ALPL was first reported in relation to* ALPL*-related autosomal recessive hypophosphatasia in 1988 (Weiss et al., PMID: 3174660). ALPL-related autosomal recessive hypophosphatasia is 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. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following autosomal recessive disease entities (Hypophosphatasia, adult, MIM:146300; Hypophosphatasia, childhood, MIM: 241510; Hypophosphatasia, infantile, MIM:241500; Odontohypophosphatasia, MIM:146300) have been lumped into one disease entity, ALPL-related autosomal recessive hypophosphatasia. The split curation for ALPL-related autosomal dominant hypophosphatasia has been curated separately.
14 missense, 2 splicing, and 1 nonsense variants that have been reported in 11 probands in 4 publications (PMIDs: 3174660, 1409720, 32160374, 25731960) 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 relationship is also supported by animal models and a rescue study (PMIDs: 30446691, 18086009, 10620060, 14982838). In summary, there is definitive evidence supporting the relationship between ALPL and ALPL-related autosomal recessive 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 January 19th, 2021 (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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