Summary of Aneuploidies Part 2

Reciprocal Translocations Translocation heterozygotes are at risk of having children with chromosomal imbalances/aneuploidy ◦ Carriers may have a high miscarriage rate Derivative Chromosome = Rearranged chromosome and is identified based on the centromere Can be de novo or observed in a family going back generations Whole-arm translocation = breakpoints within or near/at centromere Robertsonian Translocations Among the most common, balanced structural rearrangements Long arms of any two acrocentric chromosomes join to produce a single metacentric or submetacentric chromosome All 5 acrocentric chromosomes (13, 14,15, 21, 22) are capable of fusion events The close association of NORs within the nucleus may promote the formation of these translocations Robertsonian Translocations Nonhomologous Robertsonian Translocations ◦ Form between two nonhomologous chromosomes ◦ ~95% of Robertsonian Translocations are nonhomologous ◦ Most common = (13;14) 75% and (14;21) 10% ◦ Occur during oogenesis predominantly ◦ Most are actually dicentric ◦ Nonrandom suppression of one centromere OR both potentially function together as one centromere ◦ Location of breakpoint determines the type of translocation formed Under very rare conditions, a whole arm exchange may occur between homologous chromosomes = Homologous Robertsonian Translocations ◦ These may actually be misclassified “other” rearrangements (i.e. isochromosomes) Robertsonian Translocations Mechanisms ◦ Unions following breaks in both short arms ◦ Most common ◦ Causes a dicentric chromosome to form ◦ Centric fusion (fusion at centromere) ◦ Rare ◦ Union following breakage in 1 short arm and 1 long arm ◦ Rare Inheritance risk correlates with losses or gains in genetic material as well as imprinting risks Complications for Meiosis In meiosis, has the potential to form the QUADRIVALENT ◦ 4 chromosomes aligning and exchanging information ◦ The bigger the change (i.e. the more genetic material exchanged) the greater the probability of forming the quadrivalent Translocations result in the potential for complicated alignments and crossing over-events ◦ Further recombination can occur further reducing the likelihood of viability ◦ Autosome-Sex Chromosome translocations are particularly problematic ◦ Are not intended to align or exchange material ◦ Concerns with X inactivation potentially resulting in inactivation of autosomal segments and genes ◦ X-inactivation has been found to exhibit a preferential process designed to inactivate the least problematic X in these conditions ◦ However, if both X chromosomes have translocated material some autosomal material will be inactivated and some critical X material will not be The Quadrivalent and Meiosis Meiotic Outcomes Multiple options each with different outcomes 2:2 segregation ◦ Alternate ◦ Adjacent ◦ Most frequent for children of translocation heterozygotes ◦ Adjacent 1 = Nonhomologous centromeres to same daughter/homologous separate ◦ Adjacent 2 = Homologous centromeres to the same daughter (rather uncommon) 3:1 segregation ◦ Demonstrates devastations of monosomies as interchange monosomies are only ever seen at preimplantation genetic diagnosis 4:0 segregation ◦ May only be of little consideration in preimplantation genetic diagnosis Some of the data may imply a mechanism that ensures like centromeres segregate Translocation Quadrivalent in Meiosis Normal 2:2 refers to each daughter cell receiving 2 of the 4 chromosomes involved in the quadrivalent ALTERNATE Balanc ed Reciprocal Translocation Alternate Segregation: half the gametes receive both parts of the reciprocal translocation and the other half receive both normal chromosomes; all gametes are euploid ◦ normal genetic content, but half are translocation carriers Translocation Quadrivalent in Meiosis Unbalanced Adjacent is defined by centromeres next to each other around the quadrivalent Adjacent -1 has homologous centromeres separate Adjacent-1 Unbalanced