Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation

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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Fig. 1: Distribution of recurrent ALPL variants according to the geographic origin of patients.
Fig. 2: Composition of genotypes in HPP phenotypes.
Fig. 3: Comparison of the distributions of genotypes in moderate HPP with our previous study (Fauvert et al. 2009).
Fig. 4: Comparison of moderate and mild genotypes for 3 markers of HPP severity.
Fig. 5: The 3 forms of HPP according to genetic data.

Data availability

The authors state the availability of data and materials for replication of findings.

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Acknowledgements

The authors would like to thank the clinicians from 32 countries who gave us the opportunity to test their patients.

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Correspondence to Etienne Mornet.

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EM received honoraria from Alexion Pharmaceutical for expertize and presentations.

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Mornet, E., Taillandier, A., Domingues, C. et al. Hypophosphatasia: a genetic-based nosology and new insights in genotype-phenotype correlation. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-00732-6

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