Revisiting the Genetics of Hypophosphatasia

Hypophosphatasia (HPP) is a rare, inherited monogenic disorder that is typically caused by variants in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Genetic testing for ALPL variant(s) to confirm the diagnosis in patients with suspected HPP is a standard practice based on availability. This review attempts to improve the current understanding of the genetics of HPP as it addresses five key related topics: (1) HPP patterns of inheritance and the relationship between HPP genotype and phenotype, (2) how the disease can manifest (including specific genotypes) in heterozygotes, (3) potential reasons why some patients have persistently low alkaline phosphatase activity yet lack an ALPL variant, (4) the implications of and resources for variants of uncertain significance (VUS), and (5) recent information on genetic testing in fetuses and newborns. We summarize pertinent information applicable in daily clinical practice, with the objective of preventing missed, delayed, or incorrect HPP diagnoses and improving patient care.