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.

低磷酸酯酶症 (HPP) 是由ALPL基因的致病性变异引起的。严重程度有很大的连续性，从致命的围产期形式到牙齿问题。我们分析了来自欧洲地理起源或血统的 424 名 HPP 患者队列。使用 3D 建模和功能测试结果，我们对ALPL进行了分类致病变异根据其显性负面效应 (DNE) 及其严重程度。该队列由等位基因 s（严重隐性）、Sd（严重显性）和 m（中度）产生的基因型描述。许多反复出现的变体显示出一个区域锚点，指出了创始人效应而不是多个突变事件。纯合性是严重程度的加重因素，中等等位基因在数量和频率上都很少见。在隐性和显性 HPP 中都发现了具有 DNE 的致病变异。60% 的测试成年人是杂合子的变异体，没有显示出 DNE，这表明了另一种优势机制，如单倍体不足。发现没有 DNE 的具有显性 HPP 的成年人在统计学上比具有 DNE 变体的成年人受到的影响更轻。没有 DNE 的显性 HPP 成人代表了一种新的临床实体，主要是从 2010 年代诊断出来的，其特征是 HPP 的非特异性体征和低碱性磷酸酶，并且预计其患病率很高。总之，我们队列的遗传组成表明具有 3 种临床形式的疾病学：重度 HPP 是隐性和罕见的，中度 HPP 是隐性或显性的并且更常见，轻度 HPP 以低碱性磷酸酶和非特异性临床体征为主要特征。继承和非常普遍。