Segregation Of Structural Abnormalities Flashcards
Alternate segregation
Alternate centromeres segregate together producing balanced gametes.
Either normal pair or two balanced homologues
Categories of combined imbalance
Mal segregation of translocations
Recombination of inversions
Segregation of insertional translocations
Ring chromosomes
Adjacent 1 segregation
Adjacent non-homologous centromeres segregate together
1 of each centromere involved in translocation
Produces unbalanced gametes, which are viable when both segments of translocation are small
Adjacent 2 segregation
Adjacent homologous centromeres segregate together
Produces only unbalanced gametes
Viable is translocation large and centric segment small
3:1 segregation
3 centromeres segregate to 1 pole and 1 to the other
8 possible segregations
Produces only unbalanced gametes
Viable if derivative chromosome is small
Two forms
Tertiary 3:1 segregation
2 normal chromosomes and 1 segregated
Interchange 3:1 segregation
2 translocation and 1 normal
Name the most common recurrent translocation
t(11;22)(q23;q11)
Carriers have an increased risk of pregnancy loss
1 viable segregation product 47,XX,+der(22)t(11;22) Emanuel syndrome = tertiary trisomy
Emanuel syndrome
Severe ID Facial dysmorphism (deep set eyes low ears and longer upper lip) Microcephaly Micrognathia Kidney abnormalities Congenital here defects Males may show genital abnormalities Developmental delay Central hypotonia
Familial implications after diagnosis of Emanuel syndrome
Parents should be offered Chr analysis to establish if balanced translocation carrier
Genetic counselling if carrier
Increased risk of miscarriage (23-37%)
Further adult relatives maybe offered testing
Affected ed individuals unlikely to reproduce
Name a viable adjacent 1 segregation
t(4;8)(p16;p23) is a recurrent reciprocal translocation
Both adjacent 1 segregants viable
46,XX,der(4)t(4;8) Wolf Hirschhorn phenotype
46,XX,der(8)t(4;8) Less specific features
Segregation analysis
Allows an estimate of the risk to any future pregnancy
If malsegregation has resulted in a viable unbalanced child then recurrence risk is significant
Most reciprocal translocations specific to family
Adjacent 1 segregation
Adjacent non-homologous centromeres segregate together
1 of each centromere involved in translocation
Produces unbalanced gametes, which are viable when both segments of translocation are small
Adjacent 2 segregation
Adjacent homologous centromeres segregate together
Produces only unbalanced gametes
Viable is translocation large and centric segment small
3:1 segregation
3 centromeres segregate to 1 pole and 1 to the other
8 possible segregations
Produces only unbalanced gametes
Viable if derivative chromosome is small
Two forms
Tertiary 3:1 segregation
2 normal chromosomes and 1 segregated
Interchange 3:1 segregation
2 translocation and 1 normal
Name the most common recurrent translocation
t(11;22)(q23;q11)
Carriers have an increased risk of pregnancy loss
1 viable segregation product 47,XX,+der(22)t(11;22) Emanuel syndrome = tertiary trisomy
Emanuel syndrome
Severe ID Facial dysmorphism (deep set eyes low ears and longer upper lip) Microcephaly Micrognathia Kidney abnormalities Congenital here defects Males may show genital abnormalities Developmental delay Central hypotonia
Familial implications after diagnosis of Emanuel syndrome
Parents should be offered Chr analysis to establish if balanced translocation carrier
Genetic counselling if carrier
Increased risk of miscarriage (23-37%)
Further adult relatives maybe offered testing
Affected ed individuals unlikely to reproduce
Name a viable adjacent 1 segregation
t(4;8)(p16;p23) is a recurrent reciprocal translocation
Both adjacent 1 segregants viable
46,XX,der(4)t(4;8) Wolf Hirschhorn phenotype
46,XX,der(8)t(4;8) Less specific features
Segregation analysis
Allows an estimate of the risk to any future pregnancy
If malsegregation has resulted in a viable unbalanced child then recurrence risk is significant
Most reciprocal translocations specific to family
Peri centric inversion
Including centromere
Paracentric inversion
Excluding centromere
Inversions
Balanced carriers usually normal
Could have reproductive problems
Only have risk of abnormal offspring if inverted segment large, includes the centromere and the end sections are small
Risk for peri centric inversion carriers
Risk of unbalanced offspring highest if non-inverted segment small or non-coding
Risk for paracentric inversion carriers
Risk of unbalanced offspring as a result of recombination in the inversion is negligible as recombinant a are not viable
Pregnancies not usually noticed as miscarry early
Recombination of pericentric inversions
Recombination within the inversion loop gives:
Normal chromosome
Inverted chromosome
Recombinant chromosome dup p distal
Recombinant chromosome dup q distal
Recombination of paracentric inversion
Recombination gives:
Normal chromosome
Inverted chromosome
Dicentric recombinant chromosome (fail to segregate lost in mitosis)
Acentric recombinant chromosome (lost in division)
Unbalanced Chr would unlikely to be viable
Names two forms of insertional translocation
Interchromosomal: segment from one chromosome inserted into a different chromosome
Intrachromosomal: segment from one chromosome inserted into different place within same chromosome
Risk of imbalance for balanced insertion carriers
Depends on size and gene content of insertion
Risk is usually higher than for a translocation carrier as the unbalanced form is either a gain or loss
Ring chromosomes
Formed from a single chromosome with loss of distal material from the p and q arms, followed by fusion.
Two categories:
- Large ring chromosomes, little material lost (in place of normal chromosome)
- additional ring chromosome (often small or markers) +r
Ring chromosome behaviour
subject to frequent errors at mitotic division, which can result in:
- Loss
- Additional copies
- Double sized rings
Generalised ring chromosome syndrome
Associated with large rings replacing the normal homologue
Growth restriction/short stature with or without LD
Other features depend on genetic content
Results from dynamic mosaicism due to errors in mitosis
Any cells generated from a mis-segregation resulting in monosomy are unlikely to be viable
