Balkan Journal of Medical Genetics

ANDROGEN INSENSITIVITY SYNDROME DUE TO NON-CODING VARIATION IN THE ANDROGEN RECEPTOR GENE: REVIEW OF THE LITERATURE AND CASE REPORT OF A PATIENT WITH MOSAIC C.-547C>T VARIANT
Noveski P, Plaseski T, Dimitrovska M, Plaseska-Karanfilska D
*Corresponding Author: Dijana Plaseska-Karanfilska, MD, PhD, Research Centre for Genetic Engineering and Biotechnology ‘Georgi D. Efremov’, Macedonian Academy of Sciences and Arts, Krste Misirkov 2, 1000 Skopje, Republic of Macedonia, Tel. +389 2 3235 410, E-mail: dijana@manu.edu.mk
page: 51

RESULTS

Sanger sequencing did not reveal any pathogenic variant in the protein coding sequence and splice regions of the AR gene. MLPA analysis did not show the presence of deletions/duplications of the AR exons. However, we have discovered “heterozygous” nucleotide change in the 5’UTR region of the AR gene, c.-547C>T, with an unequal ratio between normal and mutated allele (T allele being over represented compared to the C allele). This was an unusual finding since every nucleotide change in patient’s X chromosome should have been presented as hemizygous, considering the patient’s 46, XY karyotype. One reason for this unusual finding could be the presence of a small proportion of cell line harboring 47,XXY karyotype, with one of the X chromosomes carrying the normal C allele. However, karyotype and multiplex QF-PCR analysis did not reveal presence of extra X chromosome. Other pos sibilities for the unbalanced ratios of the detected alleles could be the presence of DNA contamination or a mosaic mutation. To resolve this, a second blood sample from the patient was obtained, together with the blood sample from the patient’s mother. At the same time, a sample from the patient’s buccal swab was also obtained. Sanger sequencing confirmed the previous finding of both mutant and normal alleles in the DNA samples isolated from the second blood sample and the buccal swab (Figure 1, A and B). The mutation was not present in the mother (Figure 1 C), which resolved the origin of the mutation as a de novo event. Biological relatedness between patient and his mother was confirmed with the STR markers. Comparison of the areas of the normal and mutant alleles indicated that the normal allele was present in approximately 20% of the cells. This was obtained as mean value from several different electropherograms (two from Figure 1, A and B and 5 others not shown). In silico analysis with the UTRannotator showed that the c.-547C>T creates translational initiation codon ATG, and that newly created uORF terminates after 186 nucleotides. Also, UTRannotator predicted that the sequence, flanking a newly created initiation codon, shows moderate match to the Kozak consensus sequence.

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