SUN-756 - Out of Sight, Out of Mind: Characterizing the Mutational Landscape of ALPL and Associated Clinical Records of People with African Ancestry Highlights Diagnostic Failure of HPP in This Population

Hypophosphatasia (HPP) is a rare metabolic bone disease caused by pathogenic variants in the alkaline phosphatase–liver (ALPL) gene, leading to skeletal deformities, impaired growth, premature tooth loss, fractures, muscle weakness, and joint pain. In the United States, reported cases among Black/African American individuals are disproportionately few, and HPP has been described as particularly uncommon. Previous studies report that pathogenic variants in ALPL are often found on a European ancestry background, suggesting that Black/African Americans with HPP likely inherit pathogenicity from a European ancestor due to their complex genetic admixture.

This population may remain unrecognized due to disease presentations that fall outside established descriptions (e.g., phenotypic heterogeneity, subtlety of mild-to-moderate disease, reliance on clinical suspicion to prompt genetic testing). Variant interpretation in underrepresented groups may also be biased due to reference genomes lacking ancestral diversity, potentially resulting in inaccurate pathogenicity assessments. We hypothesize that genetic ancestral context, reflected in global and local ancestry, may influence disease expression and provide insights to improve diagnostic criteria for HPP in Black/African American individuals.

We deployed a phenotyping algorithm identifying pathogenic ALPL variants in ~35k whole-genome sequenced admixed individuals with majority African ancestry from the Alliance for Genomic Discovery dataset, identifying 93 heterozygous carriers and 34,366 non-carriers. We phased our cohort using SHAPEIT5 and inferred local ancestry using RFMIX v.2. We found significant differences in European ancestry proportions both globally and across ALPL among carriers and non-carriers.

Local ancestry analysis identified 17 carriers with homozygous diploid African ancestry at their ALPL mutation, and manual chart review revealed persistently low alkaline phosphatase levels, fractures, hearing loss, impaired mobility, chronic pain, joint dislocations, arthritis, early loss of secondary teeth, fatigue, and psychological distress, with some women also experiencing recurrent pregnancy loss and infertility misattributed to fibromyalgia. Many individuals exhibited a preventable diagnostic failure or delay driven by fragmented care, failure to recognize persistently low alkaline phosphatase as pathologic, and lack of integration of genetic findings with clinical presentation, possibly due to reduced clinical suspicion.

These findings demonstrate the presence of pathogenic ALPL variants on a diploid African ancestry background and highlight the need to expand established descriptions of HPP. Improving ancestry-aware diagnostic criteria may reduce misdiagnosis, prevent years of untreated disease, and mitigate substantial physical and psychological harm.

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