Genotype-first analysis redefines autosomal dominant LZTR1-related disorders susceptibility architecture

LZTR1 -associated syndromes have defined the clinical recognition of this gene, yet its population susceptibility architecture remains unclear. Here we combined population-scale variant data, systematic literature curation, standardized ACMG/AMP interpretation, and allele-frequency modeling to evaluate dominant LZTR1 -associated susceptibility using a genotype-first framework. We analyzed 4,930 LZTR1 variants from gnomAD and curated 181 reported variants from 50 publications. Pathogenic and likely pathogenic variants were distributed across functional domains without strict syndrome-specific segregation and were collectively more frequent in population datasets than expected for a condition recognized mainly through rare syndrome-based ascertainment. Allele-frequency modeling predicted a population prevalence of approximately 2.5 to 2.8 per 1,000, depending on modeling assumptions, for dominant LZTR1 -associated susceptibility. These results reveal a substantial gap between variant frequency and clinical recognition, support a model of dominant LZTR1 -associated susceptibility as a common, variably penetrant Mendelian susceptibility state, and illustrate how genotype-first approaches can refine disease architecture beyond syndrome-based classification.