Week 4 2024 - Segregation PDF

Meiotic Segregation in Reciprocal Translocations Segregation of translocations Translocation carriers can pass on a number of different combinations of that translocation. – – – – Alternate segregation Adjacent 1 segregation Adjacent 2 segregation 3:1 segregation 2:2 segregation Only Alternate segre...

Meiotic Segregation in Reciprocal Translocations Segregation of translocations Translocation carriers can pass on a number of different combinations of that translocation. – – – – Alternate segregation Adjacent 1 segregation Adjacent 2 segregation 3:1 segregation 2:2 segregation Only Alternate segregation will result in a “normal” phenotype. Other segregations can result in recurrent miscarriage or potentially an abnormal child (depending on the genetic component that is unbalanced) Understanding the likely segregation mode will help determine the most likely outcomes for different translocations. Reciprocal Translocations “The risks for carriers of reciprocal translocations of having unbalanced offspring may vary considerably from translocation to translocation They will depend on the probabilities for the production of different unbalanced gametes by the carrier parent the probabilities for the survival of unbalanced zygotes, embryos, fetuses or the newborn Both probabilities depend on the chromosome involved and the breakpoint positions…” Midro et al 1992 Clin Genet 41:113 Reciprocal Translocation der(9) 6 9 der(6) Pachytene diagram- pairing at meiosis 2:2 segregation Alternate segregation *Animated slide Adjacent 1 *Animated slide Adjacent 2 *Animated slide 3:1 Segregation Interchange trisomy *Animated slide Translocated chromosomes + normal chromosome 3:1 Segregation Tertiary trisomy Normal chromosomes + derivative *Animated slide 2:2 segregation alternate normal gamete Balanced carrier Normal 2:2 segregation - adjacent 1 Normal gamete 2:2 segregation - adjacent 2 Normal gamete 3:1 segregation 3:1 segregation Interchange trisomy Fetal karyotype: 47,XX,t(12;13),+13 Monosomy Normal gamete Trisomy Pachytene pairing at meiosis – 2:2 segregation Pachytene pairing at meiosis – 3:1 segregation 6 possible combinations: 2 alternate 2 adjacent 1 2 adjacent 2 4 possible combinations: Prediction of likely viable unbalanced segregation outcomes 46,XX,t(5;15)(p15;q15) Maternal karyotype 5 der 5 der15 15 3:1 segregation → tertiary monosomy Partial monosomy 5 and 15 AF: 45,XY,der(5),t(5;15)(p15;q15),-15 Segregation of reciprocal translocations at meiosis 46,XY,t(9;13)(q14.2;q13) 9 der(9) der(13) 13 46,XX,t(4;5)(p16.1;q33.1) der(5) 5 4 der(4) Small translocated segments Most likely outcome: ADJACENT 1 segregation Roughly equal sized translocated and centric segments Most likely outcome ALTERNATE segregation Lop sided quadrivalent involving a small acrocentric chromosome. Most likely out come: 3:1 segregation resulting in interchange trisomy Lop sided quadrivalent involving a small acrocentric derivative chromosome. Most likely out come: 3:1 segregation resulting in tertiary trisomy Small centric segments Most likely outcome: ADJACENT 2 segregation Case Summary Referred for fetal abnomalities Prenatal study on Amniotic Fluid FISH → Trisomy 13 LSI 13 LSI 21 Fetal karyotype: 47,XX,t(12;13)(p11.2;q14),+13 Maternal karyotype: 46,XX,t(12;13)(p11.2;q14) Fetal karyotype: 47,XX,der(12;13)(p11.2;q14)mat,+13 3:1 segregation: Interchange trisomy Outcomes for segregation: Alternate Normal 6 and 10 Balanced translocation t(6;10) Adjacent 1 46,N,der(10)t(6;10) = normal 6 & der(10) 46,N,der(6)t(6;10) = normal10 & der(6) Adjacent 2 46,N,+der(6)t(6;10),-10 = normal 6 & der(6) [no chr 10] 46,N,-6,+der(10)t(6;10) = normal 10 & der(10) [no chr 6] 3:1 Tertiary trisomy: 47,N,+der(6)t(6;10) = normal 6 & normal 10 & der(6) 47,N,+der(10)t(6;10) = normal 6 & normal 10 & der(10) Interchange trisomy: 47,N,t(6;10),+10 = balanaced trans & normal 10 47,N,+6,t(6;10) = balanced trans & normal 6 Tertiary monosomy: 45,N,-6,der(10)t(6;10) = only der(10) 45,N,der(6)t(6;10),-10 = only der(6) Interchange monosomy: 45,N,-6 45,N,-10 (most likely mode of segregation in this example is alternate) t(6;10) Small translocated segments Most likely mode of segregation: Adjacent 1 der(6) & 10 46,N,der(6)t(6;10) der(10) & 6 46,N,der(10)t(6:10)