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Cystic Fibrosis - Clinical and Genetic Aspects

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Presentation on theme: "Cystic Fibrosis - Clinical and Genetic Aspects"— Presentation transcript:

1 Cystic Fibrosis - Clinical and Genetic Aspects
This PowerPoint file contains a number of slides that may be useful for teaching of genetics concepts. You may use these slides and their contents for non-commercial educational purposes.

2 Cystic Fibrosis This presentation contains:
Clinical manifestations of CF. Clinical photographs and X-rays. Molecular genetic basis of CF, including the structure of the CFTR gene, PCR and sequencing. Examples of pedigrees and explanation of risk calculation. CF Case scenario.

3 Cystic fibrosis Affects 1 in 2,500 babies in the UK (240 babies annually) Recessively inherited Lifelong, life-limiting illness Affects the lungs, digestive tract and pancreas by clogging them with thick, sticky mucus Daily physiotherapy, dietary supplements and intensive treatment for chest infections Talk through bullet points Notes: In CF, there is a problem transporting chloride across cell membranes CF can affect the baby before birth causing babies to be born with blocked intestines (meconium ileus) Treatment aims to improve nutrition and reduce chest infections

4 Cystic Fibrosis (1) Commonest AR-inherited disease amongst Northern European Caucasians Incidence in UK Caucasian population 1 in 2,500 carrier risk 1 in 25 Incidence in UK Asian population 1 in 10,000 carrier risk 1 in 50

5 Cystic Fibrosis (2) Gland secretions thicker or more viscous than normal Small bowel: obstruction (meconium ileus in the newborn) Lungs : thick bronchial mucous, recurrent chest infections, progressive lung damage, heart/lung transplantation

6 Cystic Fibrosis (3) Pancreas: failure to secrete digestive enzymes causing malabsorption, failure of growth and late development Men nearly always infertile – absence/atrophy of vas deferens Lifelong potentially fatal disease

7 Cystic Fibrosis Gene Large gene encoding 1480 amino acids
Over 1,100 different mutations identified in the gene Routinely test for 29 commonest mutations If mutation/s not found in clinically affected child - send DNA to laboratory to be tested for rarer mutations

8 Cystic fibrosis gene mutations
Commonest mutation – Delta F508 UK Caucasians - 75% UK Asians - 29% Common mutation found in 1 in 10 UK Asians - Y569D (substitution G - T) Delta F508 and 28 others account for 85% mutations in the Northern European Caucasian population

9 Cystic fibrosis (a) The outlook for cystic fibrosis patients has improved over the years but they still need frequent hospital admissions, physiotherapy and constant medications. Chest X-ray of lungs of cystic fibrosis patient. Erect abdominal film of newborn with meconium ileus showing multiple fluid levels. Photos (a) and (b) courtesy of Dr Tim David, Royal Manchester Children’s Hospital. Fig. 1.2 ©Scion Publishing Ltd Photos (a) and (b) courtesy of Dr Tim David

10 Fig. 1.8 ©Scion Publishing Ltd
Pedigree of Joanne Brown’s family Note the complete absence of any family history of cystic fibrosis. Autosomal recessive conditions commonly present as a single isolated case. Although Joanne is the only member of her family to be affected with CF, other members of the family must be obligate carriers of the altered gene. Fig. 1.8 ©Scion Publishing Ltd

11 Fig. 3.8 ©Scion Publishing Ltd
Structure of the CFTR gene An alternative graphical display of Human Genome Project data, as displayed by the ENSEMBL genome browser. Some closely spaced exons appear as a single bar. The arrow shows the 5’ → 3’ direction of the sense strand. Fig. 3.8 ©Scion Publishing Ltd

12 A multiplex allele-specific PCR test for 29 common CFTR mutations
The same seven samples are amplified with different cocktails of primers in the two gels. No mutation is detected in lanes 3 or 4. Extra bands in the other lanes define particular mutations by their presence and size. Fig ©Scion Publishing Ltd Photos courtesy of Victoria Stinton and Roger Mountford

13 Fig. 5.12 ©Scion Publishing Ltd
DNA sequencer trace of part of the exon 14b PCR product from Joanne Brown’s CFTR gene At the arrowed position G and C nucleotides are both present, showing that Joanne is heterozygous for a nucleotide substitution (remember that the products of PCR and sequencing are normally a mix of the products from the two alleles). Control samples show only the G. It is usual to sequence both strands of the DNA separately to confirm any change. In this case the sequence shown is of the reverse strand, so in the sense strand the change in Joanne is C>G. Fig ©Scion Publishing Ltd

14 P Sally 6.4.79 James 9.6.76 adopted Paul Aaron 3.7.84 Helen 1.5.74 Ruth Robert June George d 42 yrs RTA Harry 3.9.93 Jane Sally (1999): 7 weeks pregnant, niece recently diagnosed with Cystic Fibrosis Emergency referral by GP (by telephone) Drawing up the family tree allows the clinician to accurately assess the risk to Sallys baby. Sally and her partner would need to be referred to a regional clinical genetics unit to be offered counselling and carrier testing . Awareness of the inheritance pattern in CF (Autosomal Recessive) would lead the clinician to conclude that Ruth and Robert are both obligate carriers, they must both carry the altered gene in order for Jane to be affected. Therefore Sally has a carrier risk of 1:2 (50 %) as either George or June must have carried the altered gene in order to pass it on. Enquiring about ethnic origin is important because if James is Caucasian his carrier risk would be 1:22 ( 4%) .The risk to the baby of being affected would therefore be approximately 1:176.

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