The Benefits of Whole-Exome Sequencing in the Differential Diagnosis of Hypophosphatasia.

Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The medical records of HPP patients and the genetic testing of the gene were reviewed. Seven patients were recruited and underwent WES using the Illumina or MGI sequencing platforms. All of the exome samples were matched onto a GRCh38.p13 reference genome assembly by using the Genome Analysis ToolKit (GATK) and the BWA MEM read aligner. We present the clinical and molecular findings of the seven patients referred for genetic analyses due to a clinical and biochemical suspicion of HPP. In two patients out of three (with identified heterozygous variants in the gene), we also identified c.682T>A in exon 3 of the gene and c.3470del in exon 23 of the gene variants for the first time. In four patients, variants in the gene were not detected, but WES allowed us to identify for the first time rare variants (c.5651A>C in exon 36 of the gene, c.880T>G in exon 6 of the gene, c.32078-1G>T in intron 159 of the gene, c.47720_47721del in exon 235 of the gene, and c.1946G>A in exon 15 of the gene) and to conduct differential diagnostics with HPP. Using WES, for the first time, we demonstrate the possibility of early differential diagnostics in HPP patients with other rare genetic diseases.