Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis

Hum Mol Genet. 2015 Jul 1;24(13):3732-41. doi: 10.1093/hmg/ddv117. Epub 2015 Apr 8.


Polymicrogyria (PMG) is a structural brain abnormality involving the cerebral cortex that results from impaired neuronal migration and although several genes have been implicated, many cases remain unsolved. In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome. In these regions, the only plausibly pathogenic mutations were compound heterozygous variants in PI4KA, which Sanger sequencing confirmed segregated consistent with autosomal recessive inheritance. The paternally transmitted variant predicted a premature stop mutation (c.2386C>T; p.R796X), whereas the maternally transmitted variant predicted a missense substitution (c.5560G>A; p.D1854N) at a conserved residue within the catalytic domain. Functional studies using expressed wild-type or mutant PI4KA enzyme confirmed the importance of p.D1854 for kinase activity. Our results emphasize the importance of phosphoinositide signalling in early brain development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Arthrogryposis / embryology
  • Arthrogryposis / enzymology*
  • Arthrogryposis / genetics
  • Base Sequence
  • Brain / embryology
  • Brain / enzymology
  • Cerebellum / abnormalities*
  • Cerebellum / embryology
  • Cerebellum / enzymology
  • Developmental Disabilities / enzymology
  • Developmental Disabilities / genetics
  • Exome
  • Female
  • Fetal Diseases / enzymology*
  • Fetal Diseases / genetics
  • Germ-Line Mutation*
  • Humans
  • Infant
  • Male
  • Minor Histocompatibility Antigens
  • Molecular Sequence Data
  • Mutation, Missense
  • Nervous System Malformations / embryology
  • Nervous System Malformations / enzymology*
  • Nervous System Malformations / genetics
  • Pedigree
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Polymicrogyria / embryology
  • Polymicrogyria / enzymology*
  • Polymicrogyria / genetics
  • Polymorphism, Single Nucleotide
  • Sequence Alignment


  • Minor Histocompatibility Antigens
  • Phosphotransferases (Alcohol Group Acceptor)
  • phosphatidylinositol phosphate 4-kinase

Supplementary concepts

  • Cerebellar Hypoplasia