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Hypophosphatasia: Results of a Country-Wide Selective Screening Program Using NGS Technology as a First-Tier Test
Aleksander A Pushkov1, Ilya S Zhanin1, Daria A Chudakova1,2
1National Medical Research Center of Children's Health, Ministry of Health of the Russian Federation, 119991 Moscow, Russia.
International Journal of Molecular Sciences
|August 13, 2026
Summary
This study screened 4912 patients for Hypophosphatasia (HPP), a rare genetic disorder. Next-generation sequencing identified causal variants in the ALPL gene, improving diagnosis for this condition.
Area of Science:
- Genetics
- Metabolic Disorders
- Rare Diseases
Background:
- Hypophosphatasia (HPP) is a rare inherited metabolic disease caused by nucleotide variants (NVs) in the ALPL gene, resulting in deficient tissue-nonspecific alkaline phosphatase (TNSALP).
- HPP presents with diverse symptoms like bone/tooth mineralization defects, respiratory issues, and neurological problems, often leading to diagnostic delays due to overlapping conditions.
- Genetic screening is crucial for accurate HPP diagnosis and understanding its prevalence.
Purpose of the Study:
- To conduct a selective screening program for Hypophosphatasia (HPP) in Russia using next-generation sequencing (NGS).
- To identify causal nucleotide variants in the ALPL gene and other relevant genes in patients with suspected HPP.
- To provide comprehensive genetic data on HPP in the Russian population.
Main Methods:
- A two-center selective screening program was conducted from 2022-2026 in Moscow and Saint Petersburg, Russia.
- Next-generation sequencing (NGS) using distinct gene panels was performed on 4912 patients with suspected HPP.
- Analysis included identifying nucleotide variants in the ALPL gene and genes associated with differential diagnoses.
Main Results:
- In Moscow, 9.45% of patients had causal ALPL variants, and 9.77% had variants in other panel genes. In Saint Petersburg, 3.5% had causal ALPL variants.
- The most common ALPL variant identified was c.571G>A (28%), suggesting a founder effect.
- Pathogenic variants were frequently found in COL1A2, COL1A1, and CASR genes, indicating phenotypic overlap with osteogenesis imperfecta and related disorders.
Conclusions:
- Targeted NGS is valuable for resolving diagnostic uncertainty in HPP, especially given its phenotypic overlap with other conditions.
- The study provides extensive genetic data on HPP within the Russian population.
- Evolving screening criteria enhanced the diagnostic yield, highlighting the importance of tailored genetic testing approaches.
