18. LCRs and the origin of genomic disorders

Question 1

What are LCRs?

Answer 1

Low copy repeats

Sequence elements with high homology - recombination events take place between LCRs by NAHR

Question 2

What type of variation to LCRs lead to? Give 2 examples

Answer 2

Recurrent deletions/duplications as some regions are prone to aberrant recombination events

Question 3

What mechanisms cause non-recurrent changes?

Answer 3

NHEJ, FoSTes, MMBIR

Question 4

Where are LCRs often located?

Answer 4

Pericentromeres and sub-telomeres

Question 5

What is NAHR?

Answer 5

Form of homologous recombination

Occurs between 2 lengths of DNA with high sequence homology but that are not alleles

Question 6

What is the consequence of NAHR in meiosis and mitosis?

Answer 6

Meiosis - germline/constitutional rearrangements (i.e. de novo)

Mitosis - somatic rearrangements

Question 7

What is a contiguous gene syndrome?

Answer 7

Disorder caused by the loss/gain of multiple adjacent genes

With a recognised clinical phenotype with features of >2 disorders

Question 8

Give 2 examples of contiguous gene syndromes

Answer 8

Deafness and male infertility (STRC-CATSPER2)

DiGeorge syndrome

Question 9

Give 5 examples of LCR/NAHR mediated dels and dups

Answer 9

17p12 - PMP22 dup/del = HMSN1A1/HNPP

17p11.2 - RAI1 dup/del = Potocki-Lupski syndrome/Smith-Magenis syndrome)

PWS/AS - 15q11-13

Williams syndrome - 7q11.23

DiGeorge syndrome - 22q11.2

Question 10

What are the two types of NAHR?

Answer 10

1. Unequal crossing over - forms reciprocal dels and ups in the same event
2. Break-induced replication - occurs when replication fork collapses. Forms dels and dups in different events