Effect of X chromosome inactivation on phenotypic manifestations of translocations X;autosome

Phenotypic manifestations of X-chromosome;autosome translocations, in contrast to autosome;autosome translocations, often depend on several factors: the location of the break points on both chromosomes and the features of X-chromosome inactivation. Due to the development of molecular cytogenetic and genetic methods, at the present time we can investigate each specific case of such translocations in details, that allows us better understanding the causes of the pathological phenotype. The aim of the present study was evaluation the effect of the X-chromosome inactivation on the clinical manifestation of various X;autosome translocations. Break points and X-inactivation were assessed by array-CGH (8х60K, Agilent Technologies) and methyl-sensitive PCR at AR gene, espectively. Three cases of X;autosome translocations, the feature of X inactivation, and the clinical picture accompanying chromosomal rearrangement were analyzed. In the case of an unbalanced translocation 46,X,t(X;3)(p11.3;q21.3), the X-chromosome inactivation has a protective effect on the phenotype, whereas second patient with the balanced translocation 46,X,t(X;9)(q22;q13) exhibits severe clinical symptoms, possibly because of partial functional monosomy of the chromosome 9. Furthermore, the phenotype of the patient may be affected by the additional microdeletion that was found by aCGH at the 22q11.22. Finally, in the third case where the distal region of the short arm of the X chromosome is involved in the translocation 46,X,t(X;10)(p22.2;q11.2), the inactivation process is not associated with the patient phenotype, since the Xp22.2 region escape inactivation. For a detailed analysis of the phenotypic manifestations of the X;autosome translocations complex investigation with various molecular diagnostic methods is required, including cytogenetic, molecular cytogenetic methods for analyzing the structure of rearranged chromosomes, and the analysis of the X chromosome inactivation.

транслокация Х, аутосома, инактивация Х-хромосомы, X, autosome translocation, X-chromosome inactivation

1. Schmidt M., Du Sart D. Functional disomies of the X chromosome influence the cell selection and hence the X inactivation pattern in females with balanced X-autosome translocations: a review of 122 cases // Am J Med Genet. 1992. V. 42. № 2. P. 161-169.

2. Giorda R., Bonaglia M.C., Milani G. et al., Molecular and cytogenetic analysis of the spreading of X inactivation in a girl with microcephaly, mild dysmorphic features and t(X;5)(q22.1;q31.1) // Eur J Hum Genet. 2008. V. 16. № 8. P. 897-905.

3. White W.M., Willard H.F., Van Dyke D.L. et al. The spreading of X inactivation into autosomal material of an X;autosome translocation: evidence for a difference between autosomal and X-chromosomal DNA // Am J Hum Genet. 1998. V. 63. № 1. P. 20-28.

4. Mutter G.L., Boynton K.A. PCR bias in amplification of androgen receptor alleles, a trinucleotide repeat marker used in clonality studies // Nucl Acids Res. 1995. V. 23. P. 1411-1418.

5. Толмачёва Е.Н., Кашеварова А.А., Суханова Н.Н. и др. Асимметричная инактивация Х-хромосомы у эмбрионов человека с мозаичной трисомией хромосомы 16 // Генетика. 2011. Т. 43. № 3. С. 401-405.

6. Razavi Z., Momtaz H.E. Balanced reciprocal translocation t(X;1) in a girl with tall stature and primary amenorrhea // Iran J Med Sci. 2017. V. 42. № 2. P. 210-214.

7. Ворсанова С.Г., Юров Ю.Б., Чернышов В.Н. Медицинская цитогенетика. Москва: Медпрактика-М. 2006. 318 c.

8. Schinzel A. Catalogue of unbalanced chromosome aberrations in man. Berlin-New York: Walter de Cauter. 2001. 966 p.

9. Vallot C., Patrat C., Collier A.J. XACT noncoding RNA competes with XIST in the control of X chromosome activity during human early development // Cell Stem Cell. 2017. V. 20. P. 102-111.

10. Moyses-Oliveira M., Fish R., Giannuzzi G et al. Balanced X autosome translocation suggests association of AMMECR1 disruption with hearing loss short stature bone and heart alterations // Molecular Cytogenetics. 2017. V. 10 (Suppl 1):20 DOI 10.1186/s13039-017-0319-3.

11. Wolff D.J., Schwartz S., Montgomery T., et al., Random X inactivation in a girl with a balanced t(X;9) and an abnormal phenotype // Am J Med Genet. 1998. V. 77. № 5. P. 401-404.

12. Du Sart D., Kalitsis P., Schmidt M. Noninactivation of a portion of Xq28 in a balanced X-autosome translocation // Am J Med Genet. 1992. V. 42. № 2. P. 156-160.

13. Кашеварова А.А., Лебедев И.Н., Назаренко Л.П. Архитектура генома и хромосомные болезни, синдромы реципрокных микроделеций и микродупликаций / Атлас под ред. академика РАН В.П. Пузырёва, Томск: «Печатная мануфактура». 2014. 54 с.