Bi-allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families

Am J Med Genet A. 2022 Jan;188(1):336-342. doi: 10.1002/ajmg.a.62513. Epub 2021 Sep 29.

Abstract

Exome and genome sequencing were used to identify the genetic etiology of a severe neurodevelopmental disorder in two unrelated Ashkenazi Jewish families with three affected individuals. The clinical findings included a prenatal presentation of microcephaly, polyhydramnios and clenched hands while postnatal findings included microcephaly, severe developmental delay, dysmorphism, neurologic deficits, and death in infancy. A shared rare homozygous, missense variant (c.274A > G; p.Ser92Gly, NM_024516.4) was identified in PAGR1, a gene currently not associated with a Mendelian disease. PAGR1 encodes a component of the histone methyltransferase MLL2/MLL3 complex and may function in the DNA damage response pathway. Complete knockout of the murine Pagr1a is embryonic-lethal. Given the available evidence, PAGR1 is a strong candidate gene for a novel autosomal recessive severe syndromic neurodevelopmental disorder.

Keywords: Ashkenazi Jews; PAGR1; infantile-lethal disorder; microcephaly; neurodevelopmental disorder.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Cycle Proteins* / genetics
  • DNA-Binding Proteins* / genetics
  • Exome / genetics
  • Humans
  • Mice
  • Microcephaly* / genetics
  • Nervous System Malformations* / genetics
  • Neurodevelopmental Disorders* / genetics
  • Pedigree

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • PAGR1 protein, human