Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature

Charlotte La Fay (1) , Celia Hoebeke (1) , Marine Juzaud (1) , Anne Spraul (2) , Pauline Heux (3) , Jean-Christophe Dubus (4, 5) , Alice Hadchouel (6) , Alexandre Fabre (1, 3)

1 Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM]
2 Bicêtre Hospital
3 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
4 Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM]
5 MEPHI - Microbes évolution phylogénie et infections
6 Service de Pneumologie Allergologie [CHU Necker]

Introduction Aminoacyl transfer RNA (tRNA) synthetases are associated with diseases when mutations occur in their encoding genes. Pulmonary alveolar proteinosis can be caused by mutation in the methionyl-tRNA synthetase (MARS) gene while mutations in the leucine-tRNA synthetase (LARS) gene lead to infantile liver failure syndrome type 1. We report the case of a patient with LARS1 pathogenics variants and two patients with MARS1 pathogenics variants. The aim of this study was to analyze the phenotypes of our three patients in detail and classify cases in the literature using Human Phenotype Ontology (HPO) terms. Results The first patient has two previously undescribed heterozygous variants in LARS1 (c.1818dup and c.463A>G). The other two patients' MARS1 variants (c.1177G>A and c.1700C>T) have already been described in the literature. All three patients had anemia, hepatomegaly, feeding difficulties, failure to thrive and hypoalbuminemia. Including ours, 65 patients are described in total, for whom 117 phenotypic abnormalities have been described at least once, 41.9% of which both in patients with LARS1 and MARS1 mutations. Conclusion Patients with LARS1 and MARS1 mutations seem to share a common phenotype but further deep phenotyping studies are required to clarify the details of these complex pathologies.

Keywords: tRNA synthetase deficiency; Infantile liver failure syndrome type 1; Pulmonary alveolar proteinosis; LARS1; MARS1

Domains: Life Sciences [q-bio]; Microbiology and Parasitology; Bacteriology; Life Sciences [q-bio]; Microbiology and Parasitology; Virology; Life Sciences [q-bio]; Microbiology and Parasitology; Parasitology; Life Sciences [q-bio]; Human health and pathology; Cardiology and cardiovascular system; Life Sciences [q-bio]; Human health and pathology; Emerging diseases; Life Sciences [q-bio]; Human health and pathology; Infectious diseases

Charlotte La Fay, Celia Hoebeke, Marine Juzaud, Anne Spraul, Pauline Heux, et al.. Deep phenotyping of MARS1 (interstitial lung and liver disease) and LARS1 (infantile liver failure syndrome 1) recessive multisystemic disease using Human Phenotype Ontology annotation: Overlap and differences. Case report and review of literature. European Journal of Medical Genetics, 2021, 64 (11), pp.104334. ⟨10.1016/j.ejmg.2021.104334⟩. ⟨hal-03429594⟩