Cytogenomic Characterization of Chromosomal X-1 Translocation to Establish a More Accurate Phenotype-Genotype Correlation in an Adolescent with Primary Ovarian Insufficiency

CASALI B; DUCATELLI ME; ARCARI A; DE BELLIS R; LAUDICINA A; GRYNGARTEN M; BOYWITT A; COCO R; MONDADORI A; MARTÍNEZ A; ESCOBAR ME; DEL REY G

Buenos Aires

Congreso; XXVI Congreso de la Sociedad Latinoamericana de Endocrinología Pedíatrica-SLEP 2016; 2016

Sociedad Latinoamericana de Endocrinología Pediátrica

Casali, B.1; Arcari, A.1; Mondadori, A.2; Ducatelli, M.E.2; Laudicina, A.3; Martinez, A.1; De Bellis, R.1; Boywitt, A.1; Escobar, M.E.1; Gryngarten, M.1; Coco, R.2; del Rey, G.1X-A translocations usually produce alterations in the gonadaldevelopment of both genders. Rearrangements of the X-chromosomein primary ovarian insufficiency (POI) has been documented by different balanced and unbalanced X-A translocations, involvingcritical regions for normal ovarian development: POF1(Xq26-q28) and POF2 (Xq13.3-q21.1). Microdeletions at thesebreakpoints have been characterized only in half of the cases. Twomechanisms have been proposed: the XIST-mediated inactivationon the autosomal region translocated, and an epigenetic effectcalled PositionVariegation that takes place when genes are locatednear a constitutive heterochromatin resulting in variegated silencing.We describe how a combination of molecular cytogenetic andSTRs analysis allowed us to detect and correlate a novel non-reciprocaltranslocation (X;1) in an adolescent with POI.We present a 14-year-old girl diagnosed with hypergonadotropichypogonadism, without somatic stigmata of Turner Syndrome.At first visit she was 3.1 years old and had short stature andno progressive motor neuropathy. She started spontaneous breastdevelopment at age 11 although at 14 she had not pubertal progress.Pelvic ultrasound showed a normal uterus and ovaries. FSHand LH were on menopausal range and low estradiol and AMHlevels were observed.Cytogenetic studies and FISH with whole-painting probes for1 and X chromosomes, heterochromatin 1q12, and Xq28 probeswere performed. Molecular analysis by QF-PCR determined theexpansion CGG of FMR1 gene (Xq27.3), and STRs: DXS8091,DXS8377, DXS1068, DXS8069, DXS15 linked to Xq28. Karyotyperevealed an apparently balanced translocation 46,X,t(X;1)(qter;q12). However, FISH showed the chromosome translocatedwithout Xq28 signal. STRs linked to Xq27.3 and DXS8091 revealedthree alleles, two of maternal and one of paternal origin. The restof STRs showed only one allele of paternal origin. Late-replicationstudies revealed the existence of skewed X inactivation in derivativeX chromosome.We characterize a de novo X-1 unbalanced translocation withdeletion Xq28 and interstitial duplication Xq27.3q28. POI iscaused by: a-Haploinsufficiency of genes in POF1. b-Duplicationof FMR1 and FMR2 genes. c-Asynapsis during meiosis leading toapoptosis of germ cells in the ovary. d-An epigenetic effect due topositioning within proximity of constitutive heterochromatin, resultingin silencing of genes in X-chromosome.