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PPP3CA truncating variants clustered in the regulatory domain cause early‐onset refractory epilepsy
Author(s) -
Panneerselvam Sugi,
Wang Julia,
Zhu Wenmiao,
Dai Hongzheng,
Pappas John G.,
Rabin Rachel,
Low Karen J.,
Rosenfeld Jill A.,
Emrick Lisa,
Xiao Rui,
Xia Fan,
Yang Yaping,
Eng Christine M.,
Anderson Anne,
Chau Vann,
SolerAlfonso Claudia,
Streff Haley,
Lalani Seema R.,
MercimekAndrews Saadet,
Bi Weimin
Publication year - 2021
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13979
Subject(s) - missense mutation , genetics , biology , frameshift mutation , loss function , epilepsy , allele , mutant , mutation , phenotype , gene , neuroscience
PPP3CA encodes the catalytic subunit of calcineurin, a calcium‐calmodulin‐regulated serine–threonine phosphatase. Loss‐of‐function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain‐of‐function (GoF) variants in the auto‐inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26‐amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early‐onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.