Holoprosencephaly (HPE) is the most common forebrain malformation in humans, characterised by the failed or incomplete division of the forebrain hemispheres. Why patients carrying the same pathogenic gene variant show a wide spectrum of HPE severity is still poorly understood. In their latest work, Annette Hammes and colleagues utilise the strain differences in the Lrp2/ mouse model of HPE, which lack LRP2 – an auxiliary sonic hedgehog (SHH) receptor – to identify previously unreported genetic modifiers contributing to HPE severity. Loss of LRP2 in C57BL/6N mice causes severe HPE, whereas the FVB/N strain is unaffected. By comparing the phenotypes of each strain, the authors show that SHH localisation is lost in the forebrain of mutant C57Bl/6N mice, but SHH is localised normally in FVB/N and activates downstream targets. To identify candidates for strain-specific HPE resistance genes, the researchers compare wild-type transcriptome data from both backgrounds, revealing that Ulk4 and Pttg1 are upregulated in FVB/N mice. Through functional analyses they show that ULK4 and PTTG1 are localised to the primary cilium and act as positive regulators of SHH signalling. Overall, these data identify two regulators that enhance SHH signalling and may protect against severe HPE in FVB/N mice.