Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients

Genet Med. 2020 Mar;22(3):610-621. doi: 10.1038/s41436-019-0698-4. Epub 2019 Nov 25.


Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis.

Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods.

Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH).

Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

Keywords: NBAS; RALF; SOPH syndrome; acute liver failure; infantile liver failure syndrome type 2.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Brain / pathology
  • Child
  • Child, Preschool
  • Female
  • Genetic Diseases, Inborn / genetics*
  • Genetic Diseases, Inborn / pathology
  • Genetic Predisposition to Disease*
  • Humans
  • Infant
  • Liver / pathology
  • Liver Transplantation / adverse effects
  • Male
  • Muscle, Skeletal / pathology
  • Mutation, Missense / genetics
  • Neoplasm Proteins / genetics*
  • Phenotype


  • NBAS protein, human
  • Neoplasm Proteins