Summary of mutations found in affected babies (panel 1 and panel 1+2)
Meconium ileus cases
Echogenic screen showed pregnancy to be F508del/F508del – family told predicted CF affected.
Baby included in CFNS and had normal IRT - reported as “CF not suspected”. Checked Guthrie for F508del and confirmed original results. Biochem then lowered their cut off levels slightly to try and prevent this happening again.
Baby with meconium ileus was missed on blood spots as no raised IRT – had F508del and R117H/5T
Urgent direct referral from a neonatal unit for a child with meconium peritonitis. Screened for the full panel of mutations and identified a c.3528delC heterozygote. Guthrie analysis reported this patient as ‘no mutation detected’ for four mutations. (Received in time frame)
R117H cases
Communication issue regarding F508del/R117H (7T/9T) compound heterozygote.
2 cases of F508del/R117H mutations. No guidance in CFNS for polyT analysis so not carried out on Guthrie referrals. Subsequent confirmatory blood samples requested PolyT analysis and both patients proved to be 7/9T. (These cases have been identified since 31/03/07)
Case NOT detected by CFNS:
Mother affected: Phe508del / rare mutation,
Father carrier: R117H / N.
Baby born with R117H / rare mutation.
1st IRT well below 99.5th C so not sent for DNA.
Sweat test and subsequent management not yet known.
F508del carrier picked up on CFNS. Cascade testing of family revealed 2 yr old cousin was F508del/R117H(7T) and had borderline sweat test. Being treated for CF.
F508del / D1152H identified in a CFNS case. Subsequent testing of siblings. Both F508del / D1152H compound heterozygotes.
One asymptomatic but one who had presented with a cough and small size and had been discharged.
Infant with F508del / 2789+insA on CFNS. 17 yr old brother (asymptomatic) requested testing.
Also F508del / 2789+insA and had positive sweat test.
Technical problems
False positive F508del/F508del using the CF30HT kit.
Reported to Tepnel and they subsequently located a polymorphism under normal F508del primer binding site. Now confirm all F508del homozygotes with alternative assay and different primers. All other homozygous mutations are confirmed by requesting parental samples.
One copy of F508del and no second mutation.
Sent to Manchester for rare mutation screen. Found R117H. Checked data again – no evidence of blue mutation peak on CFHT, but drop in height of green normal peak. Repeated blood spot and fresh blood sample, still no blue mutation peak. Contacted Tepnel.
Blood spot QA from CDC USA - CFHT kit failed to detect W1282X mutation. Informed Tepnel.
Problems / suggestions
Samples – variable quality, size, timing.
More referrals than predicted – cut off too low?
Lack of follow-up e.g. 2nd IRT data, 2nd rare mutation
Need to have a system for prenatal tests to pre-empt CFNS to avoid conflicting reports.
Regions with significant non-Caucasian population – 4 mutation panel not ideal e.g. NW Thames would like W1282X as large Ashkenazi
