A Novel Homozygous Missense Variant of PIGT Related to Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 with Elevated of Serum ALP Level in a Thai Newborn Patient
Abstract
1. Introduction
2. Results
2.1. Case Report
2.2. Germline Mutation Analysis
2.3. Effects of the c.257A>G on PIGT Function Demonstrated by GPI-AP Expression Analysis
2.4. The Intramolecular Interactions Among Amino Acids at the Site of Alteration
2.5. The Prediction of Protein Stability
3. Discussion
4. Materials and Methods
4.1. Whole Exome Sequencing and Data Analysis
4.2. Variant Analysis
4.3. Sanger Sequencing
4.4. Western Blot Analysis for CD59 Expression
4.5. In-Silico Analysis of the PIGT Mutation on Protein Stability and Structural Dynamics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
PIGT | Phosphatidylinositol glycan class T |
GPI-TA | Glycosylphosphatidylinositol transamidase |
GPI-AP | Glycosylphosphatidylinositol-anchored protein |
MCAHS3 | Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 |
WES | Whole exome sequencing |
ALP | Alkaline phosphatase |
ER | Endoplasmic reticulum |
EEG | Electroencephalogram |
ACMG/AMP | The American College of Medical Genetics and Genomics and the Association for Molecular Pathology |
PBMC | Peripheral blood mononuclear cell |
VCF | Variant calling file |
HPO | Human phenotype ontology |
GnomAD | The Genome Aggregation Database |
T-REx | The Thai Reference Exome Database |
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Study | Our Study | Ranjan A. 2023 [18] | Hur Y. J. 2021 [19] | Kohashi K. 2018 [20] | Yang L. 2018 [21] | Pagnamenta A.T. 2017 [22] | Skauli N. 2016 [23] | Lam C. 2015 [24] | Nakashima M. 2014 [7] | Kvarnung M. 2013 [4] |
---|---|---|---|---|---|---|---|---|---|---|
Case number | 1 | 1 | 1 | 1 | 1 | 3 | 2 | 2 | 1 | 4 |
Sex | Female | Male | Female | Male | Male | 1 Female/ 2 Male | Male | 1 Male 1 Female | Female | Female |
Consanguinity | Yes | No | No | No | No | NA | Yes | No | No | Yes |
Ethnicity | Thai | Indian | Korean | Japanese | Chinese | Caucasian/ Afghanistan | Somalian | NA | Japanese | Turkish |
Dysmorphic features | + | + | + | + | + | +/NA | + | + | NA | + |
Hypotonia | + | + | + | + | + | NA | + | + | + | + |
Seizure | + | + | + | + | + | + | + | + | + | + |
Seizure type | Myoclonic jerk | GTC, myoclonic, tonic | GTC | Myoclonic, Tonic, GTC, epileptic apnea | Myoclonic | GTC | Myoclonic, Tonic, GTC, complex partial seizures | Tonic, myoclonic | Myoclonic, Tonic, GTC | Myoclonic, GTC, head jerk, blinking, Absence |
Brain atrophy | + | NA | + | + | + | + | + | + | + | +(3/4) |
EEG | Multifocal epileptiform discharges from the right central parietal, left temporal, and left frontal areas | NA | Normal background rhythm, no epileptiform discharges | High-amplitude slow wave | Slow background wave | bilateral slow activity intermixed with sharp and spike waves /NA | Multiple spike-wave | Multifocal epileptiform, theta waves | High-amplitude slow wave | Multifocal epileptiform, theta waves |
AED | LEV, PB | PB, FOS, LEV, CZP | VPA | LEV | LEV | NA/NA | NA | LEV, TPM, PB, CZP, MZ, BDZ, CLN, and ketogenic diet | CBZ, CLO, PLP, VPA, ZNS, PHE | NA |
Developmental delay | Severe | NA | Severe | Severe | Severe | Severe/ Profound | Severe/ Moderate-severe | Profound | Profound | Severe |
Skeletal | + | + | Normal | + | Normal | +/NA | Normal | + | + | + |
Alkaline phosphatase level | High | Low | Low | Low | Normal | Normal/ Low, Normal | Normal | Normal | Low | Low |
Variants in PIGT | Homozygous c.257A>G (p.His86Arg) | Homozygous c.709G>C (p.Glu237Gln) | c.250G>T (p.Glu84*) and c.1582G>A (p.Val528Met) | c.250 G>T (p.Glu84*) and c.1096 G>T (p.Gly366Trp) | Homozygous c.550G>A (p.Glu184Lys) | c.1582G4A (p.Val528Met) and c.1730dupC (p.Leu578fs*35) Homozygous c.709G>C (p.Glu237Gln) | Homozygous c.1079G>T (p.Gly360Val) | c.918dupC (p.Val307Argfs*13) and c.1342C>T (p.Arg448Trp) | c.250G>T (p.Glu84*) and c.1342C>T (p.Arg488Trp) | Homozygous c.547A>C (p.Thr183Pro) |
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Klangjorhor, J.; Wiwattanadittakul, N.; Jaimalai, T.; Thongkumkoon, P.; Noisagul, P.; Khiaomai, R.; Sirikaew, N.; Moonsan, N.; Pasena, A.; Suksakit, P.; et al. A Novel Homozygous Missense Variant of PIGT Related to Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 with Elevated of Serum ALP Level in a Thai Newborn Patient. Int. J. Mol. Sci. 2025, 26, 2790. https://doi.org/10.3390/ijms26062790
Klangjorhor J, Wiwattanadittakul N, Jaimalai T, Thongkumkoon P, Noisagul P, Khiaomai R, Sirikaew N, Moonsan N, Pasena A, Suksakit P, et al. A Novel Homozygous Missense Variant of PIGT Related to Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 with Elevated of Serum ALP Level in a Thai Newborn Patient. International Journal of Molecular Sciences. 2025; 26(6):2790. https://doi.org/10.3390/ijms26062790
Chicago/Turabian StyleKlangjorhor, Jeerawan, Natrujee Wiwattanadittakul, Thanapak Jaimalai, Patcharawadee Thongkumkoon, Pitiporn Noisagul, Ratchadaporn Khiaomai, Nutnicha Sirikaew, Nonthanan Moonsan, Arnat Pasena, Pathacha Suksakit, and et al. 2025. "A Novel Homozygous Missense Variant of PIGT Related to Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 with Elevated of Serum ALP Level in a Thai Newborn Patient" International Journal of Molecular Sciences 26, no. 6: 2790. https://doi.org/10.3390/ijms26062790
APA StyleKlangjorhor, J., Wiwattanadittakul, N., Jaimalai, T., Thongkumkoon, P., Noisagul, P., Khiaomai, R., Sirikaew, N., Moonsan, N., Pasena, A., Suksakit, P., Teeyakasem, P., Chaiyawat, P., & Tengsujaritkul, M. (2025). A Novel Homozygous Missense Variant of PIGT Related to Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 with Elevated of Serum ALP Level in a Thai Newborn Patient. International Journal of Molecular Sciences, 26(6), 2790. https://doi.org/10.3390/ijms26062790