Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size^{1, 2}, is associated with defective ATR-dependent DNA damage signaling³. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition⁴. We now report that mutations in the gene encoding pericentrin (PCNT)—resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins—also cause Seckel syndrome^{5, 6}. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses⁷ or centrosomal function^{8, 9} may act in common developmental pathways determining human brain and body size.

1. Medical Research Council (MRC) Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
2. Genome Damage and Stability Centre, University of Sussex, East Sussex BN1 9RQ, UK.
3. Wellcome Trust Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Kings Buildings, Mayfield Road, Edinburgh EH9 3JR, UK.
4. Pediatric Services Division, Box 76, Dhahran Health Center, Saudi Arabia.
5. Southwest Thames Regional Genetics Service, St. George's Hospital Medical School, London, SW17 0RE UK.
6. Radboud University Nijmegen Medical Center, Department of Human Genetics 417, Geert Grooteplein 20, 6525GA, Nijmegen, The Netherlands.
7. These authors contributed equally to this work.

Correspondence to: Andrew P Jackson¹ e-mail: andrew.jackson@hgu.mrc.ac.uk

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