Mutations in ALPL, which encodes tissue-nonspecific isozyme alkaline phosphatase (TNSALP), cause hypophosphatasia (HPP). HPP is suspected by a low serum alkaline phosphatase (AlkP). We hypothesized that some patients with bone or dental disease have undiagnosed HPP caused by ALPL variants. Our objective was to discover the prevalence of these gene variants in the Vanderbilt DNA biobank (BioVU) and to assess phenotypic associations.
We identified subjects in BioVU, a repository of DNA, that had at least one of three known rare HPP disease-causing variants in ALPL: rs199669988, rs121918007, rs121918002. To evaluate for new phenotypic associations we conducted a sequential Phenome-wide Association Study (PheWAS) of ALPL variants and then performed a de-identified manual record review to refine the phenotype.
Out of 25,822 genotyped individuals, we identified 52 females and 53 males with HPP disease causing variants in ALPL, 7/1000. None had a clinical diagnosis of HPP. For patients with ALPL variants, the average serum AlkP levels were in the lower range of normal or lower. Forty percent of men and sixty-two percent of women had documented bone and/or dental disease compatible with the diagnosis of HPP. Forty percent of the female patients had ovarian pathology or other gynecological abnormalities compared 15% seen in controls.
Variants in the ALPL gene cause bone and dental disease in patients with and without the standard biomarker, low plasma AlkP. ALPL gene variants are more prevalent than currently reported and under diagnosed. Gynecologic disease appears to be associated with HPP-causing variants in ALPL.
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