Table 2.
Clinical features associated with each ALPL variant detected in the present series of adult hypophosphatasemic patients and comparison with available data in literature and/or public database
| ALPL variants | dbSNP ID | ACMGG/AMP classification* | Patient ID | Patients clinical features | Reported clinical features |
|---|---|---|---|---|---|
| c.181 + 52C > A | rs1767430 | Benign | 6 | Recurrent abortions, multiple vertebral fractures, hyperkyphosis, premature loss of teeth, hypercalciuria, familiarity for osteoporotic fractures | No report available |
| 13 | Costal fracture, joint and muscular pain, familiarity for HPP | ||||
| c.330T > C, p.(Ser110Ser) | rs1780316 | Benign | 2 | Adrenal cancer, familiarity for HPP | Found in patients with atypical femur fractures and in general population with the same frequency [27] |
| 6 | Recurrent abortions, multiple vertebral fractures, hyperkyphosis, premature loss of teeth, hypercalciuria, familiarity for osteoporotic fractures | ||||
| 7 | Pituitary macroadenoma, joint pain, familiarity for osteoporotic fractures | ||||
| 8 | Multiple vertebral fractures, joint and muscular pain, premature loss of teeth, kidney stones | ||||
| 9 | Multiple vertebral fractures, seizure, kidney stones, hypercalciuria | ||||
| 10 | Premature loss of teeth, hypercalciuria, familiarity for HPP | ||||
| 11 | Breast cancer | ||||
| 13 | Rib fracture, joint and muscular pain, familiarity for HPP | ||||
| c.407G > A, p.(Arg136His) | rs121918011 | Pathogenetic | 3 | Multiple vertebral fractures, premature loss of teeth, kidney stones, goiter | This variant was identified either as single mutation or in compound heterozigosity with other pathogenic ALPL variants in infantile, childhood, adult and odontoHPP (ALPLDB) |
| 4 | Multiple vertebral fractures, recurrent caries, hyperkyphosis, joint and muscular pain, familiarity for osteoporotic fractures | ||||
| c.455G > A, p.(Arg152His) | rs149344982 | Benign | 6 | Recurrent abortions, multiple vertebral fractures, hyperkyphosis, premature loss of teeth, hypercalciuria, familiarity for osteoporotic fractures | Fragility fractures, premature loss of teeth, joint and muscular pain (personal data by Guarnieri V.) |
| 11 | Breast cancer | ||||
| c.472 + 7C > G | rs564375559 | Benign | 13 | Costal fracture, joint and muscular pain, familiarity for HPP | No report available |
| c.526G > A, p.(Ala176Thr) | rs121918019 | Pathogenetic | 2 | Adrenal cancer, familiarity for HPP | This variant was identified either as single mutation or in compound heterozigosity with other pathogenic ALPL variants in infantile, childhood, adult and odontoHPP (ALPLDB) |
|
c.571G > A, p.(Glu191Lys) |
rs121918007 | Pathogenetic | 5 | Multiple vertebral fractures, clavicular fracture, recurrent caries | This variant was identified either as single mutation or in compound heterozigosity with other pathogenic ALPL variants in infantile, childhood, adult and odontoHPP (ALPLDB) |
|
c.787T > C, p.(Tyr263His) |
rs3200254 | Benign | 9 | Multiple vertebral fractures, seizure, kidney stones, hypercalciuria | Found in patients with atypical femur fractures and in general population with the same frequency [27] |
| 10 | Premature loss of teeth, hypercalciuria, familiarity for HPP | ||||
| 12 | Autoimmune hypothyroidism, rib fractures, kidney stones, hypercalciuria | ||||
| 13 | Costal fracture, joint and muscular pain, familiarity for HPP | ||||
| c.793-31C > T | rs1256328 | Benign | 2 | Adrenal cancer, familiarity for HPP | Associated with kidney stones in a Taiwanese [28], and in the Han Chinese populations [29] |
| c.862 + 20G > T | rs2275377 | Benign | 12 | Autoimmune hypothyroidism, rib fractures, kidney stones, hypercalciuria | Found in linkage disequilibrium in patients with mild HPP (childhood and adult HPP, odontoHPP, and perinatal benign HPP) [9] |
| 13 | Rib fracture, joint and muscular pain, familiarity for HPP | ||||
| c.862 + 51G > A | rs2275376 | Benign | 12 | Autoimmune hypothyroidism, rib fractures, kidney stones, hypercalciuria | Found in linkage disequilibrium in patients with mild HPP (childhood and adult HPP, odontoHPP, and perinatal benign HPP) [9] |
| 13 | Rib fracture, joint and muscular pain, familiarity for HPP | ||||
| c.862 + 58C > T | rs2275375 | Benign | 12 | Autoimmune hypothyroidism, rib fractures, kidney stones, hypercalciuria | Found in linkage disequilibrium in patients with mild HPP (childhood and adult HPP, odontoHPP, and perinatal benign HPP) [9] |
| 13 | Rib fracture, joint and muscular pain, familiarity for HPP | ||||
| c.863-7T > C | rs74063111 | Benign | 9 | Multiple vertebral fractures, seizure, kidney stones, hypercalciuria | No report available |
| 10 | Premature loss of teeth, hypercalciuria, familiarity for HPP | ||||
| 13 | Costal fracture, joint and muscular pain, familiarity for HPP | ||||
| c.863-12C > G | rs75829132 | Benign | 9 | Multiple vertebral fractures, seizure, kidney stones, hypercalciuria | No report available |
| 10 | Premature loss of teeth, hypercalciuria, familiarity for HPP | ||||
| 13 | Costal fracture, joint and muscular pain, familiarity for HPP | ||||
|
c.876A > G, p.(Pro292Pro) |
rs3200255 | Benign | 9 | Multiple vertebral fractures, seizure, kidney stones, hypercalciuria | Found in patients with atypical femur fractures and in general population with the same frequency [27] |
| 10 | Premature loss of teeth, hypercalciuria, familiarity for HPP | ||||
| 13 | Costal fracture, joint and muscular pain, familiarity for HPP | ||||
| c.921delG p.(Ser308Hisfs*58) | NR | Pathogenetic | 1 | Breast cancer, vertebral, wrist and humerus fractures, recurrent caries, scoliosis, familiarity for osteoporotic fractures | No report available |
| c.1309 + 46C > T | rs4654760 | Benign | 9 | Multiple vertebral fractures, seizure, kidney stones, hypercalciuria | No report available |
|
c.1565T > C, p.(Val522Ala) |
rs34605986 | Benign | 2 | Adrenal cancer, familiarity for HPP | Found in patients with atypical femur fractures and in general population with the same frequency [27] |
dbSNP Single Nucleotide Polymorphism database (https://www.ncbi.nlm.nih.gov/snp/), ALPL alkaline phosphatase gene, ALPLDB The Tissue Nonspecific Alkaline Phosphatase Gene Mutations Database (http://alplmutationdatabase.hypophosphatasie.com/), ID patient identification number used in Table 1, HPP hypophosphatasia, NR Not Reported
*Variants were classified following the ACMGG Guidelines [14], as pathogenic, likely pathogenic or Variants of Uncertain Significance (VUS) with the following criteria: (1) null variant (nonsense, frameshift, deletion, insertion, canonical ± 1 or ± 2 splicing site) in genes previously described as disease-causing by haploinsufficiency/loss-of-function; (2) mutational hot spot and/or variant located in a critical functional domain; (3) variant absent in allele frequency population databases (ExAC, gnomAD, dbSNP); (4) variant reported with a minor allele frequency (MAF) significantly lower than expected; (5) variant annotated as pathogenic in ClinVar/LOVD databases; (6) co-segregation with disease in affected family members; (7) in vitro/in vivo functional studies supportive of a damaging effect on the gene/gene product. Common (MAF > 0.01) and synonymous variants were classified as benign