United States Hypophosphatasia Molecular Research Center
This study is being done to determine if cryptic alterations exist within or near to the ALPL gene in patients with a clinical diagnosis of hypophosphatasia, but without identifiable alteration on commercial testing. Additionally, the study aims to characterize functional effects of certain variants of uncertain significance in patients with clinical diagnosis of hypophosphatasia.
∙ Aim 1-
• Diagnosis of Hypophosphatasia based on clinical features that include
‣ History consistent with diagnosis of hypophosphatasia AND
⁃ Physical examination findings consistent with a diagnosis of hypophosphatasia AND
⁃ Presence of low serum alkaline phosphatase level for age and sex AND
⁃ Elevation of at least one natural substrate of alkaline phosphatase
• Lack of detection of a variant on molecular analysis of the ALPL gene. When possible, first degree relatives (parents, siblings, or child) will be included for the sole purpose of trio testing. No additional information will be collected on first degree relatives.
∙ Aim 2-
• Missense variant in ALPL which is interpreted as a variant of uncertain significance by the American College of Medical Genetics Guidelines for Variant Interpretation
• Variant has been interpreted as pathogenic, likely pathogenic, likely benign, or benign using ex-US interpretation guidelines