Farber Lipogranulomatosis via the ASAH1 Gene

Farber lipogranulomatosis or Farber disease (OMIM 228000) is a rare lysosomal storage disorder due to deficiency in the lysosomal enzyme acid ceramidase (Farber, AMA Am J Dis Child 84:499-500, 1952; Sugita et al. Science 178:1100-1102, 1972). The enzymatic deficiency results in the accumulation of ceramide and ganglioside in various tissues including the skin, kidney, and brain. Symptoms usually begin during infancy and death occurs within the first years of life. Patients with milder forms, later onset, and longer life span have been reported. Farber disease is characterized by a hoarse cry, difficulty in feeding, and subcutaneous nodules (lipogranuloma), usually near the interphalangeal, wrist, elbow, and ankle joints. These manifestations are painful and lead to progressive joint deformations. Additional features may include variable degrees of nervous system, lung, heart, lymph node, spleen, and liver impairment (Moser et al. In The Metabolic and Molecular Bases of Inherited Disease:3573-3585, 2001; Edited by Scriver et al.).

Farber disease is inherited in an autosomal recessive manner. Variants in the ASAH1 gene are responsible for the acid ceramidase deficiency and subsequent development of the disease (Koch et al. J Biol Chem 271:33110-33115, 1996). To date, about 20 variants, distributed along the entire coding region of the gene, have been detected in patients with Farber disease from various populations. Nearly all reported variants were missense, although a frameshift and two splicing variants were also reported (http://www.hgmd.org/). Most variants are private (Muramatsu et al. J Inherit Metab Dis 25:585-592, 2002). In mice, deletion of the entire gene leads to embryonic lethality (Li et al. Genomics 79:218-224, 2002).

The ASAH1 gene encodes a heterodimeric protein consisting of a nonglycosylated alpha subunit and a glycosylated beta subunit that is cleaved post-translationally to form the mature enzyme. The ceramidase enzyme catalyzes the degradation of ceramide into sphingosine and fatty acid.

Unknown at this time.

This test provides full coverage of all coding exons of the ASAH1 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).