Review • Rev Panam Salud Publica 47 31 July 20232023 • https://doi.org/10.26633/RPSP.2023.98   copy

Clusters of rare disorders and congenital anomalies in South America

Conglomerados de trastornos y malformaciones congénitas poco frecuentes en América del Sur

Agrupamentos de doenças raras e anomalias congênitas na América do Sul

Augusto César Cardoso-dos-Santos Guillermo Reales Lavinia Schuler-Faccini About the authors

ABSTRACT

Objective.

To map geographic clusters of rare disorders and congenital anomalies reported in South America.

Methods.

Qualitative systematic review conducted in Medline/PubMed, Lilacs, and Scielo electronic databases to identify studies meeting eligibility criteria. The strategy resulted in 1 672 unique articles, from which 164 were selected for full reading by a pair of reviewers.

Results.

Fifty-five articles reported at least one cluster of genetic disorders or congenital anomalies in South American territory. From these papers, 122 clusters were identified, of which half (6161. Montenegro YHA, de Souza CFM, Kubaski F, Trapp FB, Burin MG, Michelin-Tirelli K, et al. Sanfilippo syndrome type B: Analysis of patients diagnosed by the MPS Brazil Network. Am J Med Genet A. 2022;188(3):760–7 [cited 2022 Mar 5]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.62572
https://onlinelibrary.wiley.com/doi/full... ) were related to autosomal recessive disorders. Sixty-five (53.3%) of the clusters were located in Brazil.

Conclusions.

The results of the review reinforce that rare diseases and congenital anomalies can occur in a non-random way in space, which is discussed in the perspective of the complex history of formation, social organization, and genetic structure of the South American population. Mapping clusters in population medical genetics can be an important public health tool, given that such places concentrate cases of rare diseases that frequently require multiprofessional, specialized care. Therefore, these results can support important agendas in public health related to rare diseases and congenital anomalies, such as health promotion and surveillance.

Keywords
Disease hotspot; rare diseases; congenital abnormalities; systematic review; South America.

RESUMEN

Objetivo.

Trazar los conglomerados geográficos de los trastornos y las malformaciones congénitas poco frecuentes notificados en América del Sur.

Métodos.

Se realizó una revisión sistemática cualitativa en las bases de datos electrónicas Medline/PubMed, Lilacs y Scielo para encontrar los estudios que cumplieran con los criterios de selección. Se encontraron 1672 artículos originales, de los que se seleccionaron 164 para su lectura completa por un par de revisores.

Resultados.

En 55 artículos se informó de al menos un conglomerado de trastornos genéticos o malformaciones congénitas en América del Sur. A partir de estos artículos, se encontraron 122 conglomerados, de los cuales la mitad (6161. Montenegro YHA, de Souza CFM, Kubaski F, Trapp FB, Burin MG, Michelin-Tirelli K, et al. Sanfilippo syndrome type B: Analysis of patients diagnosed by the MPS Brazil Network. Am J Med Genet A. 2022;188(3):760–7 [cited 2022 Mar 5]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.62572
https://onlinelibrary.wiley.com/doi/full... ) se asociaron con trastornos autosómicos recesivos. Sesenta y cinco (53,3%) de los conglomerados se ubicaron en Brasil.

Conclusiones.

Los resultados de la revisión confirman que las enfermedades raras y las malformaciones congénitas pueden presentarse de una forma no aleatoria en el espacio, lo que se comenta desde la perspectiva de la complejidad histórica del proceso de formación, organización social y estructura genética de la población de América del Sur. Definir geográficamente los conglomerados en la genética médica poblacional puede ser una importante herramienta de salud pública, ya que en esos lugares se concentran casos de enfermedades raras que suelen requerir una atención especializada y multidisciplinaria. Por lo tanto, estos resultados pueden servir de apoyo a importantes programas de salud pública relacionados con las enfermedades raras y las malformaciones congénitas como, por ejemplo, la promoción de la salud y la vigilancia.

Palabras clave
Punto alto de contagio de enfermedades; enfermedades raras; anomalías congénitas; revisión sistemática; América del Sur

RESUMO

Objetivo.

Mapear agrupamentos geográficos de doenças raras e anomalias congênitas relatados na América do Sul.

Métodos.

Revisão sistemática qualitativa realizada nas bases de dados eletrônicos Medline/PubMed, Lilacs e Scielo para identificar estudos que atendessem aos critérios de elegibilidade. A estratégia resultou em 1.672 artigos únicos, dos quais 164 foram selecionados para leitura completa por uma dupla de revisores.

Resultados.

Cinquenta e cinco artigos relataram pelo menos um agrupamento de distúrbios genéticos ou anomalias congênitas no território sul-americano. A partir desses artigos, foram identificados 122 agrupamentos, dos quais metade (6161. Montenegro YHA, de Souza CFM, Kubaski F, Trapp FB, Burin MG, Michelin-Tirelli K, et al. Sanfilippo syndrome type B: Analysis of patients diagnosed by the MPS Brazil Network. Am J Med Genet A. 2022;188(3):760–7 [cited 2022 Mar 5]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.a.62572
https://onlinelibrary.wiley.com/doi/full... ) estava relacionada a doenças autossômicas recessivas. Sessenta e cinco (53,3%) dos agrupamentos estavam localizados no Brasil.

Conclusões.

Os resultados da revisão reforçam a observação de que doenças raras e anomalias congênitas podem ocorrer de forma não aleatória no espaço, o que é discutido na perspectiva da complexa história de formação, organização social e estrutura genética da população sul-americana. O mapeamento de agrupamentos em genética médica populacional pode ser uma importante ferramenta de saúde pública, visto que esses locais concentram casos de doenças raras que frequentemente requerem atendimento multiprofissional especializado. Portanto, esses resultados podem apoiar importantes agendas de saúde pública relacionadas a doenças raras e anomalias congênitas, como a vigilância e a promoção da saúde.

Palabras-chave
Hotspot de doença; doenças raras; anormalidades congênitas; revisão sistemática; América do Sul

Clusters of genetic disorders are defined as geographical areas that present a high frequency of genetic diseases (11. Giugliani R, Bender F, Couto R, Bochernitsan A, Brusius-Facchin AC, Burin M, et al. Population Medical Genetics: Translating Science to the Community. Genet Mol Biol. 2019;42(suppl 1)., 22. Poletta FA, Orioli IM, Castilla EE. Genealogical data in population medical genetics: field guidelines. Genet Mol Biol. 2014;37:171–85 (suppl 1).). This concept is close to “genetic isolates,” which are cultural and/or geographically isolated subpopulations, some of which may have high frequencies of genetic diseases as a consequence of processes related to their foundation (such as founder effect) and social organization (such as reproductive or cultural isolation and endogamy) (11. Giugliani R, Bender F, Couto R, Bochernitsan A, Brusius-Facchin AC, Burin M, et al. Population Medical Genetics: Translating Science to the Community. Genet Mol Biol. 2019;42(suppl 1)., 33. Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002;61(4):233–47 [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/12030885/
https://pubmed.ncbi.nlm.nih.gov/12030885... ).

However, according to our experience in the National Census of Isolates (Censo Nacional de Isolados, CENISO), a nationwide, systematic register of human population clusters in Brazil, clusters of disorders related to medical genetics also may present environmental (such as thalidomide embryopathy and congenital Zika syndrome) and multifactorial (such as certain types of congenital anomalies) origins, and they do not occur only in isolates but also in large urban centers. Therefore, the definition of geographical clusters (from now on, only “clusters”) considered in this work is a place with an unexpectedly high frequency of rare diseases and congenital anomalies (44. Castilla EE, Schuler-Faccini L. From rumors to genetic isolates. Genet Mol Biol. 2014;37(1 suppl 1):186–93 [cited 2019 Jan 4]. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572014000200005&lng=pt&tlng=pt
http://www.scielo.br/scielo.php?script=s... , 55. Cardoso GC, de Oliveira MZ, Paixão-Côrtes VR, Castilla EE, Schuler-Faccini L. Clusters of genetic diseases in Brazil. J Community Genet. 2019;10(1):121–8 [cited 2020 Feb 18]. Available from: http://link.springer.com/10.1007/s12687-018-0369-1
http://link.springer.com/10.1007/s12687-... ).

Clusters are the main object of population medical genetics, an area of medical genetics that interacts with public health as it involves diagnosis, care, and surveillance of rare (and genetic, in most cases) disorders and congenital anomalies at the community level. Appropriate care of these communities can be a challenging task, especially when cases are concentrated in places far from reference centers and with poor socioeconomic indices (66. Passos-Bueno MR, Bertola D, Dain D, Horovitz G, Evangelista De Faria Ferraz V, Brito LA. Genetics and genomics in Brazil: a promising future. Mol Genet Genomic Med. 2014;2(4):280–291 [cited 2019 Aug 18]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113268/pdf/mgg30002-0280.pdf
https://www.ncbi.nlm.nih.gov/pmc/article... ). In addition, working with clusters has allowed advancing our knowledge about diseases and health care, including identification of genetic causes and risk factors for some disorders, improvement of diagnostic and therapeutic methods, studying of complex traits, among others (33. Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002;61(4):233–47 [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/12030885/
https://pubmed.ncbi.nlm.nih.gov/12030885... , 77. Peltonen L, Palotie A, Lange K. Use of population isolates for mapping complex traits. Nat Rev Genet. 2000;1:182–190 [cited 2022 Mar 1]. Available from: https://www.nature.com/articles/35042049
https://www.nature.com/articles/35042049... ).

Clusters can be understood as biosocial phenomena, as their origin is related to a combination of biological, social, and historical factors of a given human populational group. In this sense, South America represents a unique opportunity to deepen our knowledge about the origin and biosocial dynamics of the clusters, considering its wide diversity of natural and geographical environments, with different ancestral origins of territorial occupation and socio-cultural organization (88. Castilla EE, Adams J. Genealogical Information and the Structure of Rural Latin-American Populations: Reality and Fantasy. Hum Hered. 1996;46(5):241–55 [cited 2022 Mar 1]. Available from: https://www.karger.com/Article/FullText/154361
https://www.karger.com/Article/FullText/... ). Its population presents a complex multiethnic admixture from the 15th century, with strong contributions of native South American populations (Amerindians), European settlers, and enslaved people from Africa brought with them (99. Salzano FM, Sans M. Interethnic admixture and the evolution of Latin American populations. Genet Mol Biol. 2014;37(Suppl. 1):151–70 [cited 2022 Mar 2]. Available from: http://www.scielo.br/j/gmb/a/4zvRkCTfqdpTSHSY7K3GgLm/abstract/?lang=en
http://www.scielo.br/j/gmb/a/4zvRkCTfqdp... ).

Part of the South American population is organized in small rural semi-isolated centers, with little immigration (88. Castilla EE, Adams J. Genealogical Information and the Structure of Rural Latin-American Populations: Reality and Fantasy. Hum Hered. 1996;46(5):241–55 [cited 2022 Mar 1]. Available from: https://www.karger.com/Article/FullText/154361
https://www.karger.com/Article/FullText/... ). These features are commonly found in clusters, such as Maracaibo Lake, in Venezuela, where the world’s largest and best characterized population with Huntington’s disease (Mendelian inheritance in man [MIM] #143100) is found. Working with this community since the 1950s has contributed to mapping the HD gene (HTT, 4p16.3) and other molecular insights, searching for modifier factors, and characterizing the natural history of the disease (1010. Wexler NS. Huntington’s Disease: Advocacy Driving Science. Ann Rev Med. 2012;63:1–22 [cited 2022 Mar 1]. Available from: https://www.annualreviews.org/doi/abs/10.1146/annurev-med-050710-134457
https://www.annualreviews.org/doi/abs/10... ). However, with a few other better-known examples, the literature on clusters in South America is diffuse and multilingual. In this work, our main goal was to describe clusters of rare disorders and congenital anomalies in South America.

MATERIALS AND METHODS

We carried out a qualitative systematic literature review through an extensive search by keywords in English and Spanish and countries (including “South America”) in three major scientific literature search engines, including two Latin American-specific search engines: Medline/PubMed (https://www.ncbi.nlm.nih.gov/pubmed), Scielo (https://www.scielo.br/), and Lilacs (http://lilacs.bvsalud.org/), covering all the period previous to 31 December 2021. We used Biopython v1.79 Entrez and Medline modules in Python v3.9.7 for automated PubMed searches (1111. Cock PJA, Antao T, Chang JT, Chapman BA, Cox CJ, Dalke A, et al. Biopython: freely available Python tools for computational molecular biology and bioinformatics. Bioinformatics. 2009;25(11):1422–3 [cited 2022 Mar 6]. Available from: https://academic.oup.com/bioinformatics/article/25/11/1422/330687
https://academic.oup.com/bioinformatics/... ).

The keywords in English were: founder effect OR consanguineous marriages OR isolated population genetic diseases OR consanguinity marriage OR geographical cluster genetic disease OR geographic cluster genetic disease OR cluster genetic disease OR rumor AND [country], where country stands for “South America,” “Argentina,” “Brazil,” “Bolivia,” “Chile,” “Colombia,” “Ecuador,” “Guyana,” “Paraguay,” “Peru,” “Suriname,” “Uruguay,” and “Venezuela.” We also used the same terms in Spanish: efecto fundador OR matrimonios consanguineos OR poblaciones aisladas OR población aislada OR matrimonio consanguineo OR enfermedad genética cluster geográfico OR cluster enfermedad genética OR rumor AND [country].

For Scielo and Lilacs, we manually entered the keywords in their respective websites and downloaded the summary output. For Brazil, the search was performed from 2017 to 2021, in order to update the previous systematic review carried out by Cardoso et al. (55. Cardoso GC, de Oliveira MZ, Paixão-Côrtes VR, Castilla EE, Schuler-Faccini L. Clusters of genetic diseases in Brazil. J Community Genet. 2019;10(1):121–8 [cited 2020 Feb 18]. Available from: http://link.springer.com/10.1007/s12687-018-0369-1
http://link.springer.com/10.1007/s12687-... ).

In the first phase, two authors (AS and GR) read all titles and abstracts independently, considering articles in English, Portuguese, and Spanish, without time restriction, and made a selection based on the following inclusion criteria: articles must (11. Giugliani R, Bender F, Couto R, Bochernitsan A, Brusius-Facchin AC, Burin M, et al. Population Medical Genetics: Translating Science to the Community. Genet Mol Biol. 2019;42(suppl 1).) describe a human population living in one of the selected countries, and (22. Poletta FA, Orioli IM, Castilla EE. Genealogical data in population medical genetics: field guidelines. Genet Mol Biol. 2014;37:171–85 (suppl 1).) describe a cluster of a rare disorder or congenital anomaly. We excluded articles without a title or abstract.

We then compared shortlisted articles and discussed discrepancies. Only articles deemed relevant by both researchers passed to the next phase, in which we read the articles in full to retrieve more details about suspected clusters. We read selected articles in detail and collected key information about the population’s location and characteristics.

Clusters were grouped by country and described according to the associated inheritance pattern. Detailed geographical location and molecular information were obtained from the articles. We created a map of the distribution of the populations identified in South America using rnaturalearth package v0.1.0 (South 2017) in R version v4.1.0 software.

RESULTS

The systematic review resulted in 1 672 unique articles, of which 164 were selected for full reading and 55 reported at least one cluster of genetic disorders or congenital anomalies in South American countries (Figure 1). From these papers, we identified 122 different clusters in 10 of the South American countries (no clusters identified for Guyana and Paraguay).

As shown in Table 1, more than half (n = 65) of these clusters were reported in Brazil, with another six clusters added to the previous review (55. Cardoso GC, de Oliveira MZ, Paixão-Côrtes VR, Castilla EE, Schuler-Faccini L. Clusters of genetic diseases in Brazil. J Community Genet. 2019;10(1):121–8 [cited 2020 Feb 18]. Available from: http://link.springer.com/10.1007/s12687-018-0369-1
http://link.springer.com/10.1007/s12687-... ). Outside Brazil, Colombia and Venezuela showed the highest number of clusters (13; 10.7% each), followed by Argentina (12; 9.8%) and Ecuador (8; 6.6%). The majority were autosomal recessive genetic disorders (61; 50.0%), followed by autosomal dominant (27; 22.1%) and multifactorial (12; 9.8%). Two clusters of environmental disorders in Brazil (thalidomide embryopathy and microcephaly by Zika virus) and two of X-linked (fragile X syndrome, in Colombia, and progressive muscular dystrophy, in Brazil) were also found. In 18 (14.8%) cases, the inheritance pattern was not identified (individually, the highest proportion (5/8 or 62.5%) was found in Ecuador).

Individual details of each cluster, such as location aspects, phenotype, inheritance pattern, and molecular alteration, are shown in Table 2. Spatial distribution of clusters in South America are shown in Figure 2. In complement to Cardoso et al. (55. Cardoso GC, de Oliveira MZ, Paixão-Côrtes VR, Castilla EE, Schuler-Faccini L. Clusters of genetic diseases in Brazil. J Community Genet. 2019;10(1):121–8 [cited 2020 Feb 18]. Available from: http://link.springer.com/10.1007/s12687-018-0369-1
http://link.springer.com/10.1007/s12687-... ), clusters from Brazil are shown separately in Table 3.

DISCUSSION

The 122 clusters of rare diseases or congenital anomalies were reported in almost all South American countries. The multiplicity of peoples with diverse ancestry and cultural patterns, in combination with the wide range of natural environments, has allowed the creation of a complex scenario of clusters in South America, similar to what we have described for Brazil (44. Castilla EE, Schuler-Faccini L. From rumors to genetic isolates. Genet Mol Biol. 2014;37(1 suppl 1):186–93 [cited 2019 Jan 4]. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572014000200005&lng=pt&tlng=pt
http://www.scielo.br/scielo.php?script=s... , 55. Cardoso GC, de Oliveira MZ, Paixão-Côrtes VR, Castilla EE, Schuler-Faccini L. Clusters of genetic diseases in Brazil. J Community Genet. 2019;10(1):121–8 [cited 2020 Feb 18]. Available from: http://link.springer.com/10.1007/s12687-018-0369-1
http://link.springer.com/10.1007/s12687-... ). The population history and diversity have important medical genetic implications (1212. Laberge AM, Michaud J, Richter A, Lemyre E, Lambert M, Brais B, et al. Population history and its impact on medical genetics in Quebec. Clin Genet. 2005;68(4):287–301 [cited 2022 Mar 2]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1399-0004.2005.00497.x
https://onlinelibrary.wiley.com/doi/full... ).

Most of the South American clusters were located in Brazil, consistent with it being the largest and most populous country, and its remarkable tradition in the study of communities with a high concentration of genetic diseases or their risk factors. In fact, some of the oldest works found by this review, published from the 1950s onwards, date back to the pioneering work of the Brazilian researcher Newton Freire-Maia, who greatly contributed to the studies of inbreeding, genetic diseases, and genetic isolates (1313. Freire-Maia N. Inbreeding in Brazil. Am J Hum Genet. 1957;9(4):284–98., 1414. Freire-Maia A, Opitz JM. Historical note: The extraordinary handless and footless families of Brazil – 50 years of acheiropodia. Am J Med Genet. 1981;9(1):31–41 [cited 2022 Mar 1]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.1320090108
https://onlinelibrary.wiley.com/doi/full... ).

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FIGURE 1.
Flowchart of the selection of articles in the systematic review
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TABLE 1.
Number of disease clusters according to the country and the inheritance pattern
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TABLE 2.
Disease clusters in South America identified from the literature review (clusters in Brazil are shown in Table 3)
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FIGURE 2.
Clusters of rare diseases and congenital anomalies in South America according to the inheritance pattern
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TABLE 3.
Disease clusters from Brazil

In addition, Brazil has a national census (the CENISO) to map clusters by the National Institute of Population Medical Genetics (or INAGEMP). INAGEMP was created in 2008 supported by the Federal Government, with its headquarters located at the Hospital de Clínicas de Porto Alegre (HCPA) in Southern Brazil, with several associated institutions across the country (11. Giugliani R, Bender F, Couto R, Bochernitsan A, Brusius-Facchin AC, Burin M, et al. Population Medical Genetics: Translating Science to the Community. Genet Mol Biol. 2019;42(suppl 1).). The cluster scenario in Brazil has been specifically discussed in previous works (44. Castilla EE, Schuler-Faccini L. From rumors to genetic isolates. Genet Mol Biol. 2014;37(1 suppl 1):186–93 [cited 2019 Jan 4]. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572014000200005&lng=pt&tlng=pt
http://www.scielo.br/scielo.php?script=s... , 55. Cardoso GC, de Oliveira MZ, Paixão-Côrtes VR, Castilla EE, Schuler-Faccini L. Clusters of genetic diseases in Brazil. J Community Genet. 2019;10(1):121–8 [cited 2020 Feb 18]. Available from: http://link.springer.com/10.1007/s12687-018-0369-1
http://link.springer.com/10.1007/s12687-... ) and from now on we will focus on the other South American countries.

Half of the South American clusters corresponded to autosomal recessive diseases, strongly associated with endogamy and consanguinity. Other works describing cluster sets or similar worldwide have obtained the same results (33. Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002;61(4):233–47 [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/12030885/
https://pubmed.ncbi.nlm.nih.gov/12030885... , 55. Cardoso GC, de Oliveira MZ, Paixão-Côrtes VR, Castilla EE, Schuler-Faccini L. Clusters of genetic diseases in Brazil. J Community Genet. 2019;10(1):121–8 [cited 2020 Feb 18]. Available from: http://link.springer.com/10.1007/s12687-018-0369-1
http://link.springer.com/10.1007/s12687-... , 77. Peltonen L, Palotie A, Lange K. Use of population isolates for mapping complex traits. Nat Rev Genet. 2000;1:182–190 [cited 2022 Mar 1]. Available from: https://www.nature.com/articles/35042049
https://www.nature.com/articles/35042049... , 1515. Charoute H, Bakhchane A, Benrahma H, Romdhane L, Gabi K, Rouba H, et al. Mediterranean Founder Mutation Database (MFMD): Taking Advantage from Founder Mutations in Genetics Diagnosis, Genetic Diversity and Migration History of the Mediterranean Population. Hum Mutat. 2015;36(11):E2441–53 [cited 2022 Mar 1]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/humu.22835
https://onlinelibrary.wiley.com/doi/full... ). For example, Charoute et al. (1515. Charoute H, Bakhchane A, Benrahma H, Romdhane L, Gabi K, Rouba H, et al. Mediterranean Founder Mutation Database (MFMD): Taking Advantage from Founder Mutations in Genetics Diagnosis, Genetic Diversity and Migration History of the Mediterranean Population. Hum Mutat. 2015;36(11):E2441–53 [cited 2022 Mar 1]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/humu.22835
https://onlinelibrary.wiley.com/doi/full... ) set a database of 219 Mendelian diseases caused by founder mutations across the Mediterranean basin (in which many clusters of different genetic diseases have been reported), of which 61.7% were autosomal recessive (1515. Charoute H, Bakhchane A, Benrahma H, Romdhane L, Gabi K, Rouba H, et al. Mediterranean Founder Mutation Database (MFMD): Taking Advantage from Founder Mutations in Genetics Diagnosis, Genetic Diversity and Migration History of the Mediterranean Population. Hum Mutat. 2015;36(11):E2441–53 [cited 2022 Mar 1]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/humu.22835
https://onlinelibrary.wiley.com/doi/full... ).

In this work, we have described some communities with more than one genetic disease; in other words, regions equivalent to “multi-clusters” (1616. Bustos T, Simosa V, Pinto-Cisternas J, Abramovits W, Jolay L, Rodriguez L, et al. Autosomal recessive ectodermal dysplasia: I. An undescribed dysplasia/malformation syndrome. Am J Med Genet. 1991;41(4):398–404 [cited 2022 Mar 6]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.1320410403
https://onlinelibrary.wiley.com/doi/full... –2020. Sass JO, Jobard F, Topçu M, Mahfoud A, Werlé E, Cure S, et al. L-2-hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene. J Inherit Metab Dis. 2008;31(Suppl 2) [cited 2022 Mar 6]. Available from: https://pubmed.ncbi.nlm.nih.gov/18415700/
https://pubmed.ncbi.nlm.nih.gov/18415700... ). For instance, Antioquia, in northwestern Colombia, represented the most extreme example of a multi-cluster. With six identified clusters of Mendelian disorders (three autosomal recessive and three autosomal dominant), the population from Antioquia was established in the 16th–17th century through the admixture of Native Americans, Europeans (mainly Spanish), and Africans and grew in relative isolation until the late 19th century (2121. Pineda-Trujillo N, Carvajal-Carmona LG, Buriticá O, Moreno S, Uribe C, Pineda D, et al. A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of juvenile Parkinsonism in a population from North West Colombia. Neurosci Lett. 2001;298(2):87–90.–2626. Montoya JH, Morales OL. Four cases of Jarcho-Levin’s syndrome in the province of Antioquia, Colombia. Biomedica. 2009;29(1):25–32 [cited 2022 Mar 2]. Available from: https://revistabiomedica.org/index.php/biomedica/article/view/38
https://revistabiomedica.org/index.php/b... ).

The Antioquian population has an Amerindian–Caucasian admixture with heterogeneous and specific patterns of sex-biased gene flow, experiencing cultural and geographical isolation from the total Colombian population (33. Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002;61(4):233–47 [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/12030885/
https://pubmed.ncbi.nlm.nih.gov/12030885... , 2727. Mooney JA, Huber CD, Service S, Sul JH, Marsden CD, Zhang Z, et al. Understanding the Hidden Complexity of Latin American Population Isolates. Am J Hum Genet. 2018;103(5):707–26 [cited 2022 Mar 1]. Available from: http://www.cell.com/article/S0002929718303513/fulltext
http://www.cell.com/article/S00029297183... ). With large and multigenerational genealogies, the Antioquian population can be compared to Finland, another classic example of a genetic isolate with multi-founder effects, in terms of potential contribution to studies regarding mapping genetic diseases and complex traits (33. Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002;61(4):233–47 [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/12030885/
https://pubmed.ncbi.nlm.nih.gov/12030885... ).

In another example, in the native people from Providencia Island (about 3 400 individuals), Colombia, at least 17 individuals were diagnosed with congenital deafness with two distinct genetic etiologies. A non-syndromic genetic deafness (MIM #220290; 35delG genetic variant in the GJB2 gene), found among individuals with Caucasian origin; and Waardenburg syndrome, found in families with African ancestry. Therefore, the authors argued that this finding was a “direct consequence of the multi-ethnic history of the island” (1919. Lattig M, Gelvez N, Plaza S, Tamayo G, Uribe J, Salvatierra I, et al. Deafness on the island of Providencia - Colombia: different etiology, different genetic counseling. Genet Couns. 2008;19(4):403–12.).

Islands constitute a model of geographic isolation and, sometimes, with a small population showing high levels of inbreeding. Other studies in South America reported clusters in island communities, such as in the Macanao Peninsula of Margarita Island, Venezuela (Usher syndrome, #276900; cleft lip/palate-ectodermal dysplasia syndrome, #225060; and L-2-hydroxyglutaric aciduria, #236792) (1616. Bustos T, Simosa V, Pinto-Cisternas J, Abramovits W, Jolay L, Rodriguez L, et al. Autosomal recessive ectodermal dysplasia: I. An undescribed dysplasia/malformation syndrome. Am J Med Genet. 1991;41(4):398–404 [cited 2022 Mar 6]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/ajmg.1320410403
https://onlinelibrary.wiley.com/doi/full... –1818. Keogh IJ, Godinho RN, Wu TP, de Palacios AMD, Palacios N, de Alford MB, et al. Clinical and genetic linkage analysis of a large Venezuelan kindred with Usher syndrome. Int J Pediatr Otorhinolaryngol. 2004;68(8):1063–8., 2020. Sass JO, Jobard F, Topçu M, Mahfoud A, Werlé E, Cure S, et al. L-2-hydroxyglutaric aciduria: identification of ten novel mutations in the L2HGDH gene. J Inherit Metab Dis. 2008;31(Suppl 2) [cited 2022 Mar 6]. Available from: https://pubmed.ncbi.nlm.nih.gov/18415700/
https://pubmed.ncbi.nlm.nih.gov/18415700... ); and Robinson Crusoe (language impairment, MIM #602081) and Chiloe Islands (chondrocalcinosis, #600668), in Chile (2828. Reginato AJ, Hollander JL, Martinez V, Valenzuela F, Schiapachasse V, Covarrubias E, et al. Familial chondrocalcinosis in the Chiloe Islands, Chile. Ann Rheum Dis. 1975;34(3):260–8 [cited 2022 Mar 6]. Available from: https://ard.bmj.com/content/34/3/260
https://ard.bmj.com/content/34/3/260... –3030. Villanueva P, Newbury DF, Jara L, de Barbieri Z, Mirza G, Palamino HM, et al. Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population. Eur J Hum Genet. 2011;19(6):687–95 [cited 2022 Mar 6]. Available from: https://www.nature.com/articles/ejhg2010251
https://www.nature.com/articles/ejhg2010... ). As they are generally derived from a few founding families and exposed to similar environmental factors, these populations also constitute a valuable source of information for the study of complex characteristics (33. Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002;61(4):233–47 [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/12030885/
https://pubmed.ncbi.nlm.nih.gov/12030885... , 3030. Villanueva P, Newbury DF, Jara L, de Barbieri Z, Mirza G, Palamino HM, et al. Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population. Eur J Hum Genet. 2011;19(6):687–95 [cited 2022 Mar 6]. Available from: https://www.nature.com/articles/ejhg2010251
https://www.nature.com/articles/ejhg2010... ).

Another important model of spatial and cultural isolation in South America is constituted by the native communities, as the Amazon Rainforest is home to some of the most isolated human groups in the world, many of which have remained relatively unknown until very recent times (3131. Cardoso S, Alfonso-Sánchez MA, Valverde L, Sánchez D, Zarrabeitia MT, Odriozola A, et al. Genetic uniqueness of the Waorani tribe from the Ecuadorian Amazon. Heredity. 2012;108(6):609–15 [cited 2022 Mar 6]. Available from: https://www.nature.com/articles/hdy2011131
https://www.nature.com/articles/hdy20111... ). The forest basin encompasses 7 000 000 km2 (2 700 000 square miles), with a territory belonging to nine nations and 3 344 formally acknowledged Indigenous territories. Some of these territories concentrate many small ancestral communities that are reciprocally isolated by both cultural (linguistic) and geographical barriers (3232. Kaplan JE, Larrick JW, Yost JA. Hyperimmunoglobulinemia E in the Waorani, an Isolated Amerindian Population. Am J Trop Med Hyg. 1980;29(5):1012–7 [cited 2022 Mar 6]. Available from: https://www.ajtmh.org/view/journals/tpmd/29/5/article-p1012.xml
https://www.ajtmh.org/view/journals/tpmd... –3434. Manno N, Sherratt S, Boaretto F, Coico FM, Camus CE, Campos CJ, et al. High prevalence of chitotriosidase deficiency in Peruvian Amerindians exposed to chitin-bearing food and enteroparasites. Carbohydr Polym. 2014 Nov 26;113:607–14.).

For instance, Manno et al. (3434. Manno N, Sherratt S, Boaretto F, Coico FM, Camus CE, Campos CJ, et al. High prevalence of chitotriosidase deficiency in Peruvian Amerindians exposed to chitin-bearing food and enteroparasites. Carbohydr Polym. 2014 Nov 26;113:607–14.) have described a high prevalence of chitotriosidase deficiency (MIM #614122) among small, isolated Amerindian populations from Peru, in association with a very high frequency of 24-base pair duplication in CHIT1 gene (3434. Manno N, Sherratt S, Boaretto F, Coico FM, Camus CE, Campos CJ, et al. High prevalence of chitotriosidase deficiency in Peruvian Amerindians exposed to chitin-bearing food and enteroparasites. Carbohydr Polym. 2014 Nov 26;113:607–14.). In other work, Landires et al. (3535. Landires I, Núñez-Samudio V, Fernandez J, Sarria C, Villareal V, Córdoba F, et al. Calpainopathy: Description of a Novel Mutation and Clinical Presentation with Early Severe Contractures. Genes. 2020;11(2):129 [cited 2022 Mar 6]. Available from: https://www.mdpi.com/2073-4425/11/2/129/htm
https://www.mdpi.com/2073-4425/11/2/129/... ) reported the first Amerindian family with calpain 3-related, limb-girdle muscular dystrophy type r1 (MIM #253600) from an isolated, consanguineous, Indigenous community in Colombia (3535. Landires I, Núñez-Samudio V, Fernandez J, Sarria C, Villareal V, Córdoba F, et al. Calpainopathy: Description of a Novel Mutation and Clinical Presentation with Early Severe Contractures. Genes. 2020;11(2):129 [cited 2022 Mar 6]. Available from: https://www.mdpi.com/2073-4425/11/2/129/htm
https://www.mdpi.com/2073-4425/11/2/129/... ). Affected people presented a novel deletion of four base pairs in CAPN3. Amerindian ethnic background was associated with high birth prevalence rates of cleft lip with or without cleft palate in clusters from Argentina, Bolivia, and Ecuador (3636. Poletta FA, Castilla EE, Orioli IM, Lopez-Camelo JS. Regional analysis on the occurrence of oral clefts in South America. Am J Med Genet A. 2007;143A(24):3216–27 [cited 2022 Mar 2]. Available from: https://pubmed.ncbi.nlm.nih.gov/18000905/
https://pubmed.ncbi.nlm.nih.gov/18000905... ).

However, important bioethical issues restrict the development of studies (and, sometimes, any other type of contact) with native communities (3333. Ballew C, Beckerman SJ, Lizarralde R. High Prevalence of Cleft Lip among the Barí Indians of Western Venezuela. Cleft Palate Craniofac J. 1993;30(4):411-3 [cited 2022 Mar 6]. Available from: https://journals.sagepub.com/doi/10.1597/1545-1569_1993_030_0411_hpocla_2.3.co_2
https://journals.sagepub.com/doi/10.1597... , 3737. D’Angelo CS, Hermes A, McMaster CR, Prichep E, Richer E, van der Westhuizen FH, et al. Barriers and Considerations for Diagnosing Rare Diseases in Indigenous Populations. Front Pediatr. 2020;8:797.). This helps to explain the scarcity of studies reporting clusters in communities from the North region in Brazil, which is sparsely populated by people with a strong Native American component, many of them in isolated or semi-isolated communities (55. Cardoso GC, de Oliveira MZ, Paixão-Côrtes VR, Castilla EE, Schuler-Faccini L. Clusters of genetic diseases in Brazil. J Community Genet. 2019;10(1):121–8 [cited 2020 Feb 18]. Available from: http://link.springer.com/10.1007/s12687-018-0369-1
http://link.springer.com/10.1007/s12687-... ). Besides the Amazon Rainforest, other South American landscapes associated with clusters were related to high altitudes areas, which were hypothesized to be associated with the concentration of microtia in Quito, Ecuador, (3838. Castilla EE, Orioli IM. Prevalence Rates of Microtia in South America. Int J Epidemiol. 1986;15(3):364–8 [cited 2022 Mar 6]. Available from: https://academic.oup.com/ije/article/15/3/364/658691
https://academic.oup.com/ije/article/15/... ) and oral clefts in different places on the continent (3636. Poletta FA, Castilla EE, Orioli IM, Lopez-Camelo JS. Regional analysis on the occurrence of oral clefts in South America. Am J Med Genet A. 2007;143A(24):3216–27 [cited 2022 Mar 2]. Available from: https://pubmed.ncbi.nlm.nih.gov/18000905/
https://pubmed.ncbi.nlm.nih.gov/18000905... ).

In addition, some clusters in South America occurred in communities whose origin is related to the escape from the slavery regime, which was established throughout Latin America based on the trafficking of Africans from the 16th century, such as concentration of spinocerebellar ataxias type 7 (MIM #164500) in Yaracuy state and β-thalassemia among Bushinengue Maroon people on the French Guiana–Suriname border (1919. Lattig M, Gelvez N, Plaza S, Tamayo G, Uribe J, Salvatierra I, et al. Deafness on the island of Providencia - Colombia: different etiology, different genetic counseling. Genet Couns. 2008;19(4):403–12., 3939. Broquere C, Brudey K, Harteveld CL, Saint-Martin C, Elion J, Giordano PC, et al. Phenotypic Expression and Origin of the Rare β-Thalassemia Splice Site Mutation HBB:c.315 + 1G>T. Hemoglobin. 2010;34(3):322–6 [cited 2022 Mar 6]. Available from: https://www.tandfonline.com/doi/abs/10.3109/03630269.2010.484956
https://www.tandfonline.com/doi/abs/10.3... , 4040. Paradisi I, Arias S. Marked geographic aggregation of acute intermittent porphyria families carrying mutation Q180X in Venezuelan populations, with description of further mutations. J Inherit Metab Dis. 2010;33(Suppl. 3):455–63 [cited 2022 Mar 6]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1007/s10545-010-9228-x
https://onlinelibrary.wiley.com/doi/full... ). In Brazil, some studies have shown a high frequency of hemoglobinopathies and/or genetic variants related to them among these communities, commonly known as quilombos (4141. Soares LF, Lima EM, da Silva JA, Fernandes SS, Silva KM da C, Lins SP, et al. [Prevalence of hemoglobin variants in quilombola communities in the state of Piauí, Brazil]. Cien Saude Colet. 2017;22(11):3773–80 [cited 2022 Mar 5]. Available from: https://pubmed.ncbi.nlm.nih.gov/29211182/
https://pubmed.ncbi.nlm.nih.gov/29211182... , 4242. Santiago RP, Oliveira RM, Soares LF, Figueiredo CVB, Silva DO, Hurtado-Guerrero AF, et al. Hemoglobin Variant Profiles among Brazilian Quilombola Communities. Hemoglobin. 2017;41(2):83–8 [cited 2022 Mar 6]. Available from: https://www.tandfonline.com/doi/abs/10.1080/03630269.2017.1321014
https://www.tandfonline.com/doi/abs/10.1... ). In recent work, we have found high rates of isonymy, congenital anomalies at birth, and clusters of genetic diseases in some places within the historic limits of Quilombo dos Palmares in the Brazilian Northeast, the largest conglomerate of escaped slaves in Latin America (4343. Cardoso-Dos-Santos AC, Ramallo V, Zagonel-Oliveira M, Veronez MR, Navarro P, Monlleó IL, et al. An invincible memory: What surname analysis tells us about history, health and population medical genetics in the Brazilian Northeast. J Biosoc Sci. 2020;53(2):183–98 [cited 2021 Apr 26]. Available from: https://www.cambridge.org/core/journals/journal-of-biosocial-science/article/abs/an-invincible-memory-what-surname-analysis-tells-us-about-history-health-and-population-medical-genetics-in-the-brazilian-northeast/BEAAE4230B47C1BDA2DFE31D1D04CBF1
https://www.cambridge.org/core/journals/... ).

It is known that many of these clusters reported here (and mainly those not reported in the scientific literature) occur in regions with multiple social and health vulnerabilities. The concentration of many cases of uncommon, complex diseases, which are sometimes related to prejudice and social exclusion, can affect patients, their families, and community in multiple ways, sometimes requiring the reorganization of health care adjusted to the reality of each location. Therefore, mapping of clusters can contribute to the design of health policies, focusing on health promotion and equity (66. Passos-Bueno MR, Bertola D, Dain D, Horovitz G, Evangelista De Faria Ferraz V, Brito LA. Genetics and genomics in Brazil: a promising future. Mol Genet Genomic Med. 2014;2(4):280–291 [cited 2019 Aug 18]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113268/pdf/mgg30002-0280.pdf
https://www.ncbi.nlm.nih.gov/pmc/article... , 4444. Bronberg R, Gili J, Gimenez L, Dipierri J, Lopez Camelo J. Biosocial correlates and spatial distribution of consanguinity in South America. Am J Hum Biol. 2016;28(3):405–11 [cited 2022 Mar 6]. Available from: https://pubmed.ncbi.nlm.nih.gov/26515926/
https://pubmed.ncbi.nlm.nih.gov/26515926... ).

In terms of cluster detection and public health in South America, work using data from hospitals registered by the ECLAMC (Latin-American Collaborative Study of Congenital Malformations) network deserves to be highlighted, as many clusters of congenital anomalies (mainly, oral clefts) have been described there (3636. Poletta FA, Castilla EE, Orioli IM, Lopez-Camelo JS. Regional analysis on the occurrence of oral clefts in South America. Am J Med Genet A. 2007;143A(24):3216–27 [cited 2022 Mar 2]. Available from: https://pubmed.ncbi.nlm.nih.gov/18000905/
https://pubmed.ncbi.nlm.nih.gov/18000905... , 4545. Orioli IM, Mastroiacovo P, López-Camelo JS, Saldarriaga W, Isaza C, Aiello H, et al. Clusters of sirenomelia in South America. Birth Defects Res A Clin Mol Teratol. 2009;85(2):112–8 [cited 2022 Mar 6]. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/bdra.20492
https://onlinelibrary.wiley.com/doi/full... –4747. Gili JA, Poletta FA, Giménez LG, Pawluk MS, Campaña H, Castilla EE, et al. Descriptive analysis of high birth prevalence rate geographical clusters of congenital anomalies in South America. Birth Defects Res A Clin Mol Teratol. 2016;106(4):257–66 [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/26887535/
https://pubmed.ncbi.nlm.nih.gov/26887535... ). For instance, Gili et al. (4747. Gili JA, Poletta FA, Giménez LG, Pawluk MS, Campaña H, Castilla EE, et al. Descriptive analysis of high birth prevalence rate geographical clusters of congenital anomalies in South America. Birth Defects Res A Clin Mol Teratol. 2016;106(4):257–66 [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/26887535/
https://pubmed.ncbi.nlm.nih.gov/26887535... ) applied spatial scan analysis in order to identify clusters from clinical epidemiological data by ECLAMC. With this approach, they have described five high birth prevalence rate regions associated with five congenital anomalies in South America. An additional study has investigated risk factors related to these (4747. Gili JA, Poletta FA, Giménez LG, Pawluk MS, Campaña H, Castilla EE, et al. Descriptive analysis of high birth prevalence rate geographical clusters of congenital anomalies in South America. Birth Defects Res A Clin Mol Teratol. 2016;106(4):257–66 [cited 2022 Mar 1]. Available from: https://pubmed.ncbi.nlm.nih.gov/26887535/
https://pubmed.ncbi.nlm.nih.gov/26887535... ).

The timely detection of these clusters of congenital anomalies can allow the identification of risk or etiological factors, mitigation of damages, and prevention of new potential cases. For this, different surveillance programs for congenital anomalies, such as the ECLAMC network, have alarms to systematically observe the fluctuations in the frequencies of different birth defects from birth registries (3636. Poletta FA, Castilla EE, Orioli IM, Lopez-Camelo JS. Regional analysis on the occurrence of oral clefts in South America. Am J Med Genet A. 2007;143A(24):3216–27 [cited 2022 Mar 2]. Available from: https://pubmed.ncbi.nlm.nih.gov/18000905/
https://pubmed.ncbi.nlm.nih.gov/18000905... , 4848. Cardoso-dos-Santos AC, Magalhães VS, Medeiros-de-Souza AC, Bremm J, Alves R, Araujo V, et al. International collaboration networks for the surveillance of congenital anomalies: a narrative review. Revista do Sistema Único de Saúde do Brasil. 2020;29(4):14. Available from: https://bit.ly/3vjlScB
https://bit.ly/3vjlScB... ).

In fact, there is a growing interest in the subject of congenital anomalies and rare diseases across the South American continent. In South America, many countries promote the surveillance of congenital anomalies at the local and national levels, in addition to collaborating with international networking initiatives, such as the Latin American Network on Congenital Malformations (RELAMC) and the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR) (4848. Cardoso-dos-Santos AC, Magalhães VS, Medeiros-de-Souza AC, Bremm J, Alves R, Araujo V, et al. International collaboration networks for the surveillance of congenital anomalies: a narrative review. Revista do Sistema Único de Saúde do Brasil. 2020;29(4):14. Available from: https://bit.ly/3vjlScB
https://bit.ly/3vjlScB... ).

Therefore, this work reinforces the importance of population medical genetics in the public health debate, as mapping clusters may support agendas such as health promotion and surveillance. It is important to consider that clusters published in the scientific literature may not have been captured by our search strategy, and this is a potential limitation of our work. However, in addition to constantly reviewing the scientific literature, we have mapped clusters in Brazil based on rumors; that is, by the report (based or not on evidence) of anyone about the possible presence of clusters, by filling out an online form: https://www.inagemp.bio.br/ceniso/. In the same link, it is possible to report populations in South America in four different languages. This can be an initial step toward creating a continental census of clusters of rare disorders and congenital anomalies in Latin America.

  • Author contributions.
    LSF conceived the original idea. ACCS and GR planned the study, collected the data, analyzed the data, and interpreted the results. ACCS wrote the paper, and all authors reviewed it. All authors reviewed and approved the final version.
  • Conflict of interest.
    None declared.
  • Disclaimer.
    Authors hold sole responsibility for the views expressed in the manuscript, which may not necessarily reflect the opinion or policy of the RPSP/ PAHPH and/or the Pan American Health Organization (PAHO).

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Publication Dates

  • Publication in this collection
    31 July 2023
  • Date of issue
    2023

History

  • Received
    20 Nov 2022
  • Accepted
    21 Mar 2023
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