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

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 ALPL gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The...

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Published in:International journal of molecular sciences Vol. 25; no. 21; p. 11728
Main Authors: Glotov, Oleg S, Zhuchenko, Natalya A, Balashova, Maria S, Raspopova, Aleksandra N, Tsai, Victoria V, Chernov, Alexandr N, Chuiko, Iana V, Danilov, Lavrentii G, Morozova, Lyudmila D, Glotov, Andrey S
Format: Journal Article
Language:English
Published: Basel MDPI AG 01-11-2024
MDPI
Subjects:
Age
Amino acids
Bones
Convulsions & seizures
Disease
Enzymes
Genes
Genetic aspects
Genetic screening
Genomes
Genomics
Medical research
Medicine, Experimental
Metabolism
Mutation
Patients
Phosphatase
Phosphatases
Proteins
China
Russia
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Summary:Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the ALPL 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 ALPL 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 ALPL gene), we also identified c.682T>A in exon 3 of the WNT10A gene and c.3470del in exon 23 of the SMC1A gene variants for the first time. In four patients, variants in the ALPL gene were not detected, but WES allowed us to identify for the first time rare variants (c.5651A>C in exon 36 of the TRIO gene, c.880T>G in exon 6 of the TRPV4 gene, c.32078-1G>T in intron 159 of the TTN gene, c.47720_47721del in exon 235 of the TTN gene, and c.1946G>A in exon 15 of the SLC5A1 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.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms252111728