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

TitleGenome sequencing identifies a homozygous inversion disrupting QDPR as a cause for dihydropteridine reductase deficiency.
Publication TypeJournal Article
Year of Publication2020
AuthorsLilleväli, H, Pajusalu, S, Wojcik, MH, Goodrich, J, Collins, RL, Murumets, Ü, Tammur, P, Blau, N, Lilleväli, K, Õunap, K
JournalMol Genet Genomic Med
Volume8
Issue4
Paginatione1154
Date Published2020 Apr
ISSN2324-9269
Abstract

BACKGROUND: Dihydropteridine reductase (DHPR) is one of the key enzymes for maintaining in the organism the supply of tetrahydrobiopterin (BH ), 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.

DOI10.1002/mgg3.1154
Alternate JournalMol Genet Genomic Med
PubMed ID32022462
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
/ HL / NHLBI NIH HHS / United States
PUTJD827 / / Eesti Teadusagentuur /
PRG471 / / Eesti Teadusagentuur /
PUT355 / / Eesti Teadusagentuur /
/ HL / NHLBI NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States