Severe growth deficiency, microcephaly, intellectual disability, and characteristic facial features are due to a homozygous QARS mutation

Abstract

Glutaminyl tRNA synthase is highly expressed in the developing fetal human brain. Mutations in the glutaminyl-tRNA synthetase (QARS) gene have been reported in patients with progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. We have previously reported a new recessive syndrome of severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and intellectual disability in two sisters of Ashkenazi-Jewish origin (Eur J Med Genet 2014;57(6):288-92). Homozygosity mapping and whole exome sequencing revealed a homozygous missense (V476I) mutation in the QARS gene, located in the catalytic domain. The patient's fibroblasts demonstrated markedly reduced QARS amino acylation activity in vitro. Furthermore, the same homozygous mutation was found in an unrelated girl of Ashkenazi origin with the same phenotype. The clinical presentation of our patients differs from the original QARS-associated syndrome in the severe postnatal growth failure, absence of epilepsy, and minor MRI findings, thus further expanding the phenotypic spectrum of the glutaminyl-tRNA synthetase deficiency syndromes.

Aminoacyl-tRNA synthetase deficiencies in search of common themes

“…Similarly, sensorineural hearing impairment is frequently seen in other mitochondrial ARS deficiencies, including LARS2, HARS2, RARS2, 55 and IARS2. 54 However, anemia and hypoalbuminemia in our KARS deficient patient and hepatosplenomegaly during infancy in QARS deficiencies 46 might imply involvement of the cytosolic ARS deficiency. Conversely, although the multiorgan phenotype might suggest a mitochondriopathy, we did not find evidence for mitochondrial dysfunction caused directly by the cytosolic ARS deficiency.…”

“…It remains unclear why other highly proliferative organs like the skin are not affected, except in one patient with IARS deficiency and skin hyperelasticity 37 and two sibs with QARS deficiency with a dry rough skin. 46 PAP was previously thought to be a specific feature of MARS deficiency. [33][34][35] We show that other recessive ARS deficiencies (IARS and LARS) can also cause PAP.…”

“…5b). Concurrently, aminoacylation activity was decreased in mutant alleles from patients with AARS, 31,32 MARS, 33,34 IARS, 36 HARS, 42 SARS, 43 QARS, 44,46 and KARS 26 deficiencies, but never to an enzyme activity of <8% from normal (Table S2). The fact that heterozygous parents of patients are unaffected suggests that on the other hand there is some excess capacity in ARS activity.…”

“…The clinical presentation of these mitochondrial diseases was reported to depend on the affected ARS, with encephalopathy as the most common manifestation. Only in the past 5 years have homozygous and compound heterozygous pathogenic variations been identified in cytosolic LARS, 29,30 AARS, 31,32 MARS, [33][34][35] IARS, 36,37 YARS, 38 VARS, 39 RARS, 40 DARS, 41 HARS, 42 SARS, 43 and in the combined cytosolic and mitochondrial QARS, [44][45][46][47] GARS, [48][49][50] and KARS 26,[51][52][53][54] genes. The resulting autosomal recessive diseases show considerable clinical variability and involve numerous organs without apparent logic.…”

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

“…Further reports confirmed both nonsense and missense variants in QARS as pathogenic. 2,[11][12][13][14][15] The phenotype has been generally consistent with progressive microcephaly, cerebral atrophy, severe ID, and drug-resistant epilepsy. However, among the 12 published patients, a small subgroup with homozygous deleterious variants seems to display a milder phenotype.…”