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

Abstract

Background: Dihydropteridine reductase (DHPR) is one of the key enzymes for maintaining in the organism the supply of tetrahydrobiopterin (BH 4 ), 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 2 of 8 | LILLEVÄLI Et aL.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.

Centers for Mendelian Genomics: A decade of facilitating gene discovery

“…51 CMGs investigators have successfully applied sequencing approaches beyond the exome to identify or validate causal variant(s), including genome, RNA, bisulfite DNA methylation sequencing, and long-read sequencing, showing their utility in cases where exome sequencing fails to find a molecular diagnosis. Examples include utilizing genome sequencing to identify pathogenic SVs missed by exome, such as the homozygous inversion in QDPR detected in a patient with dihydropteridine reductase deficiency; 52 applying RNA sequencing to identify genes with aberrant expression and or splicing, including an intronic variant in trans with a missense in muscle disease gene DES that resulted in a pseudo-exon insertion and allelic imbalance; 53 using bisulfite sequencing to identify gene silencing epivariation, such as the characterization of aberrant hypermethylation associated with a pathogenic repeat expansion in the XYLT1 promoter region; 54 and the application of long-read sequencing to characterize a complex genomic rearrangement involving an inverted triplication flanked by duplications in a proband with Temple syndrome. 55 The challenges with interpreting rare variation in the genome is a major barrier for achieving genetic diagnoses.…”

Microcephaly in Neurometabolic Diseases

“…It causes hyperphenylalaninemia and neurotransmitter deficiency. The mutation is related to the QDPR gene (locus 4p15.32) [ 21 , 23 ]. The incidence of all causes of hyperphenylalaninemia detected by newborn screening programs is estimated to be approximately 1:10,000 (data for Europe).…”

“…In some cases, hypertonia and dyskinesis can occur. Feeding problems in infancy, dysphagia, hypersalivation, and irritability are also reported [ 21 , 22 , 23 , 24 ].…”

“…The disease is usually suspected due to an elevated concentration of phenylalanine during newborn screening. The diagnosis is made by measuring decreased DHPR activity in blood cells [ 21 , 23 , 24 ].…”

“…Long-acting dopamine agonists (e.g., pramipexole), monoamine oxidase inhibitors (e.g., selegiline), or benserazide can also be used. In the absence of treatment, a progressive neurological deficit occurs [ 21 , 23 , 25 ].…”