Mutations underlying Mendelian diseases provide a powerful resource to harness to understand cellular functioning and development. A particular focus of our research is on Meier-Gorlin syndrome (MGS), a rare autosomal recessive disorder characterised by extreme pre and postnatal growth retardation, as well as small ears, small kneecaps, breast agenesis and other mesenchymal abnormalities. Linkage analysis and exome sequencing led to our discovery of the first five disease genes. Three of these genes (ORC1, ORC4 and ORC6) encode subunits of the origin recognition complex (ORC), which bind across our genome at origins of DNA replication. Additional factors, including two further MGS genes, CDT1 and CDC6, interact with the ORC to recruit the MCM helicase complex. These origins are then considered licensed, to enable replication initiation during S phase. More recently, we have discovered mutations in an additional downstream member of the replication machinery, CDC45, underlies MGS. While mutations in CDC45 appear to be a relatively common cause of MGS, the majority of affected individuals also present with craniosynostosis (premature fusion of skull plates), phenotypically linking to abnormalities caused by disruption of another replication component, the CDC45-interacting protein RECQL4. The growth and mesenchymal developmental consequences of these “replication-opathies” are being explored using CRISPR-Cas9 editing in both stem cells and in a Xenopus laevis animal model.