Argininosuccinate Lyase Deficiency via the ASL Gene

Urea cycle defects are characterized by (1) hyperammonemia, (2) encephalopathy, and (3) respiratory alkalosis. Five clinical disorders have been described involving defective urea cycle enzymes: ornithine transcarbamolase deficiency (OMIM 311250), carbamoyl phosphate synthetase deficiency (OMIM 237300), argininosuccinate synthetase deficiency (Citrullinemia Type I; OMIM 215700), argininosuccinate lyase deficiency (OMIM 207900), and arginase deficiency (OMIM 207800).

Argininosuccinate lyase deficiency (ASLD) is the second most common urea cycle disorder with an estimated prevalence of 1:70,000 live births and has variable clinical presentation (Tuchman et al. 2008; Nagamani et al. 2012). Severe neonatal-onset of ASLD is characterized by acute life-threatening hyperammonemia, similar to that of other early-onset urea cycle disorders. The presence of hepatomegaly and trichorrhexis nodosa (fragile hair) at the neonatal stage may be suggestive of ASLD. The clinical presentation of late-onset ASLD is characterized by episodic hyperammonemia and/or manifestations unrelated to hyperammonemia. The latter features are unique to ASLD, including neurocognitive deficiencies, impaired liver function, hepatomegaly, liver fibrosis, trichorrhexis nodosa, and hypertension (Tuchman et al. 2008; Nagamani et al. 2012; Ficicioglu et al. 2009). First-line treatments for ASLD are lifelong dietary protein restriction and arginine base supplementation (Erez et al. 2011).

Argininosuccinate lyase deficiency is an autosomal recessive disorder that results from pathogenic variants in the ASL gene. Argininosuccinate lyase, which is expressed in a wide variety of tissues, cleaves argininosuccinate to arginine and fumarate in the urea cycle and is the only enzyme generating endogenous arginine in the body (Nagamani et al. 2012). Over 130 different pathogenic variants in the ASL gene have been reported. Missense and nonsense variants are the predominant types, and there is only one gross deletion reported (Balmer et al. 2014; Human Gene Mutation Database). The c.1153C>T variant is a founder mutation in the Finnish population, and the c.1060C>T and c.346C>T variants are two founder mutations commonly present in individuals of Arab ancestry (Nagamani et al. 2012.).

Sensitivity of this test appears to be very high. Pathogenic variants can be detected in about 90% of patients affected with ASLD via sequence analysis of the ASL coding region (Nagamani et al. 2012).

Gross deletion and duplication variants appear to be rare. Only one large deletion has been reported to date in which exons 2-5 was deleted with a change c.12+651_c.447-233del9609 (Balmer et al. 2014).

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