CF Case Studies Frances Bond West Midlands Regional Genetics Laboratory 15/10/08 SCOBEC & Birmingham Case Studies Training Day.

CF Case StudiesCF Case Studies

Frances Bond

West Midlands Regional Genetics Laboratory

15/10/08

SCOBEC & Birmingham Case Studies Training Day

CasesCases

• Case 1- CM & AK– Echogenic bowel carrier testing referral

• Case 2 – RC– Meconium ileus diagnostic referral

Case 1 – CM & AKCase 1 – CM & AK• Pregnant women and partner

– CF carrier tests - Echogenic bowel

Case 1 – CM & AKCase 1 – CM & AK

• 0.1-0.2% of pregnancies

• Several causes including:– Normal variant - with no apparent cause

• Resolves itself with no known effect on the health of the child– Prenatal manifestation of meconium ileus

• ~11% of CF-affected foetuses

• ~1.3% of foetuses with echogenic bowel have CF– Can vary to up ~6% due to the subjectivity of diagnosing

echogenic bowel

Echogenic Bowel

Case 1 – CM & AKCase 1 – CM & AKARMS29

• CM and AK both p. Phe508del heterozygotes

Upper controls

Lower controls

p. Phe508del allele

Normal allele atp. Phe508del locus

Case 1 – CM & AKCase 1 – CM & AK

• At least 1 in 4 risk foetus affected with CF– Offer to test amniocentesis sample to determine CF status of

foetus if required

Case 1 – CM & AKCase 1 – CM & AK

• Amniocentesis sample tested to determine the CF status of the foetus– Unfortunately, MCC testing inconclusive

• Cultured amniocytes– ARMS29 assay: p. Phe508del heterozygote– No evidence of MCC

Prenatal Test

Case 1 – CM & AKCase 1 – CM & AK

• Foetus is a carrier of cystic fibrosis but is not predicted to be affected– Cytogenetic and QF-PCR results also negative

– Sadly, foetus spontaneously aborted soon after

Case 2 - RCCase 2 - RC

• 8 day old male• CF diagnosis test – meconium ileus

Case 2 - RCCase 2 - RCARMS29

• p. Phe508del and p. Arg117His compound heterozygote

Upper controls

Lower controls

p. Arg117His allele

p. Phe508del allele

Normal allele atp. Phe508del locus

Case 2 - RCCase 2 - RC

PolyT assay• Effect of p. Arg117His mutation is modulated by size

of polyT tract

• Heterozygous for 5T and 9T alleles

9T allele

5T allele

7T allele

C = ControlP = Patient RC

Case 2 - RCCase 2 - RC

Interpretation– p.Phe508del muation always in cis with 9T allele

– 5T allele must be in cis with p.Arg117His

• Classical CF with pancreatic sufficiency

Case 2 - RCCase 2 - RC

• Not diagnosed as part of neonatal screening programme– Average IRT result: 64 – below cut-off for molecular analysis

– IRT testing known to be inaccurate in cases with meconium ileus