Balkan Journal of Medical Genetics

ASSOCIATION OF VARIANTS IN THE CP, ATOX1 AND COMMD1 GENES WITH WILSON DISEASE SYMPTOMS IN LATVIA
Zarina A1,2*, Tolmane I3,4, Krumina Z2, Tutane AI1, Gailite L1
*Corresponding Author: Ms. Agnese Zarina, Scientific Laboratory of Molecular Genetics, Rīga Stradiņš University, 16 Dzirciema Street, Riga, Latvia, LV-1007. Tel.: +371-6706-1542. Fax: +371-67-471-815. E-mail: agnese.zarina@rsu.lv or zarina.agnese@gmail.com
page: 37

RESULTS

The majority of the WD patients expressed hepatological symptoms as the first manifestation (detailed segregation of the WD patients according to their first symptoms and age of onset can be found in Table 1). A detailed description of WD patient genotypes in the ATP7B gene, clinical and biochemical findings can be found in the Supplemental Table 1. All identified variants corresponded to the Hardy-Weinberg equilibrium in the analyzed WD patient group (p >0.05). The CP Gene. In the CP gene promoter, seven allelic variants were observed: rs66508328, rs67870152, rs16861642, rs73020328, rs73166855, rs66953613 and rs11708215. As the first six of the variants mentioned above are in strong linkage (r2 = 1) (see Table 2), one of them was analyzed, rs66508328 along with rs11708215 (r2 = 0.562 from the 1000 genome project) [17], the frequency of which differed from the other variants. None of the variants in the WD patients was statistically significantly different from those described in the GnomAD database. Next, the frequency of alleles and genotypes (according to different inheritance models) was compared with the first clinical manifestation and genotype of the ATP7B gene (see Table 3). No statistically significant differences were found between allele frequencies and the first clinical manifestations of WD. Statistically significant differences were found between the two analyzed variants and the ATP7B genotype, rs66508328 variant AA genotype and the rs11708215 variant GG genotype (both according to recessive inheritance model) were more common in WD patients with the unconfirmed genotype by ATP7B gene molecular testing. The ATOX1 Gene. Four patients (out of 64) were found to have one allelic (intronic) variant, rs571657964 in a heterozygous state [minor alle frequency (MAF) for patients = 0.023; MAF in European (non Finnish) population = 0.0058] [16]. Analyzing the variant in the Human Splicing Finder software (http://www.umd.be/HSF/) [19], it was predicted that the allelic variant had no effect on splicing, thus the allelic variant was not included in further statistical analyses, as it was very unlikely to cause functional changes of the ATOX1 gene. The COMMD1 Gene. Three allelic variants were identified: rs569267407, rs55677935 and rs9096. The frequency of allelic variants of the COMMD1 gene found in this study was compared to the GnomAD database. See results in Table 4. The frequencies of COMMD1 variants did not significantly differ from the frequencies listed in the GnomAD database. As the variant rs569267407 is located in the non coding part of the gene, its potential effect on gene splicing was analyzed (using the Human Splicing Finder software) [19]. As the impact was not predicted, the variant was not further analyzed. The frequency of alleles or genotypes (by different inheritance models) was compared to the first clinical symptoms of WD patients (taking into account only those patients with molecularly confirmed WD, n = 49). No statistically significant differences were found between allele and genotype frequencies and the first clinical manifestations of WD. Comparing the incidence of both variants (in the dominant inheritance model) and the age of first symptoms, no differences were observed (rs9096 p = 0.112; rs55677935 p = 0.146); results are shown in Table 5.

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