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

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.

Figure 1. Spectrum of structural brain anomalies in QARS-associated microcephaly

MRI data sets of the new patients 1 (1a,b), 2 (2a,c at 14 weeks; 2b,d at 9 4/12 years), 3 (3a at 6 years; 3b,c,d at 10 years), 5 (5a,b at 27 months), 7 (7a,b at 5 weeks), 8 (8a,c at 1 week; 8b,d at 19 weeks), and 9 (9a,b). Cortical structural anomalies: axial magnetic resonance (MR) images show generalized atrophic supratentorial cerebral volume loss and enlargement of ventricles with progressive atrophy (2 and 8), severe pachygyria (1, 2, 7, 8, and 9), and moderate pachygyria (3 and 5). Trim and flair sequences in patient 3 (3a,b) demonstrate progressive cerebral demyelination. Corpus callosum: sagittal MR images show a spectrum of anomalies of the corpus callosum with relative thinning (3, 6, 7, and 8) and complete atrophy (2, 2d at follow-up).

Figure 2. Photographs of patients 2, 7, 9, and 10

Patients 2, 7, 9, and 10 show mild facial dysmorphism, including narrow foreheads, as would be expected in children with microcephaly, sparse eyebrows, long nose with upturned tip of the nose, dystopia canthorum, dysconjugate gaze, full cheeks, and downturned corners of the mouth.

Figure 3. QARS domains and distribution of variants

Observed QARS variants in a schematic illustration; NTD involved in RNA binding, CATD, and ABD. Novel variants (full arrows), published variants (empty arrows, gray). New and published QARS variants are listed in table e-3 (links.lww.com/NXG/A197). Protein Ref Seq NP_005042.1. ABD = anticodon-binding domain; CATD = catalytic domain; NTD = N-terminal domain.