Hypophosphatasia: low penetrance of pathogenic and likely-pathogenic ALPL variants identified through an unselected biorepository

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.