Monogenic diseases are frequent causes of neonatal morbidity and mortality. Over 3,500 monogenic diseases have been characterized, many of which feature clinical and genetic heterogeneity. Since disease presentation at birth is often undifferentiated, there is an immense need for molecular diagnosis in infants. Disease progression in newborns is often fast and heterogeneous, so molecular diagnosis must occur rapidly for relevant clinical decision making. Here, we describe 50-hour differential diagnosis of genetic disorders by whole genome sequencing (WGS), featuring substantially automated bioinformatic analysis. This is intended to be a prototype for deployment in neonatal intensive care units.