This study presents further research into the spectrum of variants in genes responsible for the development of phenylketonuria (PKU) and hyperphenylalaninemia (HPA) in patients in Russia. After a study of 25 frequent variants, 293 patients (327 chromosomes without detected variants) from among 1265 probands still had no confirmed diagnosis. A study involving methods of next generation sequencing (NGS) of PAH, PTS, GCH1, PCBD1, QDPR, SPR and DNAJC12 genes to search for point mutations and multiplex ligation-dependent probe amplification (MLPA) methods to search for gross deletions were conducted for these patients. Among 327 chromosomes without identified variants, variants in the PAH gene were found on 260 chromosomes, and variants in the PTS gene were found on 10 chromosomes. On 10 chromosomes gross deletions by the MLPA method were detected. 104 rare variants of the РАН gene, including 10 variants not previously described, and 6 variants of the PTS gene were revealed. The NGS method revealed additional РАН gene variants on 10.3% of chromosomes and PTS gene variants on 0.4%. Gross deletions of the РАН gene were revealed in 0.5% of chromosomes. Thus, the most complete understanding of the spectrum of variants leading to the development of the PKU and HPA in Russia with the use of all methods available today has been obtained. Such a detailed study of the spectrum of rare variants on the genetic material from Russia was undertaken for the first time.
Keywords: Hyperphenylalaninemia; Next generation sequencing; Phenylketonuria; Tetrahydrobiopterin.