RESUMO
46,XY gonadal dysgenesis (GD) is a disorder of sex development due to incomplete gonadal differentiation into testes, resulting in female to ambiguous external genitalia. Duplications at the Xp21.2 locus involving the NR0B1 (DAX1) gene have previously been associated with 46,XY GD. More recently, a complex structural variant not directly involving NR0B1 has been reported in 46,XY GD illustrating that the mechanism of how copy number variants (CNVs) at Xp21.2 may cause 46,XY gonadal dysgenesis is not yet fully understood. Here, we report on three families in which a duplication involving the NR0B1 gene was detected in the context of prenatal screening. This is the first report of duplications involving NR0B1 in three phenotypically normal males in two families. Fertility problems were present in one adult male carrier. The data reported here from an unbiased screening population broaden the phenotype associated with CNVs involving NR0B1, and this may aid clinicians in counseling and decision making in the prenatal context.
Assuntos
Receptor Nuclear Órfão DAX-1 , Disgenesia Gonadal 46 XY , Adulto , Feminino , Humanos , Masculino , Receptor Nuclear Órfão DAX-1/genética , Transtornos do Desenvolvimento Sexual/genética , Variações do Número de Cópias de DNA , Disgenesia Gonadal 46 XY/genética , FenótipoRESUMO
Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression to rank the relative contribution of over 490 cell types to plasma cfDNA. In 744 healthy individuals and patients, we uncover cell type signatures in support of emerging disease paradigms in oncology and prenatal care. We train predictive models that can differentiate patients with colorectal cancer (84.7%), early-stage breast cancer (90.1%), multiple myeloma (AUC 95.0%), and preeclampsia (88.3%) from matched controls. Importantly, our approach performs well in ultra-low coverage cfDNA datasets and can be readily transferred to diverse clinical settings for the expansion of liquid biopsy.