Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome

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Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families.

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Figure 1: Identification of PIGV mutations in individuals with HPMR syndrome.

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NCBI Reference Sequence


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This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 665) to S.M., by a grant from Bundesministerium für Bildung und Forschung (BMBF, project number 0313911) and an Australian National Health and Medical Research Council international research training fellowship to T.R., and by a grant of the Canadian Institutes of Health Research and Epilepsy Canada to M.D.T. We thank B. Fischer, U. Kornak, M. Ralser, E. van Beusekom, U. Marchfelder and D. Lefeber for their assistance in this project.

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M.R.S., M.I. and A.D. performed targeted exome resequencing. P.M.K., C.R., A.F., M.K., S.B., S.K., M.J. and P.N.R. performed bioinformatic analysis. P.M.K., C. Marcelis, J.G., B.J.d.C., F.S. and T.R. performed mutation analysis and genotyping. D.H., C. Marcelis, M.D.T., D.E.C., S.D., P.M., E.P., T.R. and H.G.B. contributed to clinical evaluation of the affected individuals and delineation of the phenotype. P.M.K., U.K. and C. Meisel performed flow cytometric analysis. Y.M. and T.K. performed analysis of wild-type and A341E PIGV clones. P.M.K., M.R.S., D.H., J.H., H.G.B., P.N.R. and S.M. carried out the project planning and preparation of the manuscript.

Correspondence to Stefan Mundlos or Peter N Robinson.

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Supplementary Methods, Supplementary Note, Supplementary Figures 1–6 and Supplementary Tables 1–7 (PDF 1270 kb)

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