Hypophosphatasia: Results of a Country-Wide Selective Screening Program Using NGS Technology as a First-Tier Test

Hypophosphatasia (HPP) is a rare hereditary metabolic disorder caused by nucleotide variants (NVs) in the ALPL gene, leading to a deficiency of tissue-nonspecific alkaline phosphatase (TNSALP). HPP has a variable clinical presentation (such as impaired mineralization of bones and teeth, respiratory dysfunctions, muscle weakness, muscle and bone pain, growth deficiency, nephrocalcinosis, seizures, encephalopathy, intracranial hypertension, and intellectual disability) overlapping with other disorders which often delays a correct diagnosis. In this study, we present the results of a two-center (Moscow and Saint Petersburg) selective screening program conducted in the period 2022–2026 in Russia, based on next-generation sequencing (NGS) of 4912 patients with suspected HPP. Each center used its own NGS gene panel. In Moscow, causal nucleotide variants in ALPL were found in 9.45% of patients, and variants in other genes from the panel were identified in 9.77% of patients. The selection criteria for the screening evolved during the study, resulting in a higher diagnostic yield. In Saint Petersburg, causal variants in ALPL were found in 3.5% of patients. The most frequent ALPL variant was c.571G>A (28%), which is consistent with its founder effect in Northern Europe. In the differential diagnosis gene panel, pathogenic or likely pathogenic variants were most commonly found in the COL1A2, COL1A1, and CASR genes, highlighting the phenotypic overlap of HPP with osteogenesis imperfecta and related disorders, and underscoring the value of targeted NGS for resolving diagnostic uncertainty in HPP. Overall, this study provides the most comprehensive data on the genetics of HPP in the Russian population to date.