ALPL has been described in association with autosomal dominant mild hypophosphatasia (Taillandier et al., 2018; PMID:29236161). Mild hypophosphatasia is the most common form of hypophosphatasia characterized by low serum alkaline phosphatase, nonspecific clinical signs, and typically presents in individuals in adulthood. This condition can and has been reported to progress to more severe forms in patients. Based upon the severity and mode of inheritance of the hypophosphatasia clinical subtypes, the curations for autosomal recessive severe hypophosphatasia, autosomal recessive moderate hypophosphatasia, and autosomal dominant moderate hypophosphatasia have been split and curated separately (PMID: 32973344). Twelve variants (missense, frameshift, splice, nonsense) that have been reported in twelve probands in 3 publications (PMIDs: 29236161, 30864637, 33191482) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by an mRNA expression study (GTEx, Illumina, BioGPS, and SAGE; https://www.genecards.org/cgi-bin/carddisp.pl?gene=ALPL&keywords=alpl#expression). In summary, ALPL is definitively associated with autosomal dominant mild hypophosphatasia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was approved by the ClinGen Skeletal Disorders Gene Curation Expert Panel on 5/19/21 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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