9. NEXT GENERATION SEQUENCING REVEALED THE GENETIC LANDSCAPE OF DISEASE-ASSOCIATED VARIANTS OF PHENYLKETONURIA
Main Article Content
Abstract
Phenylketonuria (PKU) is an autosomal recessive disorder caused by the PAH gene located on
chromosome 12. The disease is characterized by a defect in the enzyme phenylalanine hydroxylase
(PAH), causing elevated levels of phenylalanine (Phe) in the blood and subsequently leading to
neurotoxicity and mental disability. The world prevalence of PKU was about 1 in 10,000 - 20,000
newborns, still, data about PKU carriers and the disease-associated variant spectra in Vietnamese
people is minimal. The advent of Next Generation Sequencing (NGS) allows the simultaneous
detection of multiple genetic variants, including novel variants in numerous patients within a single
test, substantially reducing the testing cost. Objectives: Our study aimed to screen the carrier
frequency of the PAH gene and uncover variant spectra of this disease in Vietnamese women.
Methods: 2937 women who came for a prenatal routine healthcare check at the Center of Clinical
Genetics and Genomics - Ha Noi Medical University Hospital and Gene Solutions were screened
for disease-associated variants of the PAH gene employing NGS. Results: Of 2937 participants,
70 women were carriers (2.4%), and 12 different disease-associated variants were detected: R408Q
(1/2937), V388M (2/2937), P314T (2/2937), E280K (1/2937), R241fs (1/2937), R241C (1/2937),
Y206* (1/2937), Y204C (1/2937), Q172H (56/2937), H170Q (2/2937), R111* (1/2937), L41F
(1/2937). Q172H was predominant in our study. There are two rare variants that allele frequency
has not been reported in ClinVar and Ensemble: L41F và R241fs. Conclusion: The data from our
research will inform policymakers in constructing cost-effective genetic metabolic carrier screening
programs.
Article Details
Keywords
Phenylketonuria (PKU), variant, carriers screening, Next Generation Sequencing.
References
ammonia lyase (PAL): From discovery to
enzyme substitution therapy for phenylketonuria.
Mol Genet Metab. 2018;124(4):223-229.
doi:10.1016/j.ymgme.2018.06.002
[2] Blau N, Genetics of Phenylketonuria: Then
and Now. Hum Mutat. 2016;37(6):508-515.
doi:10.1002/humu.22980
[3] Scriver CR, The PAH gene, phenylketonuria, and
a paradigm shift. Hum Mutat. 2007;28(9):831-
845. doi:10.1002/humu.20526
[4] Garbade SF, Shen N, Himmelreich N et al., Allelic
phenotype values: a model for genotype-based
phenotype prediction in phenylketonuria. Genet
Med Off J Am Coll Med Genet. 2019;21(3):580-
590. doi:10.1038/s41436-018-0081-x
[5] Hillert A, Anikster Y, Belanger-Quintana
A et al., The Genetic Landscape and
Epidemiology of Phenylketonuria. Am J Hum
Genet. 2020;107(2):234-250. doi:10.1016/j.
ajhg.2020.06.006
[6] Tran NH, Nguyen Thi TH, Tang HS et al., Genetic
landscape of recessive diseases in the Vietnamese
population from large-scale clinical exome
sequencing. Hum Mutat. 2021;42(10):1229-
1238. doi:10.1002/humu.24253
[7] Arbesman J, Ravichandran S, Funchain P et
al., Melanoma cases demonstrate increased
carrier frequency of phenylketonuria/
hyperphenylalanemia mutations. Pigment
Cell Melanoma Res. 2018;31(4):529-533.
doi:10.1111/pcmr.12695
[8] Shoraka HR, Haghdoost AA, Baneshi MR et al.,
Global prevalence of classic phenylketonuria
based on Neonatal Screening Program Data:
systematic review and meta-analysis. Clin
Exp Pediatr. 2020;63(2):34-43. doi:10.3345/
kjp.2019.00465
[9] Nguyen TT, Le QT, Hoang DTT et al., Massively
parallel sequencing uncovered diseaseassociated
variant spectra of glucose-6-phosphate
dehydrogenase deficiency, phenylketonuria and
galactosemia in Vietnamese pregnant women.68
Mol Genet Genomic Med. 2022;10(7):e1959.
doi:10.1002/mgg3.1959
[10] Liu N, Huang Q, Li Q et al., Spectrum of PAH
gene variants among a population of Han
Chinese patients with phenylketonuria from
northern China. BMC Med Genet. 2017;18:108.
doi:10.1186/s12881-017-0467-7
[11] Liang Y, Huang MZ, Cheng CY et al., The mutation
spectrum of the phenylalanine hydroxylase
(PAH) gene and associated haplotypes reveal
ethnic heterogeneity in the Taiwanese population.
J Hum Genet. 2014;59(3):145-152. doi:10.1038/
jhg.2013.136
[12] Hillert A, Anikster Y, Belanger-Quintana
A et al., The Genetic Landscape and
Epidemiology of Phenylketonuria. Am J Hum
Genet. 2020;107(2):234-250. doi:10.1016/j.
ajhg.2020.06.006