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Genome sequencing identifies a homozygous inversion disrupting QDPR as a cause for dihydropteridine reductase deficiency


Lilleväli, Hardo; Pajusalu, Sander; Wojcik, Monica H; Goodrich, Julia; Collins, Ryan L; Murumets, Ülle; Tammur, Pille; Blau, Nenad; Lilleväli, Kersti; Õunap, Katrin (2020). Genome sequencing identifies a homozygous inversion disrupting QDPR as a cause for dihydropteridine reductase deficiency. Molecular Genetics & Genomic Medicine, 8(4):e1154.

Abstract

Background: Dihydropteridine reductase (DHPR) is one of the key enzymes for maintaining in the organism the supply of tetrahydrobiopterin (BH4 ), an essential cofactor for aromatic amino acid hydroxylases. Its dysfunction causes the condition of hyperphenylalaninemia together with the lack of neurotransmitters.

Methods: We report a patient with biochemically diagnosed DHPR deficiency, with extensive molecular investigations undertaken to detect variations in quinoid dihydropteridine reductase (QDPR) gene. Sanger sequencing of QDPR coding regions, exome sequencing, QDPR mRNA PCR, and karyotyping were followed by trio genome sequencing.

Results: Short-read genome sequencing revealed a homozygous 9-Mb inversion disrupting QDPR. Structural variant breakpoints in chromosome 4 were located to intron 2 of QDPR at Chr4(GRCh38):g.17505522 and in intron 8 of the ACOX3 gene, Chr4(GRCh38):g.8398067). Both nonrelated parents carried the variant in heterozygous state. The inversion was not present in gnomAD structural variant database.

Conclusion: Identification of the exact breakpoints now allows further straightforward molecular genetic testing of potential carriers of the inversion. This study extends the pathogenic variant spectrum of DHPR deficiency and highlights the role of structural variants in recessive metabolic disorders. To our knowledge, this is the first report on a large, canonical (rather than complex) homozygous pathogenic inversion detected by genome sequencing.

Keywords: QDPR gene; dihydropteridine reductase deficiency; genome sequencing; inversion; tetrahydrobiopterin deficiencies.

Abstract

Background: Dihydropteridine reductase (DHPR) is one of the key enzymes for maintaining in the organism the supply of tetrahydrobiopterin (BH4 ), an essential cofactor for aromatic amino acid hydroxylases. Its dysfunction causes the condition of hyperphenylalaninemia together with the lack of neurotransmitters.

Methods: We report a patient with biochemically diagnosed DHPR deficiency, with extensive molecular investigations undertaken to detect variations in quinoid dihydropteridine reductase (QDPR) gene. Sanger sequencing of QDPR coding regions, exome sequencing, QDPR mRNA PCR, and karyotyping were followed by trio genome sequencing.

Results: Short-read genome sequencing revealed a homozygous 9-Mb inversion disrupting QDPR. Structural variant breakpoints in chromosome 4 were located to intron 2 of QDPR at Chr4(GRCh38):g.17505522 and in intron 8 of the ACOX3 gene, Chr4(GRCh38):g.8398067). Both nonrelated parents carried the variant in heterozygous state. The inversion was not present in gnomAD structural variant database.

Conclusion: Identification of the exact breakpoints now allows further straightforward molecular genetic testing of potential carriers of the inversion. This study extends the pathogenic variant spectrum of DHPR deficiency and highlights the role of structural variants in recessive metabolic disorders. To our knowledge, this is the first report on a large, canonical (rather than complex) homozygous pathogenic inversion detected by genome sequencing.

Keywords: QDPR gene; dihydropteridine reductase deficiency; genome sequencing; inversion; tetrahydrobiopterin deficiencies.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Molecular Biology
Life Sciences > Genetics
Health Sciences > Genetics (clinical)
Language:German
Date:April 2020
Deposited On:18 Jan 2021 15:50
Last Modified:01 Feb 2021 16:24
Publisher:Wiley Open Access
ISSN:2324-9269
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/mgg3.1154
PubMed ID:32022462

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