enlargement, normal wall thickness and restrictive features. Yet, her other non-carrier son did not have these features [30]. The p.R721K mutation located in the converter domain of MYH7 affects myosin’s ATPase activity. RCM induced by MYH7 mutation in this domain is associated with severe diastolic heart failure, high rates of atrial fibrillation, stroke, poor prognosis and even sudden cardiac death [30]. Another p.Y386C mutation was reported in exon 13 of MYH7, which was previously seen in an infant with de novo HCM by the laboratory. The index case died at the age of 18 months, and the autopsy findings presented RCM, not HCM [31]. Interestingly, this is the first observation in a patient with RCM overlapped myocardial bridging under an MYH7 mutant background.
RCM caused by MLC-related mutation was firstly reported in an El-Salvadoran
22-year-old female. The patient underwent recurrent syncope and severe heart
failure [32]. There were homozygous mutations of MYL3 p.E143K
(c.427G
The
A novel homozygous missense mutation TPM1 p.N279H (c.835A
Actin is a highly conserved protein and encoded by ACTC1.
Mutations in this gene have been phenotypically associated with various cardiac
abnormalities. A novel p.D313H mutation (g.4642G
The MYBPC3 gene encodes the cardiac isoform of myosin-binding protein C
(MyBPC), a myosin-associated and large multi-domain protein. The role of MyBPC in
the sarcomere regulation is not yet fully understood. Previously, MYBPC3
mutations were demonstrated highly related to familial HCM [114]. However, a
nonsense mutation MYBPC3 p.Q463X (c.1387C
While nonsarcomeric mutations-associated RCM subtypes are less common, several mutations have recently been identified in index cases.
Desmin is encoded by DES and functions as the chief intermediate filament of the skeletal and cardiac tissue connecting the Z-bands to the subsarcolemmal cytoskeleton. Cardiomyopathies caused by DES mutations often present severe restrictive physiology, syncope, sudden cardiac death due to conduction defect and overlap with a heterogeneous group of skeletal myopathies [116].
In four unrelated probands with RCM complicated with the atrioventricular block
(AVB), there were three novel mutations p. R16C, p.T453I, a 10-bp deletion at the
exon-intron boundary of exon 3 and one known heterozygous mutation p.R406W
identified in DES [35]. The novel p.R16C mutation was associated with a
recessive phenotype due to the absence of RCM in three heterozygous carriers. The
novel p.T453I mutation is located in the highly conserved 9-amino acid motif
among type III intermediate filaments acting as desmin interaction with other
cytoskeletal proteins [117]. The new 10-bp deletion at the exon-intron boundary
of exon 3 damaged the exon 3 donor splice site, predicting the loss of 32 amino
acids and the accumulation of desmin-positive material [118]. The known p.R406W
mutation was located in the C-terminal of the desmin core domain and associated
with early-onset severe cardiac and skeletal myopathy [119]. Although the
probands carry different mutations affecting different domains, all shared the
identical cardiac phenotypes of RCM in combination with AVB [35]. Another novel
homozygous missense mutation DES p.Y122H (c.364T
The MYPN gene encodes myopalladin protein connecting structural regulatory molecules by translocation from the Z-lines and I-bands to the cardiomyocyte nucleus [120]. Mutations in MYPN associated with DCM, HCM and RCM have been reported. MYPN p.Q529X mutation was identified in siblings with RCM, yet their carriers’ mother was not affected. Different phenotypes were observed in family members carrying the same mutation [19]. The phenomenon of reduced penetrance of p.Q529X mutation might be explained by the possibility that the patients with RCM had other disease-associated mutations inherited from their father and absent from their mother. The knock-in heterozygote MYPN p.Q526X mutant mice revealed the diastolic dysfunction and restrictive physiology. There was preserved systolic function without overt hypertrophic remodeling. The phenotype of mutant mice resembles RCM induced by p.Q529X in humans [121].
TTN (also called titin) gene encodes the largest human protein
consisting of 364 exons and approximately 38,000 amino acid residues with a
molecular weight of 4200 kDa. The TTN protein provides architectural support and
sarcomeric organization during muscle contraction [122]. Mutations in
TTN refer to the different phenotypes of cardiomyopathies and missense
variants are very common and frequently benign in DCM [123]. A linkage analysis
study identified a missense mutation TTN p.Y7621C (c.22862A
Filamin C is an actin-cross-linking protein encoded by FLNC in heart muscle. Pathogenic mutations in FLNC have been reported to cause dominant isolated cardiomyopathy phenotype. The prevalence of patients carrying a unique FLNC pathogenic mutation in a cohort was evaluated 8% in RCM [124]. It has been identified that two novel missense mutations, FLNC p.S1624L and p.I2160F, were associated with familial RCM. It was suspected that FLNC and DES mutations shared similar pathological mechanisms due to identical behaviour of cytoplasmic aggregation [39].
Mutation in BAG3 is a rare cause of RCM. Recently, a heterozygous
mutation p.P209L (c.626C
Cardiac amyloidosis (CA) is considered as the prototype of the infiltrative form of RCM. Although CA can be acquired, there are several mutations in genes involving transthyretin (TTR). TTR primarily serves as a transporter for thyroxin and for retinol-binding protein. This protein is a tetramer, but has an innate ability to dissociate into monomers which tend to be amyloidogenic properties. There are three main types of CA: immunoglobulin light chain cardiac amyloidosis (AL-CA), wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) and mutant transthyretin cardiac amyloidosis (ATTRm-CA) [3].
ATTRm-CA is an autosomal-dominant disease in which gene mutations lead to changes in the protein TTR. The clinical symptoms vary extensively depending on many factors including specific TTR mutation site and geographical distribution. The TTR p.V30M mutation was the most common worldwide which induces progressive peripheral sensory-motor polyneuropathy with later cardiac manifestations. However, other mutations p.V122I, p.I68L, p.L111M and p.T60A cause exclusively infiltrative cardiomyopathy [125]. The p.V122I mutation is prevalent in 3.4% of African Americans, and the clinical phenotype often refers to late-onset RCM, despite a low clinical penetrance of the disease [42]. Another prospective observational Atherosclerosis Risk in Communities study reported that the p.V122I carriers had an increased risk of heart failure during the later years compared with non-carriers, indicating that p.V122I carriers are predominantly at increased risk of heart failure with an age-dependent penetrance [126, 127]. The p.I68L mutation is endemic in central-northern Italy and presents as HCM or RCM. Male preponderance is present in affected patients but not in unaffected mutation carriers [43]. The cardiac mutation p.L111M has been traced to three unrelated Danish families [44]. The patients showed developing or manifest RCM with a diastolic dysfunction as the first sign of disease. Ischemic symptoms were often present in the form of angina pectoris because of amyloid deposits in the coronary arteries [44]. Significantly, these patients with the p.L111M were younger and less likely to be male [128]. Familial amyloid polyneuropathy (FAP) resulting from the TTR p.T60A mutation was firstly described in 1986 in an Irish family [45]. Moreover, cardiac amyloidosis is always present at diagnosis in FAP p.T60A mutation, and is a major determinant of its poor prognosis. Other sporadic cases of RCM associated with TTR mutations such as p.A65G, p.H88R and p.S23N have recently been reported [46, 47, 48].
Previously, the invasive endomyocardial biopsy was needed to diagnose the primary cardiomyopathy, and genetic testing was probably underestimated. Nowadays, identifying disease-causing mutations in cardiomyopathy has shed new light on molecular mechanisms. Given the ever-broadening link between specific phenotype of RCM and pathogenic mutations, genetic testing would be advantageous to patients with severe diastolic dysfunction. Location of the mutation in gene influences the development of clinical phenotype of RCM. Therefore, recognizing the effects of shared genetic mutations and establishing a close association with clinical phenotypes is a major aim of future studies.
The data used in this study is not publicly available, but it might be available from the corresponding author upon reasonable request and permission from relevant Chinese Authorities.
RCM, restrictive cardiomyopathy; HCM, hypertrophic cardiomyopathy; DCM, dilated
cardiomyopathy; TNNI3, troponin I; TNNT2, troponin T;
MYH7,
ZY and YL—writing. JC, YL and HL—reviewed paper, quality control of clinical data and clinical design.
Not applicable.
Not applicable.
This work was supported by the Science Project of the Second People’s Hospital of Guangdong Province [TQ2019-005] and the Medical Science and Technology Research Project of Guangdong Province [A2020069].
The authors declare no conflict of interest.