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Bi‐allelic PAGR1 variants are associated with microcephaly and a severe neurodevelopmental disorder: Genetic evidence from two families
Author(s) -
Daum Hagit,
Ganapathi Mythily,
Hirsch Yoel,
Griffin Emily L.,
LeDuc Charles A.,
Hagen Jacob,
Yagel Simcha,
Meiner Vardiella,
Chung Wendy K.,
MorShaked Hagar
Publication year - 2022
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.62513
Subject(s) - microcephaly , neurodevelopmental disorder , exome sequencing , genetics , intellectual disability , missense mutation , biology , candidate gene , medicine , gene , mutation
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.