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Complex Alleles

Complex Alleles. Holly referred aged 18 months from St George’s with recurrent chest infections and FTT. She was shown to be heterozygous for F508del in the local laboratory. We sequenced the whole CFTR coding region + performed MLPA (which failed validation).

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Complex Alleles

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  1. Complex Alleles • Holly referred aged 18 months from St George’s with recurrent chest infections and FTT. • She was shown to be heterozygous for F508del in the local laboratory. • We sequenced the whole CFTR coding region + performed MLPA (which failed validation). • Two further sequence variants were identified: • Intron 7 - 1249-27delTA (c.1117-26_25del) – On CF database in a 9 year old with bronchiectasis, pancreatitis and borderline sweat test. F508del was also identified in this patient. • Exon 12 - T582I (p.Thr582Ile; c.1745C>T) – On CF database in a 71 year old with bronchiectasis, positive sweat test result and CBAVD. 5T also identified. • First Report: • We reported Holly as a compound heterozygote of the F508del and 1249-27delTA CF mutations. We commented that she was also heterozygous for the T582I variant which is of “unknown clinical significance” • “This result is likely to provide a molecular confirmation of cystic fibrosis in Holly”. • Parental samples were then sent from KGC with a request to establish phase.

  2. Complex Alleles F508del+ 1249-27delTA T582I F508del+ 1249-27delTA/T582I Clearly, we got it wrong! But, by using Alamut…..T582I

  3. Complex Alleles SIFT W F YH M CR L E I Q G KD V P N A 582T S T Not Tolerated Tolerated POLYPHEN 1249-27delTA – Splicing predicitions

  4. Complex Alleles Second Report We reported Holly as a compound heterozygote of the F508del and T582I CF mutations. We commented that she was also heterozygous for the c.1117-26_25del variant which is of “unknown clinical significance” Other Threonine to Isoleucine CFTR variants

  5. Complex Alleles • Conclusions • Alamut is a useful tool and it certainly helped us with this case. • Clearly more important is establishing phase (should we ask for parents routinely in such cases?). • The 1249-27delTA variant is rare . • After the Event • Holly is pancreatic sufficient & has a normal sweat test result. • Therefore the status of T582I is not finalised despite in silico predictions. • Important to follow up such cases (D1152H, 3849+10kbC->T etc.) • We will report this case to the CFTR database.

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