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. 2024 Oct 31;25(21):11728.
doi: 10.3390/ijms252111728.

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

Oleg S Glotov  1   2   3 , Natalya A Zhuchenko  4 , Maria S Balashova  1   4 , Aleksandra N Raspopova  3 , Victoria V Tsai  1   2   3 , Alexandr N Chernov  1   5   6 , Iana V Chuiko  7 , Lavrentii G Danilov  3   8 , Lyudmila D Morozova  4 , Andrey S Glotov  1   8
Affiliations

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

Oleg S Glotov et al. Int J Mol Sci. .

Abstract

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.

Keywords: ALPL gene pathogenic variants; clinical cases; differential diagnosis; hypophosphatasemia; phenotypic overlaps; rare diseases; whole-exome sequencing.

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Conflict of interest statement

Authors O.S.G., A.S.G. was employed by the company, CerbaLab Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) Comparison of the structure of the wild-type protein, with Val483M and Ala69Thr mutant TNSALP proteins (WT—green color; mutated—pink color). (B) Val483Met replacement. (C) Ala69Thr replacement.
Figure 2
Figure 2
Time-dependent dynamics of atomic oscillations for wild-type and mutated (Val483Met, Ala69Thr) TNSALP proteins. RMSD—root mean square deviation.
Figure 3
Figure 3
Time-dependent dynamics of amino acid residue fluctuations for wild-type and mutated (Val483Met, Ala69Thr) TNSALP proteins. RMSF—root mean square fluctuation.
Figure 4
Figure 4
(A) Comparison of the protein structures of wild-type WNT10A with the Phe228Ile mutant (WT—green color, mutated—pink color). (B) Phe228Ile replacement.
Figure 5
Figure 5
Time-dependent dynamics of atomic oscillations for wild-type and mutated (Phe228Ile) WNT10A proteins. RMSD—root mean square deviation.
Figure 6
Figure 6
Time-dependent dynamics of amino acid residue fluctuations for wild-type and Phe228Ile -mutated WNT10A proteins. RMSF—root mean square fluctuation.
See this image and copyright information in PMC

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