Bi‐allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families. Issue 1 (29th September 2021)

• Record Type: Journal Article
• Authors: Daum, Hagit; Ganapathi, Mythily; Hirsch, Yoel; Griffin, Emily L.; LeDuc, Charles A.; Hagen, Jacob; Yagel, Simcha; Meiner, Vardiella; Chung, Wendy K.; Mor‐Shaked, Hagar
• Is Part Of: American journal of medical genetics. Volume 188:Issue 1(2022)
• Page Start: 336
• Page End: 342
• Publication Date: 2021-09-29
• Subjects: Ashkenazi Jews -- infantile‐lethal disorder -- microcephaly -- neurodevelopmental disorder -- PAGR1; Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.62513
• Languages: English
• ISSNs: 1552-4825

Abstract

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.