Schematics for each protein depicting known protein domains with positions of mutations shown by filled circles. Each filled circle represents one patient. Clustalw alignment of protein residues surrounding substituted amino acids (positions of substituted resides indicated by red boxes). WA, Walker A; WB Walker B, S1, Sensor 1; S2, Sensor 2; motifs. BAH, Bromo Associated Homology domain; AAA, ATPase Associated with a wide range of cellular Activites; WH, winged helix domain.

(a) Genome replication is licensed by the binding of a number of specialised proteins to origins of replication, which form the pre-replication complex9. The first step in complex formation is the loading of the heterohexameric Origin Recognition Complex (comprising ORC1-6 proteins), onto chromatin in an ATP dependent manner during M and G1 phases of the cell cycle. Further proteins, including CDC6 and CDT1 are then recruited to the pre-replicative complex, that then permit reiterative loading of the multimeric MCM helicase. At the commencement of S-phase, replication is started by the MCM helicase unwinding DNA, and the recruitment of additional replication proteins. The five proteins implicated in Meier-Gorlin syndrome are highlighted in white text (ORC1, ORC4, ORC6, CDT1, CDC6). (b) Patient 1 has a severe developmental malformation syndrome with marked microtia and extreme retroflexion and dislocation of the knees (top row). His malformations included lobar congenital emphysema (arrow head), and a severe cortical dysplasia of the brain. Parasaggital T2 weighted MRI at age 1 month demonstrating severe pachygyria, most severe frontally along with ventricular enlargement. (c) Two patients (P11, P9) with classical Meier-Gorlin syndrome. b,c Informed consent to publish the photographs was obtained from the subjects' parents.