Novel neuroblastoma amplified sequence (NBAS) mutations in a Japanese boy with fever-triggered recurrent acute liver failure

Biallelic mutations in the neuroblastoma amplified sequence ( NBAS ) gene have been reported to cause two different clinical spectra: short stature with optic nerve atrophy and Pelger-Huët anomaly (SOPH) syndrome and infantile liver failure syndrome 2 (ILFS2). Here, we describe a case of a 3-year-old Japanese boy who presented with fever-triggered recurrent acute liver failure (ALF). The clinical characteristics were considerable elevation of liver enzymes, severe coagulopathy, and acute renal failure. In addition to the liver phenotype, he had short stature and Pelger-Huët anomaly in the peripheral granulocytes. Whole-exome and Sanger sequencing of the patient and his parents revealed that he carried novel compound heterozygous missense mutations in NBAS , c.1018G>C (p.Gly340Arg) and c.2674 G>T (p.Val892Phe). Both mutations affect evolutionarily conserved amino acid residues and are predicted to be highly damaging. Immunoblot analysis of the patient’s skin fibroblasts showed a normal NBAS protein level but a reduced protein level of its interaction partner, p31, involved in Golgi-to-endoplasmic reticulum retrograde vesicular trafficking. We recommend NBAS gene analysis in children with unexplained fever-triggered recurrent ALF or liver dysfunction. Early antipyretic therapy may prevent further episodes of ALF. Liver disease: Mutations associated with recurrent liver failure Novel mutations in a gene called NBAS have been identified in a Japanese boy with recurrent acute liver failure. Researchers led by Junko Matsuda from Kawasaki Medical School, Okayama, Japan, searched for the genetic cause of a young boy’s recurrent episodes of fever-triggered liver dysfunction. They sequenced the entire protein-coding portion of his genome and that of his parents. They found that the boy had inherited two defective copies of the NBAS (neuroblastoma amplified sequence) gene, one from each parent. Laboratory experiments indicated that these mutations impaired the ability of the protein encoded by NBAS to function correctly. The authors recommend testing for NBAS mutations in any children with unexplained liver problems, and then treating with fever-reducing therapies to prevent future life-threatening episodes of liver failure.