PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy.

Defects of the human glycosylphosphatidylinositol (GPI) anchor biosynthetic pathway show a broad range of clinical phenotypes. A homozygous mutation in PIGN, a member of genes involved in the GPI anchor-synthesis pathway, was previously reported to cause dysmorphic features, multiple congenital anomalies, severe neurological impairment, and seizure in a consanguineous family. Here, we report two affected siblings with compound heterozygous PIGN mutations [c.808T >C (p.Ser270Pro) and c.963G >A] showing congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy. The c.808C >T mutation altered an evolutionarily conserved amino acid residue (Ser270), while reverse transcription-PCR and sequencing demonstrated that c.963G >A led to aberrant splicing, in which two mutant transcripts with premature stop codons (p.Ala322Valfs*24 and p.Glu308Glyfs*2) were generated. Expression of GPI-anchored proteins such as CD16 and CD24 on granulocytes from affected siblings was significantly decreased, and expression of the GPI-anchored protein CD59 in PIGN-knockout human embryonic kidney 293 cells was partially or hardly restored by transient expression of p.Ser270Pro and p.Glu308Glyfs*2 mutants, respectively, suggesting severe and complete loss of PIGN activity. Our findings confirm that developmental delay, hypotonia, and epilepsy combined with congenital anomalies are common phenotypes of PIGN mutations and add progressive cerebellar atrophy to this clinical spectrum.