[SP6-3D-4] Newly identified glycosylphosphatidylinositol (GPI) deficiency caused by PIGG mutations shows intellectual disability, seizures and hypotonia
[Introduction] Inherited glycosylphosphatidylinositol (GPI) deficiencies (IGDs) are recently becoming established as the developmental disorders showing neurological and non-neurological signs. We report 5 patients from 3 families with a novel type of IGD caused by PIGG mutations. [Methods] Whole exome sequencing along with homozygosity mapping and copy number analysis using XHMM were performed. Functional analyses of mutated PIGG were also done. [Results] We identified two homozygous PIGG mutations, c.928C>T:p.(Gln310*) and c.2261+1G>C, in 4 patients from two consanguinious families. A heterozygous mutation in PIGG, c.2005C>T: p.(Arg669Cys), and a 2.4Mb de novo microdeletion in 4p16.3 involving PIGG, WHSC1, WHSC2, and LETM1 were identified in one patient from another family. PIGG activities of these patients were abolished, however GPI-anchored proteins were not impaired. All individuals showed intellectual disability and no dysmorphic features, and four developed seizures. Two patients (c.2261+1G>C) showed severe ataxia with cerebellar hypoplasia and mild cerebral atrophy in their brain magnetic resonance imaging. All of them showed no elevation of alkaline phosphatase. One patient (c.2005C>T, and microdeletion in 4p16.3) had pre/postnatal growth deficiency, which is one of frequent clinical features of Wolf-Hirschhorn syndrome. [Conclusion] Newly identified pathogenic variants in PIGG expand a spectrum of IGDs. Aberrations of PIGG were suggested to cause of intellectual disability with seizures and hypotonia. [Additional collaborators] Periklis Makrythanasis, Maha Zaki, Hanan Hamamy, Eamonn Sheridan, Stylianos E Antonarakis, Mahmoud Y Issa, Federico Santoni, Michel Guipponi, Audrey Letourneau, Clare Logan, Nicola Roberts, David A Parry and Colin A Johnson.