#418 Hypophosphatasia Genetics: One Gene, Many Presentations

How can variants in the same gene cause life-threatening disease in infancy for some individuals, while others experience mild symptoms or remain asymptomatic? Hypophosphatasia (HPP) challenges traditional expectations about genetic inheritance, with both autosomal dominant and autosomal recessive forms and a remarkably broad spectrum of clinical presentations.

In this episode, recorded in person in Nashville, our guest is Dr. Kathryn Dahir, Professor of Medicine in the Division of Diabetes, Endocrinology, and Metabolism at Vanderbilt University Medical Center and Director of the Program for Metabolic Bone Disorders. Drawing on decades of experience caring for patients with rare skeletal conditions, Dr. Dahir explores the complex genetics of HPP and why understanding a patient's clinical presentation is just as important as interpreting their genetic test results.

The conversation begins with a patient case that challenged Dr. Dahir's understanding of HPP. Initially treated for osteoporosis, the patient experienced recurrent fractures and worsening symptoms despite treatment. Further investigation revealed impaired bone mineralization, low alkaline phosphatase (ALP), and a single ALPL variant, illustrating how individuals with one affected copy of the gene can experience significant disease. Dr. Dahir explains how the ALPL gene encodes tissue-nonspecific alkaline phosphatase (TNSALP), an enzyme essential for healthy bone mineralization, and how disruption of its activity contributes to the manifestations of HPP.

We explore the differences between autosomal dominant and autosomal recessive inheritance, the challenges of predicting disease severity from genetic testing alone, and why even relatives carrying the same ALPL variant may have very different symptoms. Dr. Dahir discusses the importance of identifying variants in cis or trans, recognizing deletions and duplications, evaluating variants of uncertain significance, and considering how genetic modifiers, environmental exposures, and coexisting conditions can influence a patient's presentation.

Finally, we discuss the evolving landscape of HPP genetic testing, including the importance of longitudinal follow-up, resources such as the global ALPL variant database, and ongoing efforts to improve variant classification. As genomic testing becomes increasingly accessible, this conversation highlights both its potential to improve rare disease diagnosis and the limitations of using genetics alone to predict an individual's future health.

Episode Discussion Topics

• Dr. Dahir's clinical experience treating HPP and other rare metabolic bone disorders at Vanderbilt University Medical Center
• Why genetic testing must be interpreted alongside clinical symptoms, biochemical findings, and patient history
• A patient case illustrating how HPP can be mistaken for osteoporosis and why low alkaline phosphatase is an important diagnostic clue
• How the ALPL gene and tissue-nonspecific alkaline phosphatase (TNSALP) regulate bone mineralization
• The differences between autosomal dominant and autosomal recessive HPP and the challenges of distinguishing affected individuals from asymptomatic carriers
• Why genotype-phenotype correlations in HPP are complex, even among family members with the same genetic variant
• The importance of determining whether variants are in cis or trans and identifying deletions or duplications that some testing platforms may miss
• How modifier genes, epigenetics, medication exposures, and coexisting medical conditions may influence HPP symptoms and severity
• Interpreting variants of uncertain significance and the importance of genetic counseling, variant reclassification, and long-term follow-up
• The role of