Abstract
The Mennonite population has a unique history of 500 years of genetic isolation shaped by at least three demographic bottlenecks, founder effects, inbreeding, epidemics, and migrations. To evaluate their susceptibility for monogenic diseases (MD), we performed whole-exome sequencing on 325 volunteers from two South Brazilian Mennonite settlements (one urban and another rural). We identified 23 pathogenic variants (P) and 27 likely P, with 22.8% accounting for endocrine, nutritional, and metabolic MDs, 17.5% for developmental anomalies, and 10.5% for nervous system MDs. HFE rs1800562 causing hereditary hemochromatosis presented the highest frequency (7.54%), followed by BTD rs13078881 for biotinidase deficiency (7.08%), FLG rs61816761 for ichthyosis vulgaris and atopic dermatitis (3.38%), and FANCM rs147021911 for Fanconi anemia (3.08%). Genomic and genealogical analysis confirmed their European origin, with very low consanguinity and high heterozygosity coefficients, confirming a random selection of refugees that emigrated from widespread settlements in Russia to Brazil in 1930. There was also a slight deviation to Native Americans for self-reported admixed Mennonites. Even so, founder effects occurred for 96% of P, whose frequencies differed from non-Finnish Europeans, Amish, and Brazilian populations. These findings highlight the genetic risks in this population, reinforcing the importance of genetic counseling, screening programs, and Personalized and Preventive Medicine strategies to mitigate health risks associated with inherited conditions.