MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity.
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We wish to extend our sincere thanks to the original family with Pettigrew syndrome on both sides of the Atlantic, as they have borne with us for many years as we worked to solve this problem. We also thank Carlos Cardoso and Helen Kosakowski for their involvement in the initial phase of this work, Caroline Lacoste and Catherine Badens for X-chromosome inactivation analysis and the Centre de Ressources Biologiques of La Timone Children’s Hospital (Karine Bertaux, Cécile Mouradian and Andrée Robaglia-Schlupp) for assistance with the cell lines used in this study. This work was funded by the US National Institutes of Health under National Institute of Neurological Disorders and Stroke (NINDS) grant NS050375 (to WBD), and by Inserm and Aix Marseille University (to LV).
- Dandy-Walker malformation
- brain pathology
- cerebral calcifications
- intellectual disability