Bi‐allelic IARS mutations in a child with intra‐uterine growth retardation, neonatal cholestasis, and mild developmental delay

• Published in: Clinical genetics Vol. 91; no. 6; pp. 913 - 917
• Main Authors: Orenstein, N., Weiss, K., Oprescu, S.N., Shapira, R., Kidron, D., Vanagaite‐Basel, L., Antonellis, A., Muenke, M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2017
• Subjects: Alleles; Amino Acid Sequence - genetics; Cholestasis; Cholestasis - genetics; Cholestasis - pathology; connective tissue; development; Developmental disabilities; Developmental Disabilities - genetics; Developmental Disabilities - pathology; Exome Sequencing; Fetal Growth Retardation - genetics; Fetal Growth Retardation - pathology; Gallbladder diseases; Genetic disorders; Genetic Predisposition to Disease; growth; Growth rate; Homozygote; Humans; Hypervitaminosis; IARS; Infant; Infant, Newborn; Isoleucine-tRNA ligase; Isoleucine-tRNA Ligase - genetics; Liver; Liver - pathology; Male; Mutation; Neonates; Neurodevelopmental disorders; Pedigree; Skin; tRNA; Uterus; vitamin D; development; growth; IARS; cholestasis; connective tissue; vitamin D
• ISSN: 0009-9163; 1399-0004; 1399-0004
• DOI: 10.1111/cge.12930

Recently, bi‐allelic mutations in cytosolic isoleucyl‐tRNA synthetase (IARS) have been described in three individuals with growth delay, hepatic dysfunction, and neurodevelopmental disabilities. Here we report an additional subject with this condition identified by whole‐exome sequencing. Our findings support the association between this disorder and neonatal cholestasis with distinct liver pathology. Furthermore, we provide functional data on two novel missense substitutions and expand the phenotype to include mild developmental delay, skin hyper‐elasticity, and hypervitaminosis D.