Proband 1 presented with developmental retardation, pectus funnel and premature loss of deciduous tooth, of which the serumalkaline phosphatase level was slightly lower than the bound of the normal range. Two complex heterozygous missense variants c. 1120G>A and c. 1334C>G of ALPL gene were detected in the proband 1 which were inherited from his parents respectively, showing an autosomal recessive inheritance. Both the variants were predicted to inflict deleterious effects on ALPL gene function by multiple bioinformatics program, and were classified as likely pathogenetic variants according to American College of Medical Genetics and Genomics(ACMG) guidelines. Proband 2 showed three missing permanent teeth and the significantly lower level of serumalkaline phosphatase than normal range. A heterozygous variant c. 1190-3C>G of ALPL gene was detected in proband 2 whose pattern of inheritance was unknown. The clinical significance of this variant was unknown according to ACMG standards and guidelines. All of these variants were considered as novel since none of them has been reported. Along with the above combined results, proband 1 and 2 were diagnosed as childhood HPP and Odontohypophosphatasia, respectively.
Conclusion:
This study reinforced the relationship between HPP and variants in ALPL gene. Two variants, c. 1120G>A and c. 1334C>G, were located in the homodimer interface and crown domain of tissue-nonspecific alkaline phosphatase(TNSALP), respectively, while c. 1190-3C>G were located in the splice sites, which might result in low TNSALP activity.