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Simple Summary Today’s Swiss Simmental represents a local dual-purpose breed of cattle. Within closed populations, deleterious variants can reach problematic frequencies, explaining substantial proportions of inbreeding depression. Depletions in homozygous genotypes for certain haplotypes among large cohorts of animals genotyped for the purpose of genomic selection is a widely used approach to pinpoint undesired recessive alleles. In the course of a reverse genetic screen, we aimed to identify single recessive Mendelian variants that potentially affect fertility and rearing success without any phenotypic information available. We detected eleven genome regions showing obvious depletion of homozygosity based on genome-wide SNP data. Furthermore, after performing whole-genome sequencing of selected animals, we propose three candidate causative variants affecting different genes with possibly detrimental effects for embryonic development. The established haplotypes, as well as the identified protein-changing variants, can be directly implemented into breeding practice to avoid the risk of mating carriers and thereby increase breeding success. Abstract We herein report the result of a large-scale reverse genetic screen in the Swiss Simmental population, a local dual-purpose cattle breed. We aimed to detect possible recessively inherited variants affecting protein-coding genes, as such deleterious variants can impair fertility and rearing success significantly. We used 115,000 phased SNP data of almost 10 thousand cattle with pedigree data. This revealed evidence for 11 genomic regions of 1.17 Mb on average, with haplotypes (SH1 to SH11) showing a significant depletion in homozygosity and an allele frequency between 3.2 and 10.6%. For the proposed haplotypes, it was unfortunately not possible to evaluate associations with fertility traits as no corresponding data were available. For each haplotype region, possible candidate genes were listed based on their known function in development and disease. Subsequent mining of single-nucleotide variants and short indels in the genomes of 23 sequenced haplotype carriers allowed us to identify three perfectly linked candidate causative protein-changing variants: a SH5-related DIS3:p.Ile678fs loss-of-function variant, a SH8-related CYP2B6:p.Ile313Asn missense variant, and a SH9-related NUBPL:p.Ser143Tyr missense variant. None of these variants occurred in homozygous state in any of more than 5200 sequenced cattle of various breeds. Selection against these alleles in order to reduce reproductive failure and animal loss is recommended.