ArticleEuropean journal of human genetics : EJHG2021
Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation.
Article in European journal of human genetics : EJHG, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed.
- Article
- Low alkaline phosphatase in adults: implications for the diagnosis of hypophosphatasia during evaluation for osteoporosis.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2026Article
- Hypophosphatasia: Results of a Country-Wide Selective Screening Program Using NGS Technology as a First-Tier Test.International journal of molecular sciences · 2026Article
- Evolving Therapeutic Paradigms in Pediatric Hypophosphatasia: From Survival-Driven Care to Integrated Precision Management.International journal of molecular sciences · 2026Review
- Integrated Genetic and Biochemical Approach to Patients with Bone Disorders Exhibiting Low Alkaline Phosphatase.Calcified tissue international · 2026Article
- Hypophosphatasia: low penetrance of pathogenic and likely-pathogenic ALPL variants identified through an unselected biorepository.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2026Article
- Biochemical phenotype of hypophosphatasia in asymptomatic individuals carrying ALPL variants.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research · 2026Article
- Tissue nonspecific and intestinal alkaline phosphatase crosstalk: a missing link in hypophosphatasia pathophysiology?Journal of translational medicine · 2026Article
- Intrafamilial phenotypic variability in hypophosphatasia: evidence from two families and the literature.Frontiers in endocrinology · 2026Review
- Article
- Tissue-nonspecific alkaline phosphatase deficiency is associated with altered immune cell profiles in hypophosphatasia.Frontiers in immunology · 2026Article
- Infantile hypophosphatasia caused by compound heterozygous variants in theAmerican journal of translational research · 2026Article
- The Challenge of Hypophosphatasia Diagnosis in Patients with Fibromyalgia.Medical principles and practice : international journal of the Kuwait University, Health Science Centre · 2026Article
- Review
- The Global Hypophosphatasia Registry: lessons learned from a decade of real-world data.Orphanet journal of rare diseases · 2025Review
- Revisiting the Genetics of Hypophosphatasia.Journal of inherited metabolic disease · 2025Review
- A novel dominant negative variant ofJBMR plus · 2025Article
- AI-assisted phenotyping in a zebrafish hypophosphatasia model enables early and precise detection of skeletal alterations.Scientific reports · 2025Article
- Pathophysiology of Femoral Fractures in Hypophosphatasia.Current osteoporosis reports · 2025Review
- Article
11 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Hypophosphatasia (HPP) is caused by pathogenic variants in the ALPL gene. There is a large continuum in the severity, ranging from a lethal perinatal form to dental issues. We analyzed a cohort of 424 HPP patients from European geographic origin or ancestry. Using 3D modeling and results of functional tests we classified ALPL pathogenic variants according to their dominant negative effect (DNE) and their severity. The cohort was described by the genotypes resulting from alleles s (severe recessive), Sd (severe dominant), and m (moderate). Many recurrent variants showed a regional anchor pointing out founder effects rather than multiple mutational events. Homozygosity was an aggravating factor of the severity and moderate alleles were rare both in number and frequency. Pathogenic variants with DNE were found in both recessive and dominant HPP. Sixty percent of the adults tested were heterozygous for a variant showing no DNE, suggesting another mechanism of dominance like haploinsufficiency. Adults with dominant HPP without DNE were found statistically less severely affected than adults with DNE variants. Adults with dominant HPP without DNE represent a new clinical entity mostly diagnosed from 2010s, characterized by nonspecific signs of HPP and low alkaline phosphatase, and for which a high prevalence is expected. In conclusion, the genetic composition of our cohort suggests a nosology with 3 clinical forms: severe HPP is recessive and rare, moderate HPP is recessive or dominant and more common, and mild HPP, characterized by low alkaline phosphatase and unspecific clinical signs, is dominantly inherited and very common.
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