NBAS-Related Disorders via the NBAS Gene

Infantile liver failure syndrome is a life-threatening condition characterized by recurrent episodes of acute liver failure in infancy or early childhood. Recurrent acute liver failure (RALF) triggered by febrile infections can be caused by biallelic pathogenic variants in the NBAS gene (Haack et al. 2015. PubMed ID: 26073778). Liver function can be recovered completely with conservative management during the interval between infections. NBAS deficiency can lead to isolated RALF only or a multisystemic disorder with short stature, skeletal dysplasia, immunological abnormalities, and optic atrophy (resembling SOPH syndrome - short stature, optic nerve atrophy, and Pelger-Huet anomaly) (Staufner et al. 2016. PubMed ID: 26541327).

Infantile liver failure syndrome is an autosomal recessive disorder caused by defects in the NBAS gene or, much less frequently, in the LARS gene (Haack et al. 2015. PubMed ID: 26073778; Staufner et al. 2016. PubMed ID: 26541327; Casey et al. 2012. PubMed ID: 22607940).

The protein encoded by the NBAS gene (52 coding exons) is considered a component of a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. It is suggested to interact with partner p31, both involved in retrograde transport between endoplasmic reticulum (ER) and Golgi. Genetic defects within the NBAS gene include missense and various truncating variants (nonsense, splicing and frameshift) (Human Gene Mutation Database). Gross deletions have been also reported (Human Gene Mutation Database). Notably, most patients with hepatic phenotype have pathogenic variants within or before the sec39 domain of NBAS (amino acids 725–1376) (Staufner et al. 2016. PubMed ID: 26541327).

Sequencing of the NBAS gene in 15 unrelated individuals with recurrent acute liver failure (RALF) or acute liver failure (ALF) revealed biallelic pathogenic variants in five families (33%) (Haack et al. 2015. PubMed ID: 26073778).

So far, only two large deletions have been reported in the NBAS gene (Staufner et al. 2016. PubMed ID: 26541327).

This test provides full coverage of all coding exons of the NBAS gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).