Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling

Brigitte Simon‐Bouy, Agnès Taillandier, Delphine Fauvert, Isabelle Brun‐Heath, Jean‐Louis Serre, Carmen G. Armengod, Martin G. Bialer, Michèle Mathieu, Jacques Cousin, David Chitayat, Jan Liebelt, Barbara Feldman, Marion Gérard‐Blanluet, Stefani Körtge‐Jung, Cath King, Hannele Laivuori, Martine Le Merrer, Sarju Mehta, Christina Jern, Saba Sharif, Fabienne Prieur, Gabriele Gillessen‐Kaesbach, Andreas Zankl, Etienne Mornet

We studied hypophosphatasia (HP) mutations in 19 cases prenatally detected by ultrasonography without familial history of HP. We correlated the mutations with the reported ultrasound signs, and discussed genetic counseling with regard to the particular dominantly inherited prenatal benign form of HP. The coding sequence of the tissue nonspecific alkaline phosphatase (TNSALP) gene was analyzed by DNA sequencing, and 3D modeling was used to locate the mutated amino acids with regard to the functional domains of TNSALP. Although reported ultrasound signs were heterogeneous, two mutated alleles were found in 18 of the 19 cases studied, indicating recessive transmission of the disease. Functional domains of TNSALP were affected by 74% of missense mutations. In all the cases, including one with only a heterozygous mutation, molecular, biological, and familial data do not corroborate the hypothesis of prenatal benign HP. The mutation c.1133A>T observed in the prenatal benign form of HP and common in USA was not found in this series. The results point out the prenatally detectable allelic heterogeneity of HP. The nature of the detected mutations and the evidence of recessive inheritance do not support these cases being affected with prenatal benign HP.