TY - JOUR
T1 - Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy
AU - Johannesen, Katrine M
AU - Mitter, Diana
AU - Janowski, Robert
AU - Roth, Christian
AU - Toulouse, Joseph
AU - Poulat, Anne-Lise
AU - Ville, Dorothee M
AU - Chatron, Nicolas
AU - Brilstra, Eva
AU - Geleijns, Karin
AU - Born, Alfred Peter
AU - McLean, Scott
AU - Nugent, Kimberly
AU - Baynam, Gareth
AU - Poulton, Cathryn
AU - Dreyer, Lauren
AU - Gration, Dylan
AU - Schulz, Solveig
AU - Dieckmann, Andrea
AU - Helbig, Katherine L
AU - Merkenschlager, Andreas
AU - Jamra, Rami
AU - Finck, Anja
AU - Gardella, Elena
AU - Hjalgrim, Helle
AU - Mirzaa, Ghayda
AU - Brancati, Francesco
AU - Bierhals, Tatjana
AU - Denecke, Jonas
AU - Hempel, Maja
AU - Lemke, Johannes R
AU - Rubboli, Guido
AU - Muschke, Petra
AU - Guerrini, Renzo
AU - Vetro, Annalisa
AU - Niessing, Dierk
AU - Lesca, Gaetan
AU - Møller, Rikke S
N1 - Funding Information:
G. Mirzaa is funded by the NINDS by award K08NS092898 and Jordan’s Guardian Angels, United States. G. Baynam and C. Poulton received funding from Undiagnosed Diseases Program, Genetic Services of Western Australia, acknowledging funding from the Angela Wright Bennett Foundation and the McCusker Charitable Foundation. F. Brancati was funded by the Undiagnosed Disease Network - Italy (UDN-Italy) PGR00229-PGR00919 and Farmindustria, acknowledging founding members Domenica Taruscio and Marco Salvatore from Istituto Superiore di Sanità, Roma, Italy. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funding sources had no role in the design and conduct of the study, collection, management, analysis and interpretation of the data, preparation, review, or approval of the manuscript, or decision to submit the manuscript for publication.
Publisher Copyright:
Copyright © 2019 The Author(s).
PY - 2019/12
Y1 - 2019/12
N2 - Objective: The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy.Methods: Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.Results: Biallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.Conclusions: These data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.
AB - Objective: The study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy.Methods: Through diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.Results: Biallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.Conclusions: These data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.
UR - http://www.scopus.com/inward/record.url?scp=85092586034&partnerID=8YFLogxK
U2 - 10.1212/NXG.0000000000000373
DO - 10.1212/NXG.0000000000000373
M3 - Article
C2 - 32042906
SN - 2376-7839
VL - 5
JO - Neurology. Genetics
JF - Neurology. Genetics
IS - 6
M1 - e373
ER -