2021 Articles

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

Daum, Hagit; Ganapathi, Mythily; Hirsch, Yoel; Griffin, Emily Leann; LeDuc, Charles A.; Hagen, Jacob J.; Yagel, Simcha; Meiner, Vardiella; Chung, Wendy K.; Mor-Shaked, Hagar

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.