ADSL was first reported in relation to autosomal recessive adenylosuccinate lyase (ADSL) deficiency in 1984 (PMID: 6150139). ADSL deficiency results in psychomotor retardation, seizures, hypotonia and autistic behaviors, and encompasses a wide phenotypic spectrum with three forms: neonatal fatal, severe (type I) and mild (type II) (PMIDs: 10888601, 18524658, 25112391). ADSL deficiency is diagnosed biochemically by the presence of two compounds, succinylaminoimidazole cardoxamide riboside (SAICAr) and succinyladenosine (S-Ado), that occur as a result of deficient ADSL enzyme function. At least 80 patients with ADSL deficiency have been reported to date with over 50 variants identified, including missense, nonsense, frameshift and in-frame indels (PMIDs: 10888601, 18524658, 25112391). Pathogenic ADSL variants result in decreased or impaired ADSL enzyme function, indicating homozygous loss-of-function as the mechanism of pathogenicity. This gene-disease relationship is also supported by biochemical function and functional assays (PMID: 20127976).
In summary, there is definitive evidence supporting the relationship between ADSL and autosomal recessive ADSL deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 7, 2020 (SOP Version 7).
ADSL was first reported in association with autosomal recessive adenylosuccinate lyase (ADSL) deficiency in 1984 (PMID: 6150139). ADSL deficiency results in psychomotor retardation, seizures, hypotonia and autistic behaviors, and encompasses a wide phenotypic spectrum with three forms: neonatal fatal, severe (type I) and mild (type II) (PMID: 25112391, 18524658, 10888601). ADSL deficiency is diagnosed biochemically by the presence of two compounds, succinylaminoimidazole cardoxamide riboside (SAICAr) and succinyladenosine (S-Ado), that occur as a result of deficient ADSL enzyme function. At least 80 patients with ADSL deficiency have been reported to date with over 50 variants identified, including missense, nonsense, frameshift and in-frame indels (PMID: 25112391, 18524658, 10888601). Pathogenic ADSL variants result in decreased or impaired ADSL enzyme function, indicating homozygous loss-of-function as the mechanism of disease. The gene-disease association is further supported by biochemical and functional assays (PMID: 20127976). In summary, the ADSL gene is definitively associated with autosomal recessive ADSL deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Working Group on 09/07/2020 (SOP Version 7).
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