autosomal recessive disease and reproduction Flashcards
Where are all recessive condition mutations located on a chromsome
Between 1-22 on chromosome = autosomes
What is compund heterozygous vs recessive
Compund heterozygous - both alleles contain a different variant affected by recessive condtioon
Recessive = 2 copies of same gene with same mutation on that chromosome
incidence of CF in the UK
1 in 2500
What causes cystic fibrosis
CFTR gene mutation on chromsome 7 , most commonly delta 508 mutation
Cystic fibrosis transmembrane conductance regulator = cell mebrane chloride transporter
What is tay sachs disease
HEXA gene mutation codes for enzyme that breaks down toxic CNS products - severe neurodegnerative condition
What chances do a carrier coupleof having diseased children (each has one faulty copy) recessive disease
1 in 4 unaffected entirely or affected child
1 in 2 carrier
Of the unaffected children 2 in 3 are carrers
What are the outcomes of pregnancy for affected and unaffected partner recessive disease
All offspring will be carriers
if other parent is carrier offspring - 1in 2 chance of affected childrne
Direct children otherwise not affected unless chromsome deletions etc
Features of autosomal recessive pedigrees
Horiozontal pattern - siblings affected
Cant always follow disease through pedigree (usually not one generation after the oterh)
Parents and children of afected individuals usually unaffected
Males and females affected equally
More likely in consaguineous pedigrees or closed populations
What is consanguinity
Having children with relations second cousin or closer
ASK FH
How is consagnuinity shown on pedigree
Double horizontal line between couple
How is carrier testing offered
If someone found to be a carrier, offer testing to first degree relatives and partners
Find out chance of having affected child
Specifically test for idetifited mutation
Not done in children
How calculate risk calculation of passing on autosomal recessive disease
3 things - father and mother must be a carrier, both must pass on mutation - 1 in4
Chance of mum being a carrier x chance of dad being a carrier x 0.25
eg population chance of being a carrier or known carrier status = 1
What aware about when testing recessive disorders in partners of carriers
90% of CFTR mutations tested for - reduces risk significantly but could have rarer mutation
Consider different ethnic groups who may have different genetic mutations
What is pre implantation genetic diagnosis
Assisted production eg IVF/ICSI embryo biopsy taken from day 5-7
Testsing by FISH analysis, SNP array or test for known mutation in single gene disorder
What need to meet for PGD crtieria
Like IVF
Age, health, already have child?, couples relationship eg living together
Chorionic villous sampling - look at paeds!!
Sampling of cells taken from chorion between 11 -14 weeks
Why can results be uncertain from chorionic villous sampling
Placental mosaicism - mutation may onyl be in cells of placenta, not embryo
What is amniocentesis
Foetal cells in amnitoic fluid smapled at 15 weeks gestation
Can cause oligohydraminos and miiscarriage
Chance of miscarriage in chroionic villous smapling vs amniocentesis
0.5% amniocentesis at 15 weeks
1% CVS at 11-14 weeks
What is non invasice prenatal testing (screening) /diagnosis (for sepcific mutatuon)
Aneuploidy screening - analysis of cell-free DNA (cffDNA) in maternal bloodstream
NEPT - non invasing Testing
NIPD - non inveasive [reantal daignosis
When can you do prenatal non invasive testing
Only sufficient for analysis from 10 weeks
present from 4 weeks in blood but not enough to analyse
Who is offered X linked testing on NHS
X linked disorders
Disorders w gender specific phenotypes eg congenital adrenal hyperplasia
Ecamples of x linked disorders that can mean sex tested for
Duchennes musuclar dystrophy- severe in boys, female carriers normally unaffected
Congenital adrenal hyperplasia why can test for sex with this condition
Ambigious genitalia in females and severe salt wasting neonatally
Can improve outcomes in pregnancy with materanl dexamethasone which is why tested for
How test for sex of baby with NIPD
Maternal serum sample
Test for Y chromsome specific DNA sequences - absent = female, present = male
What can NIPD be used for
Sex testing
Specific mutation in singel gene disorder
Where is NIPD useful in single genetic disorder testing
De novo muation identified in prev preganncy or affected chid
Paternal mutation in dominant disorder
Known patenral mutation in recessive condition where both parents care carriers
Extremely low cahnce affected if not detected
Higher if it is detected
How is NIPT used in aneuploidy testing
Sinlge molecule DNA counting
See more DNA in a chromosome -> trisomy
Need to confirm with invasice testing before diagnosis
Maternal factors affecting NIPD/T
Some women have v low foetal DNA fractions eg overweight, gestational age - less likely pick up
Problem with DNA extraction/amplification
Underlying chromosomal abnormality or tumour may affect results
Pregnancy factors affecting NIPD/T
Twin pregnancies
Resolving second gestational sac
Placental mosaicism
When test cord blood for genetic condition
Implications for management or care during childhood
Otherwise no genetic testing needed
What is DYPD testing
Prescribed flurouracil-based chemotherapy considered need to do this test
DYPD deficiency of enzyme -> severe toxicity to drugs eg 5-fluorouracil
