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CF case study: Prenatal Diagnosis of an Adult Abi Jones

CF case study: Prenatal Diagnosis of an Adult Abi Jones Cheshire and Merseyside Regional Genetics laboratory. Index case. One yr old child referred from Whiston ? CF (also ?DiGeorge syndrome, ? Mosaic Down syndrome) CFHT: 1 copy of p.Phe508del. Sweat test: CF likely

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CF case study: Prenatal Diagnosis of an Adult Abi Jones

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  1. CF case study: Prenatal Diagnosis of an Adult Abi Jones Cheshire and Merseyside Regional Genetics laboratory

  2. Index case • One yr old child referred from Whiston ? CF (also ?DiGeorge syndrome, ? Mosaic Down syndrome) • CFHT: 1 copy of p.Phe508del. • Sweat test: CF likely • 2nd mutation identified: c.297-3 C>T, • seen before (France & Sweden) but uncertain effect on CFTR protein

  3. Parental testing • One year later: Mother 5/40 pregnant. Parents referred to Clinical Genetics. • Counselled 1 in 4 recurrence risk • 2nd consultation, 1 week later to discuss testing & options. Blood samples taken • Mother confirmed as a carrier of p.Phe508del • Testing for c.297-3 C>T mutation set up in LWH laboratory (not routinely available) • Mother’s DNA used as a normal control • Unexpected variant identified in mother: p.Arg75Gln, mild CF mutation of unknown pathogenicity

  4. Unexpectedresult Father Mother c.297-3 C>T p.Arg75Gln

  5. Outcome • Mother has previous Hospital admission for severe chest infection, brother with uncontrollable asthma. • Referred to adult CF clinic, had absent sinuses. Likely to have variant form of CF • Parents counselled about possible higher recurrence risk (?1 in 2 of some form of CF). Opted for prenatal diagnosis • Tests on CVS showed fetus had: • inherited p.Arg75Gln not p.Phe508del from mother • not inherited c.297-3 C>T from father. • Negligible risk of any form of CF

  6. Acknowledgments • Laboratory • Emma McCarthy • Natalie Nolan • Clinical • Emma McCann

  7. Discussion Points • ? Evidence for pathogenicity of R75Q • ? Evidence for pathogenicity of 297-3C>T • 1: Hum Genet. 1994 Jul;94(1):65-8. Unexpected inactivation of acceptor consensus splice sequence by a -3 C to T transition in intron 2 of the CFTR gene. Bienvenu T et al [Skipping of exon 3] • May be seen in complex alleles e.g. F508del / 4279insA / 297-3C>T (phase not fixed) • R75Q is a benign variant (although not according to COPD studies – Aleksandra Divac). Other evidence that it may be a respiratory modifier. • ?? May be seen at increased frequency in asthma... • R75Q frequently seen in cis with other mutations (esp S549N)

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