ALPL was reported in relation to autosomal recessive severe hypophosphatasia as early as 1988 (Weiss et al., PMID: 3174660). Severe hypophosphatasia is a rare, severe form of hypophosphatasia characterized by infantile rickets without elevated serum alkaline phosphatase (ALP) activity and a wide range of clinical manifestations due to hypomineralization. Individuals often present with these features in infancy or in the perinatal period. Based upon the severity and mode of inheritance of the hypophosphatasia clinical subtypes, the curations for autosomal recessive moderate hypophosphatasia, autosomal dominant moderate hypophosphatasia, and autosomal dominant mild hypophosphatasia have been split and curated separately (PMID: 32973344). Sixteen variants (missense, nonsense, splice) that have been reported in 9 probands in 6 publications (PMIDs: 3174660, 1409720, 18523927, 17922851, 29159075, 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 animal models and a rescue study (PMIDs: 10620060, 14982838, 30700765, 18086009). In summary, ALPL is definitively associated with autosomal recessive severe 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 11/4/20 (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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