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Eur J Hum Genet. 2014 Jun;22(6):762-7. doi: 10.1038/ejhg.2013.241. Epub 2013 Oct 16.

Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome.

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Institut für Medizinische Genetik und Humangenetik, Charité Universitätsmedizin Berlin, Berlin, Germany.
Institut für Humangenetik Essen, Universitätsklinikum Essen, Essen, Germany.
Clinical Genetics, Genetic Medicine, St Mary's Hospital, Manchester, UK.
1] Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia [2] University of Zagreb, School of Medicine, Zagreb, Croatia.
University of Zagreb, School of Medicine, Zagreb, Croatia.
Department of Pediatrics, University Hospital Center Zagreb, Zagreb, Croatia.
Praxis für Humangenetik Erfurt, Erfurt, Germany.
Praxis für Humangenetik Cottbus, Cottbus, Germany.
Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Münster, Münster, Germany.


Three different genes of the glycosylphosphatidylinositol anchor synthesis pathway, PIGV, PIGO, and PGAP2, have recently been implicated in hyperphosphatasia-mental retardation syndrome (HPMRS), also known as Mabry syndrome, a rare autosomal recessive form of intellectual disability. The aim of this study was to delineate the PIGV mutation spectrum as well as the associated phenotypic spectrum in a cohort of 16 individuals diagnosed with HPMRS on the basis of intellectual disability and elevated serum alkaline phosphate as minimal diagnostic criteria. All PIGV exons and intronic boundaries were sequenced in 16 individuals. Biallelic PIGV mutations were identified in 8 of 16 unrelated families with HPMRS. The most frequent mutation detected in about 80% of affected families including the cases reported here is the c.1022C>A PIGV mutation, which was found in both the homozygous as well as the heterozygous state. Four further mutations found in this study (c. 176T>G, c.53G>A, c.905T>C, and c.1405C>T) are novel. Our findings in the largest reported cohort to date significantly extend the range of reported manifestations associated with PIGV mutations and demonstrate that the severe end of the clinical spectrum presents as a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations. PIGV mutations are the major cause of HPMRS, which displays a broad clinical variability regarding associated malformations and growth patterns. Severe developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in PIGV-positive individuals.

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