Family mapping of previously identified patients with pathogenic or likely pathogenic variants using predictive genotyping and detailed phenotyping approach: the FAME case-control study.

Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function variants in the gene, which encodes the tissue nonspecific isozyme of alkaline phosphatase (ALP). There is no typical phenotype in adults. We used a genotyping first approach to determine whether pathogenic variants were associated with musculoskeletal symptoms, mineral metabolism abnormalities, and an impact on quality of life. We recruited individuals with a pathogenic (or likely pathogenic) variant in gene ( = 26) and their relatives ( = 44). We performed genetic tests and compared the relatives with positive ( = 20) and negative ( = 24) genetic test. We applied standard questionnaires and physical tests (Brief Pain Inventory [BPI]; Western Ontario and McMaster Universities Arthritis [WOMAC]; Modified Hypophosphatasia Impact Patient Survey; Short Form of 36 Survey [SF-36]; and the Short Physical Performance Battery). In fasting blood samples, we measured creatinine, calcium, phosphate (P), parathyroid hormone (PTH), ALP, bone ALP, 25OHD-, 1,25(OH)2D, CTX, type 1 procollagen N-terminal peptide (PINP), osteocalcin, and tartrate-resistant acid phosphatase5b (TRACP5b). Relatives with positive genetic test had lower ALP (IU/L) [32.5(12.8) vs 87.8(32.6)  < .001], bone ALP (ng/mL) [6.3(4.3, 9.8) vs 17.5 (13.12-25.7)  < .001], PTH (pg/L) [28.6(20.6, 38.1) vs 40.05(25.7, 52.3)  = .03], and higher PLP(nmol/L) [162.0 (91.75, 337.5) vs 37.5 (18.25, 60.5)  < .001] and P(mmol/L) [1.36 (0.18) vs 1.05 (0.2)  < .001]. We did not find significant differences in fractures or musculoskeletal features between the groups. Greater pain scores were observed on BPI in relatives with positive genetic tests, and bone and muscle pain were more often reported by this group, but statistical tests were not significant. No differences were found in physical performance or quality of life. In conclusion, we assessed relatives of individuals with pathogenic or likely pathogenic variants in the gene regardless of the presence of signs and symptoms. Biochemical abnormalities were more common in gene-positive relatives, but the prevalence of musculoskeletal symptoms was comparable in relatives with positive and negative genetic tests.