ALPL has been described in association with autosomal recessive moderate hypophosphatasia (Taillandier et al., 2000; PMID:10679946). Moderate hypophosphatasia is a rare, moderate form of hypophosphatasia characterized by defective mineralization of bone and/or teeth, premature loss of teeth with intact roots, and reduced serum alkaline phosphatase (ALP) activity. Individuals can present with this form of hypophosphatasia in infancy, childhood, or adulthood. Based upon the severity and mode of inheritance of the hypophosphatasia clinical subtypes, the curations for autosomal recessive severe hypophosphatasia, autosomal dominant moderate hypophosphatasia, and autosomal dominant mild hypophosphatasia have been split and curated separately (PMID: 32973344). Eighteen variants (missense, splice, frameshift) that have been reported in 12 probands in 3 publications (PMIDs: 10679946, 25731960, 32160374) 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 disease is reported to be loss of function. This gene-disease association is also supported by an animal model (PMID: 30446691). In summary, ALPL is definitively associated with autosomal recessive moderate hypophosphatasia. 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 Skeletal Disorders GCEP on the meeting date 1/19/21 (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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