To the Editor: Infantile liver failure syndrome 1 (ILFS1, OMIM #615438) is an autosomal recessive disease due to mutation in leucyl-tRNA synthetase1 gene (LARS 1; OMIM 151350) [1]. The tRNAs are short noncoding RNAs required during protein synthesis, and the related disorders are phenotypically very heterogeneous [2]. ILFS1 presents as multisystem involvement with/without liver failure. After the first description in an Irish traveller family in 2012, up to 26 cases have been reported [3].

A 2-mo-old infant presented with lethargy, refusal to feed, loose stools, and three episodes of tonic seizures which lasted for few seconds. The parents were married consanguineously and had lost 2 children to similar illness. There were signs of pallor, tachycardia, hepatomegaly, mild transaminitis, and failure to thrive. Bone marrow showed marked erythroid hypoplasia. Blood and urine culture grew acinetobacter and E. coli, respectively. Baby received intravenous antibiotics, blood transfusions, and anticonvulsants but there was little improvement. Baby required rehospitalization twice for similar complaints and finally succumbed at 5 mo of age.

As no clinical diagnosis could be reached and in view of multisystem involvement, an exome sequencing was performed which revealed a novel homozygous missense variation (c.1159G>A) in exon 12 of the LARS1 gene (chr5:g.145533368C>T; Depth: 114x) that results in the amino acid substitution of serine for glycine at codon 387 (p.Gly387Ser; ENST00000394434.2). The reference codon is conserved across species. Parents tested heterozygous for the variation in Sanger sequencing. The variant was interpreted as likely pathogenic (PM2, PM3, PP2, PP3, PP4) using ACMG 2015 criteria [4]. The presentation and the mutation result confirmed ILFS1.

The manifestations of ILFS1 become more apparent or get triggered during infection/illness. The clinical features are nonspecific and are common with sepsis, systemic illness, hemophagocytic lymphohistiocytosis, and inborn errors of metabolism. In cases of recurrent transaminitis with encephalopathy, failure to thrive, anemia, seizures, and developmental delay, the threshold for testing of LARS 1 gene mutation should be low. In such highly fatal inherited disorders with heterogeneous phenotypic manifestations, molecular diagnosis helps in counseling and prenatal testing to prevent recurrences.