JBRA Assist. Reprod. 2025;29(2):258-271
ORIGINAL ARTICLE
doi: 10.5935/1518-0557.20240102
Carrier Frequency of Autosomal Recessive Diseases in a Population Attending a Human Fertility Institute in Colombia
1InSer Institute of Human Fertility, Bogotá, Colombia
2El Country Clinical Gynecology Department. GISE Menopause and Clinical Gynecological Endocrinology of the Country. Bogota Colombia
CONFLICTS OF INTEREST
The authors declare no conflict of interest.
ABSTRACT
Objective: To determine the carrier frequency of X-linked and autosomal recessive diseases in patients attending a human fertility institute in Colombia.
Methods: This retrospective observational study included patients and gamete donors attending a Human Fertility Institute in Colombia between January 2017 and June 2023. Sociodemographic data and results of Next Generation Sequencing laboratory panels for screening of recessive disease-causing mutations were collected and analyzed.
Results: Data from 746 samples were analyzed; 599 (80.3%) were Colombian origin individuals and 147 (19.7%) were foreigners. At least one mutation was detected in 526 (70.5%) individuals. Of note, 893 pathogenic genetic variants were identified.The genetic variants most frequently observed in all the individuals studied were associated with the following diseases (carrier frequency): alpha thalassemia (10.5%), alpha-1 antitrypsin deficiency (10%), congenital adrenal hyperplasia due to 21-hydroxylase deficiency (9.4%), cystic fibrosis (7.3%), spinal muscular atrophy type 1 (5.6%) and Stargardt disease type 1 (5.0%). The most frequent genetic variant observed in the subgroup of Colombian origin individuals was associated with alpha-1 antitrypsin deficiency (11.3%).
Conclusions: Information on the frequency of recessive diseases in Colombia is limited. This pioneering carrier genetic screening identified a high percentage of carriers for at least one recessive autosomal or X-linked in the population evaluated. Screening for recessive mutations could lead to an evolution in family planning programs and a decrease in the number of patients affected by recessive disorders. Furthermore, it could become a routine test not only in cases of assisted reproduction but also in cases of natural gestation.
Keywords: recessive diseases, mutation, assisted reproduction treatment, carrier screening, variants frequently
INTRODUCTION
Carrier screening (CS) was introduced in the 1970s to identify gene mutations related with the transmission of autosomal recessive or X-linked diseases (Kraft et al., 2019; Payne et al., 2021). Initially, CS tests were limited to specific ethnic groups with an increased frequency of autosomal recessive disease, for example, Jewish communities in which Tay-Sachs disease is prevalent (Harper et al., 2018). Over time, CS has been extended to the general population, and in 2010, expanded carrier genetic tests (CGTs) based on next-generation sequencing (NGS) technology were introduced to detect a larger number of genetic mutations (Srinivasan et al., 2010).
Recessive diseases are conditions caused by mutations of genes located on autosomal or sexual chromosomes. An individual manifests the disease by inheriting two mutated alleles, one from each parent. When an individual harbors one normal allele and one mutated allele, he/she is known as a carrier and does not have the disease. If both parents carry the mutated gene, the probability that their offspring will inherit two abnormal copies and thus develop the disease is 25%. Inbreeding is the leading risk factor for recessive diseases, as both parents are more likely to be carriers of the same genetic mutation (Gross & Gheorghe, 2020).
Currently, CGTs play an essential role in assisted reproductive technology (ART) procedures for infertility treatment. Individuals who choose ART methods using their own or donated gametes, as well as fertility centers, consider the evaluation of recessive mutations relevant because of the possibility of transmitting genetic diseases to offspring (Serrano-Serrano, 2012). CGT results are unique to each individual and serve to establish the risk of their offspring developing an autosomal recessive disease (Gregg et al., 2021). CGT helps individuals to decide autonomously about their reproductive choices.
The CGT is carried out using next-generation sequencing (NGS) based laboratory panels. This technology facilitates the universal screening of many mutations in coding regions of genes associated with recessive diseases. Thanks to improved technology, high demand of genetic testing in the market, and massification of NGS-based tests, the cost of CGT has progressively decreased over time (Reguera, 2021).
Recessive mutations can be detected in peripheral blood samples. Deoxyribonucleic acid (DNA) is extracted and purified from blood cells. Then, targeted exons are identified, amplified to construct libraries, and massively sequenced using a standardized platform. Subsequent bioinformatics analysis makes it possible to detect the presence of specific mutations (Reguera, 2021). Finally, the clinical relevance of the results is built on gene databases that include genetic variants classified as pathogenic (with strong evidence of association with the disease) or likely pathogenic (probably responsible for causing disease, although scientific evidence for such an association is insufficient (Rubio et al., 2020).
Carrier genetic testing panels help to identify single nucleotide changes and insertions and deletions of less than 20 base pairs in exons. However, there are technical limitations that make it challenging to identify mutations such as large deletions, duplications, inversions, ploidy changes, mosaicism, epigenetic alterations, germline mutations, chromosomal abnormalities, mitochondrial DNA mutations, non-coding region variants, pseudogenes, and genes with partial sequence coverage (Reguera, 2021).
Mutations identified by the genetic screening panels must have been previously published by the Human Gene Mutation DATABASE (HGMD®). Scientific societies such as the American College of Medical Genetics and Genomics (ACMG), the European Society of Human Reproduction and Embryology (ESHRE), and the Spanish Fertility Society (SEF) publish their own criteria for defining the diseases to be included in the carrier genetic screening (Martin et al., 2015).
The prevalence of autosomal recessive diseases varies according to geographic location and ethnicity of the populations. For example, sickle cell anemia is highly prevalent due to 21-hydroxylase deficiency (21-OHD) has a carrier rate of 1:60 in the general population (Huidobro Fernández et al., 2012) The incidence of cystic fibrosis (CF) is approximately 1:2500 in individuals of European descent (Scotet et al., 2020). Notably, the prevalence of Tay-Sachs disease is high (1:3600) in Ashkenazi Jewish population compared to other populations (1:320 000) (Xiao & Lauschke, 2021).
In Colombia, the frequency of genetic diseases ranges between 37.3 and 52.8 per 1000 inhabitants (Bernal & Suárez, 1996). Studies reveal that the prevalence of some recessive diseases follows a characteristic pattern depending on the ethnicity of the populations. For example, recessive diseases are more frequent in rural areas of Boyacá, Santander, and Antioquia departments due to their high prevalence of consanguinity (De Castro & Restrepo, 2015).
Information on the prevalence of genetic diseases in Colombia is scarce. The prevalence of CF has been estimated to be higher than 1:12 000 individuals; however, this indicator could be underestimated due to the delay in diagnosis, the high number of undiagnosed cases, and the early mortality caused by the disease (De Castro & Restrepo, 2015) Variable data on hemoglobinopathies have been published. Romero-Sánchez et al. retrospectively studied (2009 - 2012) a group of patients from different Colombian cities with suspected hemoglobinopathy. They reported a frequency of hemoglobinopathy of 34.5%, with thalassemia as the most frequent quantitative hemoglobinopathy (Romero-Sánchez et al., 2015). In another retrospective study of 2224 individuals, Vargas-Hernandez et al. observed that the prevalence of thalassemia was 14.3% (Vargas-Hernández et al., 2023). Another investigation conducted in Cali evaluated a cohort of 152 patients (0-18 years aged), and reported a frequency of hemoglobinopathies of 42.7%, with sickle cell trait being the most frequent variant (14.5%), followed by sickle cell disease (11.8%) (Aguirre et al., 2020). A recent study in a cohort of 1107 patients with chronic obstructive pulmonary disease revealed that 13.01% of them had alpha-1 antitrypsin deficiency (Alí-Munive et al., 2023).
The miscegenation in Colombia -originated from migration of different populations during the last five centuries-has resulted in a high incidence of mutations. These mutations are frequent in some geographical areas of the country due to genetic drift and the impact of colonization. However, information on the prevalence of other autosomal recessive or X-linked diseases, such as spinal muscular atrophy (SMA), congenital adrenal hyperplasia, Tay-Sachs disease, phenylketonuria, or Wilson disease, is scarce in Colombia.
This study aimed to determine the carrier frequency of autosomal recessive or X-linked diseases in individuals attending a human fertility institute in Colombia. For this purpose, data from patients and gamete donors who underwent CGT were collected and analyzed.
MATERIAL AND METHODS
Study design
This retrospective observational study included 746 individuals attending the inSer Human Fertility Institute clinics in Bogotá, Medellín, Pereira, and Cartagena between January 2017 and June 2023. Data from individuals who underwent CGT for autosomal recessive or X-linked diseases were collected and analyzed.
The study was approved by the medical and research ethics committee of inSer Human Fertility Institute clinics, ensuring the compliance of the research process to ethical standards and those defined in the 1975 Helsinki declaration, revised in 2013. All patients filled out and signed an institutional and reference laboratory informed consent form, accepting the procedures, risks and possible complications.
Study population
Patients and gamete donors who underwent CGT for autosomal recessive or X-linked diseases as part of the institutional protocol before ART procedures.
Carrier Genetic Testing
Peripheral blood samples were collected and sent to Igenomix and Sistemas Genómicos/Synlab for CGT. The following CGT panels were used:
CGT PLUS® (Igenomix): Expanded panel that analyzes 470 genes in males and 536 (66 X-linked) in females. It determines the presence of more than 30 000 genetic variants and more than 500 diseases.
Preconception Focus GeneProfile® (Sistemas Genómicos): This panel identifies more than 8 000 variants in 299 genes, responsible for 332 autosomal recessive diseases and 31 X-linked diseases.
Preconception universal GeneProfile® (Sistemas Genómicos): This exome-targeted test analyzes variants of 298 genes, corresponding to 331 autosomal recessive diseases and 31 X-linked diseases.
Statistical analysis
Results for all individuals were retrieved from Igenomix and Sistemas Genómicos. A database was constructed with the following variables: Identification, age, sex, type of individual (patients and gamete donors), place of origin, date of examination, the laboratory that carried out the screening, type of genetic screening panel, genetic variants detected, number of pathogenic genetic variants, mutated genes, and associated diseases.
The “place of origin” variable was initially categorized as continents and subcontinents. However, as many patients came from the Americas, the categories “North America”, “Central America”, “South America”, and “the Antilles” were added.
A descriptive analysis of the qualitative variables was done using absolute and relative frequencies. According to data distribution, quantitative variables were described as mean and standard deviation (SD) or median and interquartile range (IQR).
RESULTS
The study included 746 individuals aged 18 to 76 years; 376 (50.4%) were men, 370 (49.5%) were women; 495 (66.3%) were patients, and 251 (33.6%) were gamete donors; 599 (80.3%) were Colombians, and 147 (19.7%) were foreigners (Table 1).
Table 1. Distribution of the study population according to place of origin.
Blood samples from gamete donors and patients for CGT were sent to Sistemas Genómicos and Igenomix laboratories. Sistemas Genómicos analyzed 641 (85.9%) samples, and Igenomix analyzed 105 (14.1%) samples.
Of the individuals studied, 526 (70.5%) were positive for at least one pathogenic genetic variant. Pathogenic genetic variants per individual varied between 1-6 (Mean=1.70; 95%CI=1.62-1.77) (Table 2). A total of 893 pathogenic genetic variants were identified (Table 3).
Table 2. Distribution of pathogenic genetic variants detected by the CGT panels.
Table 3. Number of pathogenic genetic variants per individual.
The most frequently observed diseases in the analyzed population were: alpha thalasemia (α-thalassemia) (10.5%), alpha-1 antitrypsin deficiency (10%), congenital adrenal hyperplasia due to 21-OHD (9.4%), CF (7.3%), SMA type 1 (5.6%) and Stargardt disease type 1 (5.0%) (Table 4). In the Colombian subgroup, the most frequently observed diseases were: alpha-1 antitrypsin deficiency (11.3%), congenital adrenal hyperplasia due to 21-OHD (10.2%), α-thalassemia (10%), CF (6.9%), SMA type 1 (6.1%) and Stargardt disease type 1 (5.1%) (Table 5).
Table 4. Gene frequency in the study population.
Table 5. Gene frequency in Colombian subgroup.
DISCUSSION
The CGT has been done for more than 30 years to detect recessive diseases in the general population (Gregg, 2018). Advances in genomics have made it possible to evolve from identifying point mutations to universal, rapid, and efficient screening of genetic variants. Today, NGS-based CGTs makes it possible to detect different disease-causing mutations in a single test and has even led to the discovery of new clinically relevant genetic variants (Reguera, 2021).
In 2016, Anna Abulí et al. studied a cohort of 1301 individuals from a reproductive program in Barcelona. The cohort comprised 635 (48.8%) male couples undergoing ART with donated eggs, 483 (37.1%) egg donor candidates, 105 (8.1%) female couples undergoing ART with donated sperm, and 39 (6.0%) heterosexual couples who attended for preconception examination or treated by ART with own gametes. All individuals underwent CGT for 200 genes associated with 368 (277 autosomal recessive, 37 X-linked, and 54 autosomal dominant) disorders. The results showed that 733/1331 (56.3%) individuals carried at least one pathogenic or likely pathogenic mutation. In addition, 1.7% of the egg donors were carriers of X-linked diseases. The five most frequent autosomal recessive diseases (gene associated, number, and [percentage] of carriers) were GJB2-related DFNB1 nonsyndromic hearing loss (GJB2, 69 [5.3%]); CF (CFTR, 45, [3.5%]); α-thalassemia, (HBA1/HBA2, 40, [3.1%]); phenylketonuria (PAH, 39 [3.0%]); and spinal muscular atrophy (SMN1, 37 [2.8%]) (Abulí et al., 2016).
In 2020, Xi Yanping et al. conducted a prospective cohort study in a Chinese fertility clinic to evaluate the CGT results of 2923 patients undergoing ART treatment. The CGT panel analyzed 201 genes associated with 135 recessive (autosomal or X-linked) diseases. The results showed that 46.73% of individuals carried at least one pathogenic or likely pathogenic mutation. They found that 2836 patients with no family history carried genetic variants associated with the following diseases (number and [frequency] of carriers): citrin deficiency (111 [3.91%]), GJB2-related DFNB1 nonsyndromic hearing loss (106 [3.74%]), Krabbes disease (80 [2.82%]), Usher syndrome type 2A (76 [2.68%]), α-thalassemia (66 [2.33%]), and Wilson disease (66 [2.33%]) (Xi et al., 2020).
In 2021, Ngoc Hieu Tran et al. analyzed CGT results for recessive diseases in a cohort of 985 Vietnamese individuals by clinical exome sequencing of 4503 genes. They identified 118 recessive diseases associated with 164 pathogenic or likely pathogenic variants. The most prevalent recessive disorders (gene associated; carrier frequency) were: autosomal recessive deafness (GJB2; 17.2%), Cohen syndrome (VPS13B; 4.5%), beta-thalassemia (HBB; 4.3%), citrin deficiency (SLC25A13; 3.2%), cataract 13 with adult I phenotype (GCNT2; 3.74%), Joubert syndrome (TMEM67; 2.6%), and phenylketonuria (PHA; 2.5%) (Tran et al., 2021).
In contrast to the studies above, the carrier frequency of at least one mutation in the population analyzed in the present study was 70.5%. This figure is higher than those reported in a Chinese group (46.73%) (Xi et al., 2020) and in Barcelona (56.3%) (Abulí et al., 2016). This difference can be attributed to the miscegenation characteristic of the population here evaluated and to the inbreeding occurring in some regions of Colombia.
It is striking that some of the highest recessive disease frequencies observed in the present study were α-thalassemia (10.5%), alpha-1 antitrypsin deficiency (10%), congenital adrenal hyperplasia due to 21-OHD (9.4%), cystic fibrosis (7.3%), spinal muscular atrophy type 1 (5.6%) and Stargardt disease type 1 (5.0%). Interestingly, some of these diseases were also the most frequent in Abulí’s study in Barcelona: cystic fibrosis (3.5%), αthalassemia (3.1%), and spinal muscular atrophy type 1 (2.8%). This result could not be attributed to chance but to the Spanish colonization of Colombian lands more than five centuries ago.
Published information on recessive diseases in Colombia is limited. Most of it refers to specific diseases and is found in non-indexed journals. Data on the frequency of disease carriers derived from expanded genetic screening is lacking. The present study is one of the first to describe the Carrier Frequency of Autosomal Recessive Diseases in a presumably healthy population. The main pathogenic or likely pathogenic mutations detected in Colombians and foreigners were associated with the following diseases, in order of frequency: α-thalassemia, alpha-1 antitrypsin deficiency, congenital adrenal hyperplasia due to 21-OHD, CF, SMA type 1 and Stargardt disease type 1. In turn, the main mutations identified in the Colombian population were related to the following diseases in order of frequency: alpha-1 antitrypsin deficiency, congenital adrenal hyperplasia due to 21-OHD, α-thalassemia, CF, SMA type 1 and Stargardt disease type 1. Descriptions of these disorders are briefly described below.
Alpha 1 antitrypsin deficiency
This disease is associated with chronic obstructive pulmonary disease (COPD), mainly of the emphysematous type, liver disease (cirrhosis), and, less frequently, panniculitis and vasculitis. The gene encoding alpha-1-antitrypsin has several alleles, which are transmitted to offspring by simple Mendelian inheritance with autosomal codominant behavior. Most individuals (85 - 90%) inherit the normal alleles, designated M. The deficient alleles, designated S and Z, have a variable prevalence according to geographical location. In Europe, the disease is more prevalent (1:1500-2000) in the northwestern coastal regions, gradually decreasing eastward (1:10 000 - 1:90 000) and disappearing closer to Asia. In America, the prevalence of the disease is highest among northern Caucasian populations (1:5000 - 6000 individuals) and decreases five times in the south of the continent. In Argentina, depending on the combination of alleles, the prevalence of alpha 1 antitrypsin deficiency varies between 1:2400 and 1:26 000 individuals (Menga et al., 2014). In Colombia, a study of 2023 reported that genetic mutations (M/S - M/Z) were 13% of a group of patients with COPD (Alí-Munive et al., 2023).
Congenital adrenal hyperplasia due to alpha 21-OHD
Congenital adrenal hyperplasia comprises autosomal recessive disorders of adrenal steroidogenesis. Between 90 - 99% of cases result from mutations in the CYP21A2 gene (Chr 6p21.3), which encodes the enzyme 21-hydroxylase. The disease is characterized by deficient production of sex steroids but normal gonadal development. Virilization of the female external genitalia is observed, with variable degrees of clitoral enlargement and labial fusion (Claahsen-van der Grinten et al., 2022). More than 230 CYP21A2 pathogenic variants have been identified (Kocova et al., 2022).
The global estimated prevalence of 21-hydroxylase deficiency (21-OHD) is 1:60 but may be as high as 1:3 in communities with a smaller gene pool. The highest prevalence rates are observed in China and India, and the lowest in Japan and New Zealand (Kocova et al., 2022). In the United States, 21-OHD has an incidence of approximately 1:15 000 in whites, but it is more prevalent among Native Americans and Yupik Eskimos (Momodu et al., 2023). In 2023, Navarro-Zambrana and Sheets reported that according to the neonatal screening performed in 31 countries (58 studies between 1969 and 2017), the global incidence of 21-OHD was 1:9498; highest in the Eastern Mediterranean and Southeast Asia (> 15:100 000) and lowest in the Western Pacific countries of Asia (< 5:100 000). No significant differences were observed in Hispanic/Latino and white groups but a higher incidence was observed in individuals of African descent. In Latin America, Argentina had the highest incidence (1:8937) (Navarro-Zambrana & Sheets, 2023). Information on prevalence, frequency, and incidence of congenital adrenal hyperplasia due to alpha 21-OHD in Colombia is limited.
Alpha thalassemia
The α-thalassemia is an autosomal recessive hemoglobinopathy that affects 5% of the global population. The disease is most prevalent in China, India, Africa, Southeast Asia, and the Middle East. However, migratory patterns have contributed to the worldwide distribution of the disease (Horvei et al., 2021). In California (UEA), 1 in 10 000 children is born with clinically significant α-thalassemia (Horvei et al., 2021). The frequency of α-thalassemia carriers varies by geographic region; in tropical and subtropical areas, it can be as high as 80% - 90% (Farashi & Harteveld, 2018).
The α-thalassemia results from mutations in the alpha globin genes (1 to 4 genes) (Chr 16p) (Horvei et al., 2021). The disease is caused by a deficiency in the synthesis of the α-globin chains of hemoglobin, resulting in decreased hemoglobin concentration and anemia. The severity of the disease depends on the number of lacking genes. It can range from the asymptomatic form, through α-thalassemia minor, hemoglobin H disease, to α-thalassemia major, called hemoglobin Bart hydrops fetalis (Hb Bart) syndrome (Farashi & Harteveld, 2018). There are no studies on the frequency of α-thalassemia in Colombia.
Cystic fibrosis
Cystic fibrosis is an autosomal recessive monogenic disease of worldwide distribution. The incidence, carrier rate, and prevalent mutation vary according to the population studied, with Caucasians being the most affected (López-Valdez et al., 2021). Cystic fibrosis originates as a consequence of pathogenic changes in the CFTR gene (Chr7q.31), which encodes the protein known as cystic fibrosis transmembrane conductance regulator (CFTR) (López-Valdez et al., 2021; Salcedo et al., 2012). Dysfunction of this protein alters the ion transport on the apical surface of epithelial cells, mainly affecting the lungs, pancreas, liver, intestine, and testes.
Since 1938, when CF was described, 2114 CFTR mutations have been identified (http://www.genet.sickkids.on.ca/cftr/StatisticsPage.html; accessed on August 16, 2023), the most frequent being the delta F508. This mutation is present in 70% to 80% of Americans affected by the disease (Acuña et al., 2004), and although to a lesser degree, it is also the most common in Mexico, Venezuela, and Colombia. According to a collaborative study of these three countries, the frequency of the delta F508 mutation ranged from 29.63% to 47.7% (Pérez et al., 2007). Another study in Colombia with a larger number of patients reported that the delta F508 mutation had a frequency of 28%, with wide regional variations. Although such mutation was the most frequent, it does not exceed 40% (Restrepo et al., 2000).
The only actual figure for CF in Colombia comes from a neonatal screening performed in Bogotá in 2011. This genetic screening for CF -with the immunoreactive trypsinogen (IRT) test, followed by molecular studies- showed that CF has an incidence of 1:8297 newborns in our country (Amado González, 2011).
Spinal muscular atrophy type 1
It is one of the most frequent monogenic neurodegenerative diseases. Its global incidence is estimated to be between 1:6000 and 1:10 000 live births (Lunn & Wang, 2008; Ogino et al., 2002; Schorling et al., 2020; Verhaart et al., 2017). Approximately 95% of cases of SMA are caused by deletions or point mutations in the SMN1 (Surviving Motor Neuron 1) gene (Chr5q11.2-5q13.3) (5q-SMA). The remaining cases are due to mutations in other genes (non-5q-SMA) (Schorling et al., 2020). SMN1 mutations cause the absence of functional SMN protein, leading to the degeneracy of alpha motor neurons in the spinal cord and, thus, weakness, atrophy, and eventually, muscle paralysis (Mercuri et al., 2018).
Different phenotypes of SMA have been described. They are related to the age of symptom onset and the maximal motor ability achieved. These phenotypes depend on the number of copies of the SMN2 gene (support gene). SMA type 1, which begins before six months of age, is the most severe form with more neurological compromise. Without treatment and ventilatory support, it is the leading cause of death due to genetic neurodegenerative disease in early childhood, with a life expectancy of less than two years (Farrar et al., 2013; Zerres & Schöneborn, 1995). SMA type 2, with onset between 6 and 18 months of age and milder symptoms, manifests in children able to sit up on their own but unable to walk. In SMA type 3, symptoms develop with varying degrees of weakness, joint contracture, scoliosis, and loss of ambulation beginning in infancy or adolescence. SMA type 4 manifests in adulthood and has a similar development to SMA type 3, although it progresses more slowly (Mercuri et al., 2018).
Identification of a couple’s carrier status, together with genetic counseling, allows for adequate pregnancy planning. In vitro fertilization and preimplantation genetic studies increase the probability of having a healthy child (Keinath et al., 2021). Few studies on SMA have been published in Colombia; precise statistics on its incidence or prevalence are needed (Cardona et al., 2022).
Stargardt disease
Hereditary retinal dystrophy (HRD) comprises a group of diseases that cause degeneracy of the photoreceptors, both cones and rods. These specialized cells play a crucial role in biological processes such as phototransduction and the visual cycle.
According to different studies, the global prevalence for this disease varies from 1:8000 to 1:10 000 (46). In Colombia, 2 cases (0.03%) were reported in the 2022 orphan/rare disease report (SIVIGILA) (SIVIGILA, 2022).
Stargardt disease is the most common form of macular dystrophy. It is an autosomal recessive disorder caused by mutations in the ABCA4 (STGD1) gene (Del Pozo-Valero et al., 2020). Affected individuals manifest central and bilateral centrifugal vision loss and macular atrophy due to subretinal deposition of lipofuscin-like substances (Huang et al., 2022). The age of onset is an indirect marker of prognosis: the earlier the onset, the more severe the disease course (Tsang & Sharma, 2018).
Clinical diagnosis is difficult to make when patients do not consult early. In advanced stages, the phenotype of retinal dystrophies is often very similar, and the diagnosis may be inadequate. However, new molecular diagnostic tools can help confirm a Stargardt disease diagnosis (Acevedo, 2021).
Studies on indicators of disease, disability, and death due to hereditary disorders are limited in Colombia (Grisales-Romero et al., 2018); however, the effects of these disorders are potentially fatal or debilitating in the long term. Although inherited diseases may have a low incidence, they collectively affect 6% of the global population and represent a significant family, social, and economic burden (del Pilar Ramírez Rey, 2013). Preconception screening by CGT and prenatal counseling are valuable tools to reduce the risk of transmitting recessive diseases to offspring, as well as their social and economic cost (Verma & Puri, 2015).
In recent years, ART procedures have evolved to impact family planning significantly. ART procedures have conventionally been considered an alternative for treating infertility. However, over time, they have become valuable tools to help determine how and when to achieve a successful pregnancy. Vitrification of oocytes, sperm, and embryos, for example, allows individuals to use such biological material, at least in theory, whenever they deem it relevant throughout their lives. Although still a controversial topic, new generations of patients and healthcare providers are more aware of the existence of ART procedures and consider them useful for planning their families by medically assisted means. ART procedures are undoubtedly related to advances in reproductive genetics, in which CGT plays a key role. Future generations will likely employ preconception diagnosis of carrier status to decrease the likelihood of transmitting recessive diseases to their offspring.
At present, carrier genetic screening is limited to patients attending assisted reproduction centers, especially those using donor gametes, where priority is to reduce the risk of hereditary diseases, which can be easily prevented with a timely diagnosis.
Finally, it is essential to remember the ethical limits that must be respected when using genetic carrier screening. Far from having eugenic purposes, this test aims to prevent the transmission of genetic mutations associated with diseases that have a hypothetical negative impact on the individual, the family, and even public health.
CONCLUSION
Information on the frequency of recessive diseases in Colombia is very scarce; there are only reports of specific diseases in some country populations with high inbreeding rates. The present study identified a high frequency of genetic mutations in the population analyzed by CGT. This screening is a valuable tool that can alert and prevent the transmission of genetic diseases to offspring and reduce treatment costs for the family and public healthcare services. Genetic carrier screening and ART procedures for indicated cases could lead to an evolution in family planning.
It is likely that, in the near future, genetic carrier screening will not be limited to the population undergoing ART but will also be implemented in the population desiring a natural pregnancy. It is important to emphasize that all these possible applications of carrier screening and ART procedures cannot undermine the inherent ethical boundaries. Such boundaries must always prevail in medical practice and scientific work.
ACKNOWLEDGMENT
We also thank to Dra. Martha Mesa for her English language wording, detailed review, and correction.
Financial support:
This research was funded by the Human Fertility Institute, InSer, Bogotá.
REFERENCES
Abulí A, Boada M, Rodríguez-Santiago B, Coroleu B, Veiga A, Armengol L, Barri PN, Pérez-Jurado LA, Estivill X. NGS-Based Assay for the Identification of Individuals Carrying Recessive Genetic Mutations in Reproductive Medicine. Hum Mutat. 2016;37:516-23. PMID: 26990548 DOI: 10.1002/humu.22989 Medline
Aguirre M, Medina D, Araujo MV, Campo MA, Castro A, Fernández-Trujillo L, Alcalá M, Sua LF. Importancia de la detección temprana de hemoglobinopatias en la población pediátrica en países en desarrollo. Rev Chil Pediatr. 2020;91:568-72. PMID: 33399734 DOI: 10.32641/RCHPED.VI91I4.1438 Medline
Alí-Munive A, Leidy P, Proaños NJ, Pedrozo-Pupo J, Giraldo A, Cano D, Diaz-Bossa C, Mosquera R, Paul H, Gonzalez-García M, Aguirre-Franco C, López-Campos JL, Casas-Herrera A. Prevalence of genetic mutations in alpha-1 antitrypsin deficiency (aatd) in patients with chronic obstructive pulmonary disease in Colombia. BMC Pulm Med. 2023;23:156. PMID: 37143026 DOI: 10.1186/S12890-023-02453-0/FIGURES/1 Medline
Cardona N, Ocampo SJ, Estrada JM, Mojica MI, Porras GL. Clinical-functional characterization of patients with spinal muscular atrophy in Central-Western Colombia. Biomedica. 2022;42:89-99. PMID: 35866733 DOI: 10.7705/biomedica.6178 Medline
Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, Arlt W, Auchus RJ, Falhammar H, Flück CE, Guasti L, Huebner A, Kortmann BBM, Krone N, Merke DP, Miller WL, Nordenström A, Reisch N, Sandberg DE, Stikkelbroeck NMML, Touraine P, Utari A, Wudy SA, et al. Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management. Endocr Rev. 2022;43:91-159. PMID: 33961029 DOI: 10.1210/ENDREV/BNAB016 Medline
De Castro M, Restrepo CM. Genetics and genomic medicine in Colombia. Mol Genet Genomic Med. 2015;3:84-91. PMID: 25802878 DOI: 10.1002/mgg3.139 Medline
Del Pozo-Valero M, Riveiro-Alvarez R, Blanco-Kelly F, Aguirre-Lamban J, Martin-Merida I, Iancu IF, Swafiri S, Lorda-Sanchez I, Rodriguez-Pinilla E, Trujillo-Tiebas MJ, Jimenez-Rolando B, Carreño E, Mahillo-Fernandez I, Rivolta C, Corton M, Avila-Fernandez A, Garcia-Sandoval B, Ayuso C. Genotype-Phenotype Correlations in a Spanish Cohort of 506 Families With Biallelic ABCA4 Pathogenic Variants. Am J Ophthalmol. 2020;219:195-204. PMID: 32619608 DOI: 10.1016/j.ajo.2020.06.027 Medline
Farashi S, Harteveld CL. Molecular basis of α-thalassemia. Blood Cells Mol Dis. 2018;70:43-53. PMID: 29032940 DOI: 10.1016/j.bcmd.2017.09.004 Medline
Farrar MA, Vucic S, Johnston HM, du Sart D, Kiernan MC. Pathophysiological insights derived by natural history and motor function of spinal muscular atrophy. J Pediatr. 2013;162:155-9. PMID: 22809660 DOI: 10.1016/j.jpeds.2012.05.067 Medline
Gregg AR. Expanded Carrier Screening. Obstet Gynecol Clin North Am. 2018;45:103-12. PMID: 29428278 DOI: 10.1016/j.ogc.2017.10.005 Medline
Gregg AR, Aarabi M, Klugman S, Leach NT, Bashford MT, Goldwaser T, Chen E, Sparks TN, Reddi HV, Rajkovic A, Dungan JS; ACMG Professional Practice and Guidelines Committee. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:1793-806. PMID: 34285390 DOI: 10.1038/s41436-021-01203-z Medline
Harper JC, Aittomäki K, Borry P, Cornel MC, de Wert G, Dondorp W, Geraedts J, Gianaroli L, Ketterson K, Liebaers I, Lundin K, Mertes H, Morris M, Pennings G, Sermon K, Spits C, Soini S, van Montfoort APA, Veiga A, Vermeesch JR, et al.; on behalf of the European Society of Human Reproduction and Embryology and European Society of Human Genetics. Recent developments in genetics and medically assisted reproduction: from research to clinical applications. Eur J Hum Genet. 2018;26:12-33. PMID: 29199274 DOI: 10.1038/s41431-017-0016-z Medline
Horvei P, MacKenzie T, Kharbanda S. Advances in the management of α-thalassemia major: reasons to be optimistic. Hematology Am Soc Hematol Educ Program. 2021;2021:592-9. PMID: 34889445 DOI: 10.1182/hematology.2021000295 Medline
Huang D, Heath Jeffery RC, Aung-Htut MT, McLenachan S, Fletcher S, Wilton SD, Chen FK. Stargardt disease and progress in therapeutic strategies. Ophthalmic Genet. 2022;43:1-26. PMID: 34455905 DOI: 10.1080/13816810.2021.1966053 Medline
Huidobro Fernández B, Roldán Martín MB, Rodríguez Arnao MD, Ezquieta Zubicaray B. Consejo genético en la hiperplasia suprarrenal congénita por déficit de 21-hidroxilasa. An Pediatr (Barc). 2012;76:51-2. PMID: 22015055 DOI: 10.1016/j.anpedi.2011.08.004 Medline
Keinath MC, Prior DE, Prior TW. Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance. Appl Clin Genet. 2021;14:11-25. PMID: 33531827 DOI: 10.2147/TACG.S239603 Medline
Kocova M, Concolino P, Falhammar H. Characteristics of In2G Variant in Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. Front Endocrinol (Lausanne). 2022;12:788812. PMID: 35140681 DOI: 10.3389/FENDO.2021.788812/BIBTEX Medline
Kraft SA, Duenas D, Wilfond BS, Goddard KAB. The evolving landscape of expanded carrier screening: challenges and opportunities. Genet Med. 2019;21:790-7. PMID: 30245516 DOI: 10.1038/s41436-018-0273-4 Medline
López-Valdez JA, Aguilar-Alonso LA, Gándara-Quezada V, Ruiz-Rico GE, Ávila-Soledad JM, Reyes AA, Pedroza-Jiménez FD. Cystic fibrosis: current concepts. Bol Med Hosp Infant Mex. 2021;78:584-96. PMID: 34934215 DOI: 10.24875/BMHIM.20000372 Medline
Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371:2120-33. PMID: 18572081 DOI: 10.1016/S0140-6736(08)60921-6 Medline
Martin J, Asan, Yi Y, Alberola T, Rodríguez-Iglesias B, Jiménez-Almazán J, Li Q, Du H, Alama P, Ruiz A, Bosch E, Garrido N, Simon C. Comprehensive carrier genetic test using next-generation deoxyribonucleic acid sequencing in infertile couples wishing to conceive through assisted reproductive technology. Fertil Steril. 2015;104:1286-93. PMID: 26354092 DOI: 10.1016/j.fertnstert.2015.07.1166 Medline
Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, et al.; SMA Care Group. Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28:103-15. PMID: 29290580 DOI: 10.1016/j.nmd.2017.11.005 Medline
Navarro-Zambrana AN, Sheets LR. Ethnic and National Differences in Congenital Adrenal Hyperplasia Incidence: A Systematic Review and Meta-Analysis. Horm Res Paediatr. 2023;96:249-58. PMID: 35973409 DOI: 10.1159/000526401 Medline
Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet. 2002;110:301-7. PMID: 12116201 DOI: 10.1002/ajmg.10425 Medline
Payne MR, Skytte AB, Harper JC. The use of expanded carrier screening of gamete donors. Hum Reprod. 2021;36:1702-10. PMID: 33842976 DOI: 10.1093/humrep/deab067 Medline
Pérez MM, Luna MC, Pivetta OH, Keyeux G. CFTR gene analysis in Latin American CF patients: heterogeneous origin and distribution of mutations across the continent. J Cyst Fibros. 2007;6:194-208. PMID: 16963320 DOI: 10.1016/j.jcf.2006.07.004 Medline
Restrepo CM, Pineda L, Rojas-Martínez A, Gutiérrez CA, Morales A, Gómez Y, Villalobos MC, Borjas L, Delgado W, Myers A, Barrera-Saldaña HA. CFTR mutations in three Latin American countries. Am J Med Genet. 2000;91:277-9. PMID: 10766983 DOI: 10.1002/(SICI)1096-8628(20000410)91:4<277::AID-AJMG7>3.0.CO;2-A Medline
Romero-Sánchez C, Gómez Gutiérrez A, Duarte Y, Amazo C, Manosalva C, Chila M L, Casas-Gómez MC, Briceño Balcázar I. Variantes de hemoglobina en una población con impresión diagnóstica positiva para hemoglobinopatías en Colombia. Rev Med Chil. 2015;143:1260-8. PMID: 26633269 DOI: 10.4067/S0034-98872015001000004 Medline
Schorling DC, Pechmann A, Kirschner J. Advances in Treatment of Spinal Muscular Atrophy - New Phenotypes, New Challenges, New Implications for Care. J Neuromuscul Dis. 2020;7:1-13. PMID: 31707373 DOI: 10.3233/JND-190424 Medline
Scotet V, Gutierrez H, Farrell PM. Newborn Screening for CF across the Globe-Where Is It Worthwhile? Int J Neonatal Screen. 2020;6:18. PMID: 33073015 DOI: 10.3390/ijns6010018 Medline
Srinivasan BS, Evans EA, Flannick J, Patterson AS, Chang CC, Pham T, Young S, Kaushal A, Lee J, Jacobson JL, Patrizio P. A universal carrier test for the long tail of Mendelian disease. Reprod Biomed Online. 2010;21:537-51. PMID: 20729146 DOI: 10.1016/j.rbmo.2010.05.012 Medline
Tran NH, Nguyen Thi TH, Tang HS, Hoang LP, Nguyen TL, Tran NT, Trinh TN, Nguyen VT, Nguyen BH, Nguyen HT, Doan LP, Phan NM, Nguyen KT, Nguyen HL, Quach MT, Nguyen TT, Tran VU, Tran DV, Nguyen QT, Do TT, et al. Genetic landscape of recessive diseases in the Vietnamese population from large-scale clinical exome sequencing. Hum Mutat. 2021;42:1229-38. PMID: 34233069 DOI: 10.1002/humu.24253 Medline
Tsang SH, Sharma T. Stargardt Disease. Adv Exp Med Biol. 2018;1085:139-51. PMID: 30578500 DOI: 10.1007/978-3-319-95046-4_27 Medline
Vargas-Hernández DA, Uscategui-Ruiz AC, De Avila J, Romero-Sánchez C. Differences in the distribution of hemoglobin variants according to the geographic regions in a Colombian population. Hematol Transfus Cell Ther. 2023;45:140-7. PMID: 36764860 DOI: 10.1016/j.htct.2022.11.012 Medline
Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, Cook SF, Lochmüller H. Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review. Orphanet J Rare Dis. 2017;12:124. PMID: 28676062 DOI: 10.1186/s13023-017-0671-8 Medline
Verma IC, Puri RD. Global burden of genetic disease and the role of genetic screening. Semin Fetal Neonatal Med. 2015;20:354-63. PMID: 26251359 DOI: 10.1016/j.siny.2015.07.002 Medline
Xi Y, Chen G, Lei C, Wu J, Zhang S, Xiao M, Zhang W, Zhang Y, Sun X. Expanded carrier screening in Chinese patients seeking the help of assisted reproductive technology. Mol Genet Genomic Med. 2020;8:e1340. PMID: 32573981 DOI: 10.1002/mgg3.1340 Medline
Xiao Q, Lauschke VM. The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders. NPJ Genom Med. 2021;6:41. PMID: 34078906 DOI: 10.1038/s41525-021-00203-x Medline
Zerres K, Rudnik-Schöneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol. 1995;52:518-23. PMID: 7733848 DOI: 10.1001/archneur.1995.00540290108025 Medline