Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy

Katrine M Johannesen; Diana Mitter; Robert Janowski; Christian Roth; Joseph Toulouse; Anne-Lise Poulat; Dorothee M Ville; Nicolas Chatron; Eva Brilstra; Karin Geleijns; Alfred Peter Born; Scott McLean; Kimberly Nugent; Gareth Baynam; Cathryn Poulton; Lauren Dreyer; Dylan Gration; Solveig Schulz; Andrea Dieckmann; Katherine L Helbig; Andreas Merkenschlager; Rami Jamra; Anja Finck; Elena Gardella; Helle Hjalgrim; Ghayda Mirzaa; Francesco Brancati; Tatjana Bierhals; Jonas Denecke; Maja Hempel; Johannes R Lemke; Guido Rubboli; Petra Muschke; Renzo Guerrini; Annalisa Vetro; Dierk Niessing; Gaetan Lesca; Rikke S Møller

doi:10.1212/NXG.0000000000000373

Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy

Neurol Genet. 2019 Dec 10;5(6):e373. doi: 10.1212/NXG.0000000000000373. eCollection 2019 Dec.

Authors

Katrine M Johannesen¹, Diana Mitter¹, Robert Janowski¹, Christian Roth¹, Joseph Toulouse¹, Anne-Lise Poulat¹, Dorothee M Ville¹, Nicolas Chatron¹, Eva Brilstra¹, Karin Geleijns¹, Alfred Peter Born¹, Scott McLean¹, Kimberly Nugent¹, Gareth Baynam¹, Cathryn Poulton¹, Lauren Dreyer¹, Dylan Gration¹, Solveig Schulz¹, Andrea Dieckmann¹, Katherine L Helbig¹, Andreas Merkenschlager¹, Rami Jamra¹, Anja Finck¹, Elena Gardella¹, Helle Hjalgrim¹, Ghayda Mirzaa¹, Francesco Brancati¹, Tatjana Bierhals¹, Jonas Denecke¹, Maja Hempel¹, Johannes R Lemke¹, Guido Rubboli¹, Petra Muschke¹, Renzo Guerrini¹, Annalisa Vetro¹, Dierk Niessing¹, Gaetan Lesca¹, Rikke S Møller¹

Affiliation

¹ Department of Epilepsy Genetics and Precision Medicine (K.J.M., E.G., G.R., R.S.M.), The Danish Epilepsy Centre Filadelfia, Dianalund, Denmark; Institute for Regional Health Services (K.J.M., E.G., R.S.M.), University of Southern Denmark, Odense; Institute of Human Genetics (D.M., R. Jamra, A.F., J.R.L.), University of Leipzig Medical Center, Germany; Institute of Structural Biology (R. Janowski, D.N.), Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany; Department of Paediatric Radiology (C.R.), University of Leipzig Medical Center, Germany; Department of Epilepsy, Sleep and Pediatric Neurophysiology (J.T.), Lyon University Hospital, France; Neuropediatric Unit (A.-L.P., D.M.V., G.L.), Lyon University Hospital, France; Department of Medical Genetics (N.C., G.L.), Lyon University Hospital, France; GenDev Team (N.C.), CNRS UMR 5292, INSERM U1028, CNRL and University of Lyon, France; Department of Genetics (E.B.), University Medical Center Utrecht, The Netherlands; Department of Child Neurology (K.G.), Brain Center Rudolf Magnus, University Medical Center Utrecht, The Netherlands; Department of Paediatrics (A.P.B.), Copenhagen University Hospital Rigshospitalet, Denmark; Baylor College of Medicine (S.M., K.N.), Children's Hospital of San Antonio; Undiagnosed Diseases Program (G.B., C.P.), Genetic Services of Western Australia, Department of Health, Government of Western Australia, Perth; Western Australian Register of Developmental Anomalies (G.B., D.G.), Australia; Telethon Kids Institute and the School of Paediatrics and Child Health (G.B.), University of Western Australia, Perth; Linear Clinical Research (L.D.), WA, Australia; Center of Human Genetics (S.S), Jena University Hospital, Germany; Department of Neuropediatrics (A.D.), Jena University Hospital, Germany; Division of Neurology (K.L.H.), Children's Hospital of Philadelphia, PA; Division of Neuropediatrics (A.M.), University of Leipzig Medical Center, Germany; Amplexa Genetics (H.H.), Odense, Denmark; Clinic for Children (H.H.), Værløse, Denmark; Center for Integrative Brain Research (G.M.), Seattle Children's Research Institute, WA; Department of Pediatrics (G.M.), University of Washington, Seattle; Medical Genetics Unit (F.B.), Department of Life, Health and Environmental Sciences, University of L'Aquila, Italy; Istituto Dermopatico dell'Immacolata (F.B.), IDI-IRCCS, Rome, Italy; Institute of Human Genetics (T.B., M.H.), University Medical Center Hamburg-Eppendorf, Germany; Childrens Hospital (J.D.), University Medical Center Hamburg-Eppendorf, Germany; University of Copenhagen (G.R.), Denmark; Institute for Human Genetics (P.M.), University Hospital Magdeburg, Germany; Children's Hospital A. Meyer (R.G., A.V.), University of Florence, Italy; and Institute of Pharmaceutical Biotechnology (D.N.), Ulm University, Germany.

Abstract

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.