ArticleJournal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research2026
Hypophosphatasia: low penetrance of pathogenic and likely-pathogenic ALPL variants identified through an unselected biorepository.
Article in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Hypophosphatasia (HPP) is a heritable multisystem disorder caused by pathogenic variants in the tissue nonspecific alkaline phosphatase (ALP)-coding gene ALPL. The genotype-phenotype correlation in heterozygous adults with HPP remains incompletely understood. In this genotype-based study, we aimed to measure the prevalence of pathogenic or likely-pathogenic ALPL variants and to test the hypothesis that HPP penetrance is low in adult carriers. A total of 37 147 genomes from unselected individuals visiting a tertiary care, academic medical center were investigated. Variants classified as pathogenic or likely-pathogenic were observed with a prevalence of 0.3% (n = 109) or 1/341. Variant c.571G>A was most frequent (67.9%). A subset of 70 individuals had linked electronic health records (EHRs) and were termed ALPL+. All 70 ALPL+ individuals showed mild, mainly neurological, symptoms often reported in adults with HPP. However, low serum ALP, a hallmark of HPP, was found in only 65.7% (38/70) of ALPL+ individuals, and 12.9% (9/70) met the diagnostic criteria for HPP based on consensus guidelines, thus complete penetrance was low. Compared to controls lacking pathogenic or likely-pathogenic variants (ALPL-), the ALPL+ individuals had a higher probability of progression for mobility issues (median age 73 yr ALPL+ vs 82 yr ALPL-, p = .03), as well as a similar probability of progression for fatigue, arthritis, or dental problems. Unexpectedly, 3.4% (5/148) of individuals in the ALPL- group met the diagnostic criteria for HPP, possibly due to unidentified variants or non-ALPL genetic factors. Overall, the data support our hypothesis and aids the management of carriers of pathogenic ALPL variants.
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