The analysis of using a panel of the most common variants in the PAH gene for the newborn screening in Ukraine.

Phenylketonuria (PKU) is hyperphenylalaninemia that develops due to a deficiency of the phenylalanine hydroxylase enzyme (PAH). Identification of variants in the PAH gene is necessary for verification of the diagnosis, choice of treatment tactics, detection of heterozygous carriers. The aim of the study was to analyze the effectiveness of identification of selected pathological variants in the PAH gene during the newborn screening program. This study relied on the results of the examination of 257 patients (138 boys and 119 girls) with hyperphenylalaninemia from different regions of Ukraine. Genotyping was performed on nine pathogenic variants in PAH gene: I65T, R261Q, G272*, R252W, R261*, R408W, IVS12 + 1G > A, Y414C, IVS10-11G > A. According to the results of the study, variants R408W (AF = 52.7%), R252W (AF = 3.5%) and Y414C (AF = 1.8%) were the most common. More than half of the examined patients (51.7%) had a compound genotype with a major variant of R408W in one allele. Approximately a quarter of the examined patients (26.8%) had the R408W/R408W genotype. In 12.1% of patients, the applied panel of variants of the РАН gene did not allow us to identify the pathogenic variant in any allele. We conclude that the selected panel allowed us to identify the presence of variants in 87.9% of patients with PKU. The panel of genetic testing in the PAH gene for the newborns that we used for the study allows accurate prediction of some phenotypes for therapy planning. But in-depth analysis of pathological gene variants may be necessary for unclear and difficult cases of the disease, and for genetic counseling of patients families.

Novel mutations in arylsulfatase A gene in three Ukrainian families with metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ARSA) or saposin B. The majority of mutations identified in patients with MLD are unique within individual families. Here, we report on the novel missense mutations (F247S, D381E, and A469G) and the known mutations "A" allele and P136S in the ARSA gene in three unrelated Ukrainian families with MLD. The mutations F247S and P136S were found in compound heterozygous with the "A" allele in two patients with juvenile onset MLD. The clinical features of the typical patient with genotype D381E/A469G (early onset with very rapid manifestation of disease) suggest the reason to distinguish an early infantile MLD variant.