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Identification of rare genetic diseases clusters in the Colombian pacific region: clinical, molecular, and geographical characterization

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Population Genetics
  • Secondary Categories:
    • Population Genetics
Introduction:
Rare genetic disease clusters represent areas or periods of high prevalence of specific conditions, often due to geographical, cultural, or social isolation in particular populations. Given the rarity and characteristics of genetic disorders, genetic epidemiology suggests analyzing clusters with a focus on the frequency of genes and specific genotypes or variants rather than phenotypes. In Colombia, there are few studies on these clusters (e.g., hearing loss due to GJB2 in Providencia and Santa Catalina Islands, Roberts syndrome in rural Bogotá, Huntington’s disease in the Atlántico region, mucopolysaccharidoses –I, III, and IV in Cundinamarca, IV in Valle del Cauca–, Fragile X syndrome in Valle del Cauca), particularly in the Pacific region (Chocó, Valle del Cauca, Cauca, and Nariño), where the genetic structure of the inhabitants remains under-characterized, mainly due to social determinants of health such as isolation, poverty, limited access to public healthcare, and genetic studies, among others. The objective of this study was to identify and describe clusters of genetic diseases in patients with a molecular diagnosis from the departments of the Colombian Pacific region.

Methods:
A retrospective cross-sectional study was conducted, evaluating patients with confirmed diagnoses of genetic diseases through next-generation sequencing, originating from the departments of the Colombian Pacific region, and treated at Fundación Valle del Lili between 2012 and 2023. Clinical, geographical, and molecular characterizations (analysis of identified variants) were performed, along with georeferencing, frequency estimation, and statistical analysis, including the Observed/Expected Ratio (O/E) with significance testing using the Poisson test (p) to suggest potential clusters.

Results:
Of the 7,052 individuals evaluated, 1,029 presented with rare genetics diseases. Over 50 conditions had prevalence rates higher than expected for the population, but these corresponded to cases of familial aggregation, different genetic variants, and/or individuals with diverse places of origin. Potential clusters were identified with recurrent pathogenic variants (according to ACMG/AMP criteria) among participants, including mucopolysaccharidosis IVA (8 cases, Tuluá-El Dovio, Valle del Cauca; GALNS (NM_000512.5).901G>T p.Gly301Cys; O/E: 5.58, p≈0.00012), non-ketotic hyperglycinemia (8 cases, Cali-Valle del Cauca, with Paisa ancestry; GLDC (NM_000170.3).2714T>G p.Val905Gly; O/E: 20.27, p≈1.03 × 10−8), Schimke immuno-osseous dysplasia (3 cases, Santander de Quilichao/Rosas, Cauca; O/E: 11.91, p≈0.0022), and autosomal recessive congenital ichthyosis type 1 (3 cases, El Tambo, Nariño; O/E: 40.27, p≈6.52 × 10−5).

Conclusion:
The identification of recurrent specific genetic variants in these previously undescribed clusters of autosomal recessive diseases suggests the presence of potential founder effects in these populations of the Colombian Pacific region. Aware of the study's limitations and those of the region, these findings underscore the importance of additional projects, such as the fieldwork conducted by our team through the Pacific Genome Expedition, to better understand the genetic structure of these communities and evaluate the cluster hypothesis. Identifying populations with rare diseases in low- and middle-income regions and centralizing available information on these patients would increase scientific interest and Public Health and Policy focus towards these conditions. This could provide evidence for the existence of a common ancestor through haplotype analysis, and also, facilitate genetic counseling, enable early diagnosis, and guide targeted intervention strategies for the region, ultimately improving medical care and support for patients and their families

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