Identification of a Novel Compound Heterozygous Variant in the ALPL Gene Linked to Hypophosphatasia in a Chinese Family.

Context: Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by loss-of-function variant(s) of the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP).

Objective: To enrich the genetic spectrum of HPP and establish a genetic basis for the diagnosis and treatment of the proband.

Methods: A detailed medical history and systematic clinical evaluation were conducted for the proband. Variants in genes relevant to the proband's clinical phenotype were identified through whole-exome sequencing and confirmed by Sanger sequencing. The effect of ALPL gene variants on TNSALP function and their dominant negative effect (DNE) was assessed by transient transfection of recombinant plasmids into HEK293T cells, followed by an analysis of enzyme specific activity (ESA).

Results: Two missense variants, c.269A > G and c.787T > C, and one intronic variant, c.182-9C > T, were identified in the ALPL gene of the proband. ESA assays revealed that c.269A > G and c.182-9C > T exhibited reduced alkaline phosphatase (ALP) activity, whereas no significant change was observed for c.787T > C. Co-transfection experiments with wild-type and mutant (c.269A > G or c.182-9C > T) TNSALP revealed that both c.269A > G and c.182-9C > T have DNE.

Conclusion: The compound heterozygous variant comprised of c.269A > G and c.182-9C > T in the ALPL gene may contribute to decreased ALP activity and the disease phenotype of the proband. Moreover, an experienced multidisciplinary team needs to monitor the effect of DNE on carriers and track the relevant clinical symptoms emerging at a later stage.