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Introduction
Rare diseases affect between 3.5 and 5.9% of the world’s population, impacting around 350 million people at any time in life. Rare diseases are a heterogeneous group of disorders with a genetic etiology in almost 72%.1-3 There is no global consensus about the definition of a rare disease, but in general terms, a rare disease is defined as a disease that affects < 50/100,000 people.4
Rare genetic cardiovascular diseases affect the cardiovascular system with or without extracardiac manifestations, with an individually low prevalence, mainly caused by rare and ultra-rare genetic variants with heritable potential.2,5,6
There are currently scarce epidemiological studies on rare genetic cardiovascular diseases that delineate their distribution and situation in different world regions, clinical settings, and healthcare systems.7 Moreover, most studies are biased toward estimating the prevalence of some diseases, providing a fractioned and limited perspective of rare genetic cardiovascular diseases’ global panorama.3,8 These are routinely seen in cardiovascular clinical practice. However, the overall rare genetic and nongenetic cardiovascular prevalence in cardiology is hitherto unknown.
It is crucial to estimate the total number of people affected with rare genetic cardiovascular diseases to provide helpful information for improving medical care in the future. Furthermore, this information could establish some bases to encourage translational research that promotes the creation of health policies consistent with the needs of patients suffering from these diseases. Therefore, the objective herein was to conduct a descriptive epidemiological analysis of the rare genetic cardiovascular diseases in the outpatient clinic of a third-level cardiology hospital, emphasizing the estimation of their overall prevalence. Additionally, cardiovascular phenotype distribution, the outpatient prevalence per disease, type of genetic disease, type of rare disease, and other related demographic characteristics were analyzed to evaluate the situation of rare genetic cardiovascular diseases in a cardiovascular clinical setting.
Material and methods
Study design and setting
The design was a retrospective, descriptive epidemiological study of the full range of patients with rare genetic cardiovascular diseases in a third-level cardiovascular hospital outpatient clinic in Mexico City (Instituto Nacional de Cardiología Ignacio Chávez) from January to December 2019. The hospital is a recognized national reference for the attention of pediatric and adult cardiovascular diseases.
Definitions, study population, and data collection
The operational definition of a rare genetic cardiovascular disease was a rare disease cataloged in the online rare diseases database Orphanet2 with a genetic etiology (monogenic or chromosomal disorders) affecting the cardiovascular system with or without extra cardiovascular clinical features. The diagnoses of patients with rare genetic cardiovascular diseases were identified through an exhaustive review of all the diagnoses settled in the electronic clinical records of the 31,487 patients who visited the outpatient clinic. A medical geneticist conducted the review. The study included confirmed clinical diagnoses of patients with rare genetic cardiovascular diseases. The medical geneticist assessed each diagnosis to determine if it met the specific criteria of each rare genetic cardiovascular disease, regardless of whether a confirmatory genetic test was conducted. Diagnoses of common cardiovascular diseases or rare diseases without cardiovascular involvement were excluded from the study. In addition, the clinical data for each patient with a rare genetic cardiovascular disease, including the diagnosis (disease name), cardiovascular phenotype, age, and sex, were collected for further analysis. Each rare genetic cardiovascular disease name was matched with its related preferred disease term and ORPHAcode, obtained from Orphanet.2 In diseases without a specific ORPHAcode, the ORPHAcode of a group of disorders was assigned according to the phenotype.
Type of genetic disorder
Identified rare genetic cardiovascular diseases were classified according to the type of genetic disorder in two categories: chromosomal disorders and monogenic disorders. Chromosomal disorders include numerical and structural chromosomal abnormalities and genomic rearrangements. Monogenic include Mendelian inheritance patterns and non-Mendelian patterns. The information regarding the etiology was obtained from Orphanet2 and OMIM (Online Mendelian Inheritance in Man).9
Type of rare disease
In order to analyze the situation of the rare genetic cardiovascular diseases identified in the outpatient clinic, each rare cardiovascular disease was categorized into three types of rare diseases according to the disease prevalence reported in Orphanet.2 The prevalence reported for each disease could be related to the prevalence in the general population or birth prevalence. Therefore, the type of rare diseases was categorized as follows: rare (prevalence between < 1/2,000 - > 1/50,000),4 ultrarare (prevalence between ≤ 1/50,000 - < 1/1’000,000),10 and unknown prevalence.
Cardiovascular phenotype distribution
To analyze the distribution of the cardiovascular phenotype of the identified patients with rare genetic cardiovascular diseases, the cardiovascular phenotype of each patient was classified into one of the six groups (arrhythmic and conduction disorders, cardiac tumor disorders, cardiomyopathies, congenital heart diseases, vascular disorders, and other cardiovascular disorders) and its corresponding morphological subgroup.
Statistical analysis
The overall prevalence of rare genetic cardiovascular diseases, the prevalence per disease, and the prevalence of monogenic and chromosomal disorders were estimated using the total number of patients who attended the outpatient clinic in 2019 as a denominator. The 95% confidence interval (CI) was estimated for overall, monogenic, and chromosomal disorders prevalences. The prevalence per disease was calculated per 10,000 patients. Continuous variables were expressed as median (25th - 75th percentile). Categorical variables were expressed as absolute and relative frequencies, as appropriate. The differences in continuous variables among groups of cardiovascular phenotypes were calculated with the Kruskal-Wallis H test and, in categorical variables, with the χ2 test. Data and statistical analyses were performed in Stata Statistical Software: Release 16 (StataCorp LLC. 2019).
Results
Of the total population of patients who attended the outpatient clinic in 2019 (n = 31,487), 794 patients had a diagnosis of a rare genetic cardiovascular disease. The overall period prevalence of rare genetic cardiovascular diseases was 2.5% (95%CI, 2.3-2.7) of the patients in the outpatient clinic of the analyzed third-level cardiovascular hospital. The patients with rare genetic cardiovascular diseases corresponded to 104 disease names (Table 1). The frequency of patients and the prevalence in the outpatient clinic per 10,000 patients for each rare genetic cardiovascular disease are shown in Table 1. Of the patients with rare genetic cardiovascular diseases, 51% were women, and the median age was 23 (13-38). Thirty-nine percent of patients correspond to pediatrics ages (0-18 years).
Table 1: Rare genetic cardiovascular diseases identified in the outpatient clinic of a cardiology hospital in 2019.
| Name of rare genetic cardiovascular disease | ORPHAcode(2) | n | Prevalence per 10,000 patients in the outpatient clinic | Type of rare disease* | Type of genetic disease |
|---|---|---|---|---|---|
| Marfan syndrome | 558 | 178 | 56.5 | Rare | Monogenic |
| Romano ward syndrome (long QT syndrome type 1, 2, and 3) | 101,016 | 79 | 25.1 | Rare | Monogenic |
| Noonan syndrome | 648 | 72 | 22.9 | Rare | Monogenic |
| 22q11.2 deletion syndrome | 567 | 43 | 13.7 | Rare | Chromosomal |
| Williams syndrome | 904 | 42 | 13.3 | Rare | Chromosomal |
| Loeys-Dietz syndrome | 60,030 | 38 | 12.1 | Unknown | Monogenic |
| Left ventricular noncompaction | 54,260 | 29 | 9.2 | Unknown | Monogenic |
| Turner syndrome | 881 | 24 | 7.6 | Rare | Chromosomal |
| Brugada syndrome (types 1, 2, and 3) | 130 | 21 | 6.7 | Rare | Monogenic |
| Familial isolated dilated cardiomyopathy | 217,656 | 20 | 6.4 | Rare | Monogenic |
| Holt-Oram syndrome | 392 | 18 | 5.7 | Ultrarare | Monogenic |
| Familial isolated arrhythmogenic right ventricular dysplasia | 154 | 16 | 5.1 | Unknown | Monogenic |
| Supravalvular aortic stenosis | 3,193 | 14 | 4.4 | Rare | Monogenic |
| Classical Ehlers-Danlos syndrome | 287 | 11 | 3.5 | Rare | Monogenic |
| Familial thoracic aortic aneurysm and aortic dissection | 91,387 | 11 | 3.5 | Ultrarare | Monogenic |
| Heterotaxia (visceral heterotaxy) | 450 | 9 | 2.9 | Rare | Monogenic |
| Neurofibromatosis type 1 | 636 | 9 | 2.9 | Rare | Monogenic |
| Andersen-Tawil syndrome | 37,553 | 8 | 2.5 | Unknown | Monogenic |
| Tuberous sclerosis complex | 805 | 8 | 2.5 | Rare | Monogenic |
| Congenital contractural arachnodactyly | 115 | 6 | 1.9 | Unknown | Monogenic |
| Jervell and Lange-Nielsen syndrome | 768 | 6 | 1.9 | Ultrarare | Monogenic |
| Vascular Ehlers-Danlos syndrome | 286 | 6 | 1.9 | Ultrarare | Monogenic |
| Hypermobile Ehlers-Danlos syndrome | 285 | 5 | 1.6 | Rare | Monogenic |
| Klippel-Feil syndrome | 2,345 | 5 | 1.6 | Ultrarare | Monogenic |
| CHARGE syndrome | 138 | 4 | 1.3 | Rare | Monogenic |
| Lown-Ganong-Levine syndrome | 844 | 4 | 1.3 | Ultrarare | Monogenic |
| Wolf-Hirschhorn syndrome | 280 | 4 | 1.3 | Rare | Chromosomal |
| Cardiofaciocutaneous syndrome | 1,340 | 3 | 1 | Unknown | Monogenic |
| Coffin-Lowry syndrome | 192 | 3 | 1 | Ultrarare | Monogenic |
| Cornelia de Lange syndrome | 199 | 3 | 1 | Ultrarare | Monogenic |
| Friedreich ataxia | 95 | 3 | 1 | Ultrarare | Monogenic |
| Hereditary hemorrhagic telangiectasia | 774 | 3 | 1 | Rare | Monogenic |
| Klippel-Trenaunay syndrome | 90,308 | 3 | 1 | Ultrarare | Monogenic |
| Sotos syndrome | 821 | 3 | 1 | Rare | Monogenic |
| Alagille syndrome | 52 | 2 | 0.6 | Ultrarare | Monogenic |
| Apert syndrome | 87 | 2 | 0.6 | Ultrarare | Monogenic |
| Crouzon syndrome | 207 | 2 | 0.6 | Ultrarare | Monogenic |
| Duchenne muscular dystrophy | 98,896 | 2 | 0.6 | Rare | Monogenic |
| Emery-Dreifuss dystrophy | 261 | 2 | 0.6 | Ultrarare | Monogenic |
| Frontonasal dysplasia | 250 | 2 | 0.6 | Unknown | Monogenic |
| Hereditary ATTR amyloidosis | 271,861 | 2 | 0.6 | Unknown | Monogenic |
| Johanson-Blizzard syndrome | 2,315 | 2 | 0.6 | Ultrarare | Monogenic |
| Kearns-Sayre syndrome | 480 | 2 | 0.6 | Ultrarare | Monogenic |
| MASS syndrome | 156,532 | 2 | 0.6 | Unknown | Monogenic |
| Noonan syndrome with multiple lentigines (LEOPARD) | 500 | 2 | 0.6 | Unknown | Monogenic |
| Smith-Magenis syndrome | 819 | 2 | 0.6 | Rare | Monogenic |
| Spondylocostal dysostosis | 1,797 | 2 | 0.6 | Unknown | Monogenic |
| 47,XYY syndrome | 8 | 1 | 0.3 | Rare | Chromosomal |
| Aarskog-Scott syndrome | 915 | 1 | 0.3 | Rare | Monogenic |
| Achondroplasia | 15 | 1 | 0.3 | Rare | Monogenic |
| Acute intermittent porphyria | 79,276 | 1 | 0.3 | Ultrarare | Monogenic |
| Arterial tortuosity syndrome | 3,342 | 1 | 0.3 | Ultrarare | Monogenic |
| Autosomal dominant interatrial communication | 1,478 | 1 | 0.3 | Unknown | Monogenic |
| Autosomal recessive multiple pterygium syndrome | 2,990 | 1 | 0.3 | Ultrarare | Monogenic |
| Axenfeld-Rieger syndrome | 782 | 1 | 0.3 | Ultrarare | Monogenic |
| Becker muscular dystrophy | 98,895 | 1 | 0.3 | Ultrarare | Monogenic |
| Blackfan-Diamond anemia | 124 | 1 | 0.3 | Ultrarare | Monogenic |
| Carney complex | 1,359 | 1 | 0.3 | Unknown | Monogenic |
| Catecholaminergic polymorphic ventricular tachycardia | 3,286 | 1 | 0.3 | Rare | Monogenic |
| Complex chromosomal rearrangement; t(1;3) | 263,708 | 1 | 0.3 | Unknown | Chromosomal |
| Complex chromosomal rearrangement; t(14;22) | 263,708 | 1 | 0.3 | Unknown | Chromosomal |
| Complex chromosomal rearrangement; t(7;12) | 263,708 | 1 | 0.3 | Unknown | Chromosomal |
| Complex chromosomal rearrangement; t(8;18) | 263,708 | 1 | 0.3 | Unknown | Chromosomal |
| Congenital heart block | 60,041 | 1 | 0.3 | Unknown | Monogenic |
| Costello syndrome | 3,071 | 1 | 0.3 | Ultrarare | Monogenic |
| Distal trisomy 18q | 1,716 | 1 | 0.3 | Unknown | Chromosomal |
| Distal trisomy 6p | 1,745 | 1 | 0.3 | Ultrarare | Chromosomal |
| Ellis Van Creveld syndrome | 289 | 1 | 0.3 | Unknown | Monogenic |
| Fabry disease | 324 | 1 | 0.3 | Rare | Monogenic |
| Familial atrial fibrillation | 334 | 1 | 0.3 | Unknown | Monogenic |
| Familial dilated cardiomyopathy with conduction defect due to LMNA mutation | 300,751 | 1 | 0.3 | Unknown | Monogenic |
| Fragile X syndrome | 908 | 1 | 0.3 | Rare | Monogenic |
| Incontinentia pigmenti | 464 | 1 | 0.3 | Ultrarare | Monogenic |
| Kabuki syndrome | 2,322 | 1 | 0.3 | Rare | Monogenic |
| Kallmann syndrome-heart disease syndrome | 2,326 | 1 | 0.3 | Ultrarare | Monogenic |
| Kyphoscoliotic Ehlers-Danlos syndrome | 536,545 | 1 | 0.3 | Unknown | Monogenic |
| Larsen syndrome | 503 | 1 | 0.3 | Ultrarare | Monogenic |
| McCune Albright syndrome | 562 | 1 | 0.3 | Ultrarare | Monogenic |
| Meckel syndrome | 564 | 1 | 0.3 | Rare | Monogenic |
| Mosaic trisomy 8 | 96,061 | 1 | 0.3 | Unknown | Chromosomal |
| Mucopolysaccharidosis type 2 (Hunter) | 580 | 1 | 0.3 | Ultrarare | Monogenic |
| Mucopolysaccharidosis type 6 (Maroteaux-Lamy) | 583 | 1 | 0.3 | Ultrarare | Monogenic |
| Muenke syndrome | 53,271 | 1 | 0.3 | Rare | Monogenic |
| Multiminicore myopathy | 598 | 1 | 0.3 | Unknown | Monogenic |
| Oculopharyngeal muscular dystrophy | 270 | 1 | 0.3 | Ultrarare | Monogenic |
| Opitz GBBB syndrome | 2,745 | 1 | 0.3 | Ultrarare | Monogenic |
| Partial duplication of the long arm of chromosome 13; t(13;14) | 262,932 | 1 | 0.3 | Unknown | Chromosomal |
| Partial duplication of the long arm of chromosome 13; t(13;15) | 262,932 | 1 | 0.3 | Unknown | Chromosomal |
| Partial duplication of the short arm of chromosome 11 | 262,785 | 1 | 0.3 | Unknown | Chromosomal |
| Pfeiffer syndrome | 710 | 1 | 0.3 | Unknown | Monogenic |
| Pseudopseudohypoparathyroidism | 79,445 | 1 | 0.3 | Unknown | Monogenic |
| Robinow syndrome | 97,360 | 1 | 0.3 | Unknown | Monogenic |
| Rubinstein-Taybi syndrome | 783 | 1 | 0.3 | Ultrarare | Monogenic |
| Seckel syndrome | 808 | 1 | 0.3 | Ultrarare | Monogenic |
| Short QT syndrome | 51,083 | 1 | 0.3 | Unknown | Monogenic |
| Shprintzen-Goldberg syndrome | 2,462 | 1 | 0.3 | Ultrarare | Monogenic |
| Steinert myotonic dystrophy | 273 | 1 | 0.3 | Rare | Monogenic |
| Stickler syndrome | 828 | 1 | 0.3 | Rare | Monogenic |
| TARP syndrome | 2,886 | 1 | 0.3 | Ultrarare | Monogenic |
| Tel Hashomer camptodactyly syndrome | 3,292 | 1 | 0.3 | Ultrarare | Monogenic |
| Tetrasomy 12p (Pallister-Killian syndrome) | 884 | 1 | 0.3 | Rare | Chromosomal |
| Trisomy X | 3,375 | 1 | 0.3 | Rare | Chromosomal |
| TTR-related cardiac amyloidosis | 85,451 | 1 | 0.3 | Unknown | Monogenic |
| Van den Ende-Gupta syndrome | 2,460 | 1 | 0.3 | Ultrarare | Monogenic |
CHARGE = coloboma, heart defects, atresia of the choanae, retardation of growth and development, genital abnormalities, and ear abnormalities. ATTR = transthyretin-related amyloidosis. MASS = mitral valve, aorta, skeletal, and skin. LMNA = lamin. GBBB = first letter from the last names of the families that was first diagnosed. TARP = talipes equinovarus, atrial septal defect, robin sequence, and persistence of left superior vena cava. TTR = transthyretin.
* According to the diseases prevalences in Orphanet;2 rare (< 1/2,000 - > 1/50,000), ultrarare (≤ 1/50,000 - < 1/1’000,000), and unknown prevalence.
Eighty-seven out of 104 diseases observed corresponded to monogenic disorders, and 17 were chromosomal disorders (Table 1). Therefore, the number of patients affected with monogenic disorders was 668/794 (84.1%), and patients with chromosomal disorders accounted for 126/794 (15.9%). The prevalence of monogenic and chromosomal disorders of the rare genetic cardiovascular diseases in the outpatient clinic was 2.1% (95%CI, 2.0-2.3) and 0.4% (95%CI, 0.3-0.5), respectively.
According to the reported prevalence for each disease in Orphanet,2 33 diseases correspond to the definition of rare diseases with a prevalence between < 1/2,000 and > 1/50,000, 38 correspond to ultrarare diseases (≤ 1/50,000 - < 1/1,000,000), and 33 had an unknown prevalence in the general population or at birth (Table 1). Ultrarare diseases and rare genetic cardiovascular diseases with an unknown prevalence comprise a diverse spectrum, including skeletal dysplasias, cardiac neoplasm syndromes, unbalanced reciprocal translocation syndromes, muscular dystrophies, inborn errors of metabolism, and other syndromes, as shown in Table 1.
The cardiovascular phenotype presented in each rare genetic cardiovascular disease patient was classified to determine its distribution. The frequency per cardiovascular phenotype groups and subgroups is shown in Table 2. The most frequent cardiovascular phenotype was congenital heart diseases (42.4%; n = 337/794), followed by vascular disorders (27.2%; n = 216/794), arrhythmic and conduction disorders (16.4%; n = 130/794), cardiomyopathies (11.2%; n = 89/794), and the less frequent phenotypes were other cardiovascular disorders (1.9%; n = 15/794) and cardiac tumor disorders (0.9%; n = 7/794). There was a statistically significant difference among the cardiovascular phenotype groups in age (χ5 = 106; p= 0.0001) (Figure 1) and sex (χ5 = 17.9; p = 0.003) (Figure 2). The youngest and oldest cardiovascular phenotype groups were cardiac tumor disorders (4 [1-13] years) and cardiomyopathies (37 [24-50] years), respectively (Figure 1). In addition, cardiac tumor disorders had a higher proportion of females (85.7%) (Figure 2). Sixty-two percent of all patients (n = 489/794) with rare genetic cardiovascular diseases corresponded to three cardiovascular phenotype subgroups. The cardiovascular phenotype subgroup related to thoracic aortic aneurysm and dissection had the largest number of patients, corresponding to 26.6% of all patients (n = 211/794), followed by obstructive congenital heart disease lesions (20.3%; n = 161/794) and primary electrical diseases (14.7%; n = 117/794) (Table 2). These three subgroups of cardiovascular phenotypes correspond principally to Marfan syndrome, Loeys-Dietz syndrome, Noonan syndrome, Williams syndrome, Romano-Ward syndrome, Brugada syndrome, and others.
Table 2: Cardiovascular phenotype distribution of the 794 patients with rare genetic cardiovascular in the outpatient clinic.
| Cardiovascular phenotype | n (%) |
|---|---|
| Arrhythmic and conduction disorders | |
| Primary electrical diseases | 117 (90.0) |
| Preexcitation syndrome | 5 (3.9) |
| Atrioventricular block | 3 (2.3) |
| Other cardiac arrhythmias* | 3 (2.3) |
| Atrial fibrillation and flutter | 2 (1.5) |
| Cardiac tumor disorders | |
| Cardiac rhabdomyoma | 6 (85.7) |
| Cardiac myxoma | 1 (14.3) |
| Cardiomyopathies | |
| Left ventricular noncompaction | 29 (32.6) |
| Dilated cardiomyopathy | 27 (30.3) |
| Arrhythmogenic right ventricular cardiomyopathy | 16 (18.0) |
| Hypertrophic cardiomyopathy | 15 (16.9) |
| Restrictive cardiomyopathy | 2 (2.2) |
| Congenital heart diseases | |
| R-sided and L-sided obstructive lesions‡ | 161 (47.8) |
| Septal defects§ | 67 (19.9) |
| Conotruncal heart defects¶ | 45 (13.3) |
| Valvular heart diseases|| | 38 (11.3) |
| Other congenital heart diseases** | 16 (4.7) |
| Heterotaxy | 10 (3.0) |
| Vascular disorders | |
| Thoracic aortic aneurysm and dissection | 211 (97.7) |
| Arteriovenous malformation | 3 (1.4) |
| Varicose veins | 2 (0.9) |
| Other cardiovascular disorders | |
| Primary pulmonary hypertension | 6 (40.0) |
| Cardiac dysautonomia | 5 (33.3) |
| Ischemic heart disease | 2 (13.3) |
| Pericardial effusion | 1 (6.7) |
| Ventricular dysfunction | 1 (6.7) |
* Sinus node disease, supraventricular tachycardia, and ventricular premature depolarization.
‡ Right-sided obstructive lesions (pulmonary stenosis, stenosis of the pulmonary arteries, and pulmonary atresia with intact ventricular septum) and left-sided obstructive lesions (aortic stenosis, bicuspid aortic valve, coarctation of the aorta, supravalvular aortic stenosis, hypoplastic left heart syndrome, mitral stenosis, and mitral double outlet).
§ Atrial septal defects, ventricular septal defects and atrio ventricular septal defects (with or without minor abnormalities).
¶ Tetralogy of Fallot, pulmonary atresia with ventricular septal defects, double outlet of the left ventricle, pentalogy of Fallot, pulmonary valve agenesis, truncus arteriosus, transposition of great arteries, and interrupted aortic arch.
|| Mitral prolapse valve, pulmonary, and tricuspid, aortic and mitral insufficiency.
** Total and partial anomalous pulmonary venous return, Epstein’s anomaly, vascular ring, patent arterial duct, persistent left superior vena cava, and anomalous pulmonary venous drainage.
Figure 1: Distribution of age of patients with rare genetic cardiovascular diseases among cardiovascular phenotype groups.
Discussion
Scarce studies have addressed the number and prevalence of rare cardiovascular diseases because of their low prevalence and difficulty in recognition.1,78 However, knowing the prevalence of rare genetic cardiovascular diseases is of utmost importance since there is an increase in prevention and follow-up algorithms,11,12 new treatments, and gene therapies that may benefit patients.13 Rare genetic cardiovascular diseases are frequently encountered in clinical practice, but the overall prevalence of rare genetic cardiovascular conditions in a clinical setting was previously unknown in Mexico and worldwide. In the present research, the overall period prevalence of rare genetic cardiovascular diseases was 2.5%; in other words, almost 1 in 40 patients has a rare genetic cardiovascular disease in a cardiovascular outpatient clinic. Although the prevalence may appear low relative to other cardiovascular diseases, it is not insignificant, especially considering that a significant proportion of rare genetic cardiovascular diseases harm the quality of life, reduce life expectancy, and have economic implications that could cause higher medical care costs.14-16
In the present study, the prevalence of monogenic rare genetic cardiovascular diseases was 2.1%. In this regard, a recent study estimated the prevalence of monogenic cardiovascular diseases in patients referred to cardiac catheterization with an unbiased whole-exome sequencing approach. The prevalence of patients with pathogenic and likely-pathogenic variants with a clinical phenotype was 1.7%.17 Nevertheless, the estimated prevalence includes both common genetic diseases and rare genetic cardiovascular diseases without reporting the overall estimated prevalence for those rare diseases. The higher prevalence of monogenic disorders observed in the present study could be related to a broader spectrum of conditions in the cardiovascular outpatient clinic and the inclusion of pediatric ages.
A curated database initiative (PhenoDis)5 has annotated the existence of 327 rare cardiac diseases so far,5 without counting those that affect the vascular system or other rare cardiovascular diseases. The present study detected the broad spectrum of rare genetic cardiovascular diseases that can occur in cardiovascular clinical practice. The spectrum includes rare genetic cardiovascular diseases affecting the heart structure and functioning, blood vessels, cardiac conduction, autonomic systems, and others. A total of 104 different rare genetic cardiovascular disease diagnoses were identified, not limited to a few widely known syndromes. We should be aware that a great proportion of the rare genetic cardiovascular diseases found in the present study have an unknown prevalence or are considered ultrarare diseases with an extremely low prevalence (≤ 1/50,000 - < 1/1’000,000) in the general population.10 Ultrarare diseases are routinely excluded from public health policies and comprise highly heterogeneous phenotypes with complex molecular mechanisms. Therefore, it is essential to highlight the importance of its recognition to promote comprehensive diagnostic approaches, the formation of doctors specialized in them, drug development, novel therapies, and the creation of health policies consistent with the needs of the patients suffering from these diseases.18
The cardiovascular phenotype distribution observed among rare genetic cardiovascular diseases showed some expected results, such as a higher frequency of congenital heart diseases19 and a lower frequency related to rare genetic disorders with cardiac tumors.20 Unexpectedly, cardiomyopathy disorders had a lower frequency compared to other cardiovascular phenotypes. In this regard, it is widely known that hypertrophic cardiomyopathy as a composite is one of the most common genetic diseases, with a prevalence between 1/200 and 1/500 in the general population.21 Although not all the subtypes of hypertrophic cardiomyopathies are rare,12 a higher proportion of cases was expected than observed. Several factors related to characteristics inherent to these types of rare genetic cardiovascular diseases, such as variable expressivity, attenuated phenotypes, incomplete or reduced penetrance, atypical phenotypes, absence of genetic family history, or lack of genomic diagnosis that could make its recognition, referral, and diagnosis difficult may be contributing to this.21-23 A finding to consider was the proportion of cases corresponding to thoracic aortic aneurysms and dissection disorders (Marfan syndrome, Loeys-Dietz syndrome, and others) that represented almost a third of all cases with rare genetic cardiovascular diseases in the outpatient clinic. The early recognition and diagnosis of these diseases are crucial to conducting proper follow-up, genetic counseling, treatment, and surgical procedures to prevent fatal outcomes.
The retrospective design has well-known limitations, and probably some rare genetic cardiovascular diseases could have been masked among highly prevalent diseases or were not suspected yet.22,23 Nevertheless, the retrospective design offers a good alternative for detecting low-prevalence disorders in the absence of registries, insufficient epidemiological data, and missing specific International Classification of Diseases (ICD) codes for rare diseases.3 Moreover, no studies have been conducted regarding the prevalence of rare genetic cardiovascular disease in a cardiovascular clinical setting or other hospitals. Although the cardiology hospital studied is a cardiovascular reference in Mexico, the prevalence per disease in the outpatient clinic reported in the present study remained as newly descriptive data to inform about the situation of these diseases and could not be compared with the general population or regional disease prevalences. However, the number and prevalence observed in the present study could increase in the future with the improvement and implementation of more diagnostic technologies and the incorporation of cardiogenetics clinics. Despite the limitations, the present study sets a step forward to close knowledge gaps concerning rare cardiovascular disease prevalence and, hopefully, encourage further research.
Conclusions
Rare diseases face considerable challenges because of their low prevalence in the general population. Scarce studies have focused on knowing the number and distribution to delineate the magnitude in different clinical contexts. The current study has provided the first estimate of the overall prevalence of rare genetic cardiovascular diseases in a cardiovascular hospital. In this hospital, almost one in forty patients was affected. Moreover, the present study identified the vast spectrum of rare genetic cardiovascular diseases and their most common cardiovascular phenotype in a cardiovascular clinical setting.
Further research in other cardiovascular hospitals and the general population is needed to achieve a global panorama concerning these diseases. Recognition and visibility of rare diseases are the first steps toward better clinical care. Also, it is imperative to create comprehensive clinical registries for rare genetic and nongenetic cardiovascular diseases. This study reminds us that rare genetic cardiovascular diseases are rare, complex, and not easy to recognize but not invisible.
