Infantile hypophosphatasia: localization within chromosome region 1p36.1-34 and prenatal diagnosis using linked DNA markers.

Linkage analysis was performed on data from Manitoba Mennonite families identified by a proband with infantile hypophosphatasia (HOPS), an autosomal recessive disorder characterized by defective skeletal mineralization. Southern blot analysis of Msp-I-digested DNA from HOPS nuclear families probed with a 2.55-kb liver/bone/kidney alkaline phosphatase (ALPL) cDNA revealed two previously undescribed RFLPs at 2.4/2.3 kb and 2.0/1.9 kb. Maximum combined lod score equals 13.25 at theta = 0. This establishes very close linkage between ALPL and HOPS and allows for the regional assignment of the HOPS gene to chromosome 1p36.1-34. Prenatal RFLP studies in an informative Mennonite family correctly predicted an unaffected fetus following chorionic villus sampling at 12 wk gestation. In addition in our Mennonite population, a nonrandom association exists between the polymorphic ALPL alleles and HOPS. These results suggest that strong linkage disequilibrium exists between HOPS and the ALPL markers. This will allow for improved carrier assignment in this high-risk population. Preliminary analysis suggests approximately 1/25 Manitoba Mennonites are HOPS carriers.