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.

Fig. 1. Distribution of recurrent ALPL variants according to the geographic origin of patients.

Variants are shown according to their frequency and their genetic status in ten regions defined to represent 32 countries: France/Switzerland, Germany/Austria, UK/Ireland, Belgium/Netherlands, North Europe (Denmark, Finland, Sweden, Norway, Lithuania), East Europe (Hungary, Croatia, Georgia, Poland, Czech republic), South Europe (Spain, Portugal, Greece, Italy), North America (USA/Canada), Australia/New Zeland and Middle East (Saudi Arabia, Israel, Japan, Jordan, Tunisia, Turkey). Moderate alleles are shown in green, severe alleles with no DNE in red and severe alleles with DNE in purple. Variants not classified are not shown.

Fig. 2. Composition of genotypes in HPP phenotypes.

Only genotypes with classifiable alleles are included. a In our cohort. For each phenotype the figure shows the number of genotypes according to our classification of alleles. The prenatal benign form is not shown because this particular form is assumed to finally result in all but one (perinatal lethal) phenotypes. The distribution allow to sort genotypes according to resulting phenotypes: severe (divisible into into subgroups: very severe and severe), moderate and mild. N normal (wild type); Sd severe dominant; s severe recessive (i.e., no DNE); m moderate; b In the pediatric US cohort [10] for comparison.

Fig. 3. Comparison of the distributions of genotypes in moderate HPP with our previous study (Fauvert et al. 2009).

The actual distribution in blue is compared to our previous study in orange [28].

Fig. 4. Comparison of moderate and mild genotypes for 3 markers of HPP severity.

The figure shows only adults with genotypes Sd/N in (blue) and genotypes m/N and s/N (orange). Age: age at diagnosis in years; AP: alkaline phosphatase in % of the lower limit for age and sex; Age is the age at diagnosis expressed in years. Fractures are given in % of patients reported with no fractures or history of nontraumatic or atypical fractures.

Fig. 5. The 3 forms of HPP according to genetic data.

The figure summarizes a genetic-based nosology of HPP, with inheritance and prevalence, and a hypothesis about the mechanism of dominance in mild HPP.