TO: MEMBERS OF THE CYSTIC FIBROSIS GENETIC ANALYSIS CONSORTIUM

Amos, Boston U, USA Jaume-Roig, Son Dureta, Spain

Anvret, Stockholm, Sweden Kalaydjieva, Sofia, Bulgaria

Barker, U Alabama Birm, USA Kant, U Penn, USA

Barton, Cambridge, England Kitzis, CHU-Paris, France

Beaudet, Baylor, USA Klinger, Integ Genet, USA

Baranov, Leningrad, USSR Komel, Ljubljiana, Yugoslavia

Boué, Paris, France Knight, London, England

Cao, U Cagliari, Italy Krueger, Hahnemann, USA

Carbonara, Torino, Italy Lavinha, Lisboa Codex, Portugal

Cassiman, U Leuven, Belgium Lissens, Vrije U Brussels, Belgium

Claustres, Montpellier, France Loukopoulos, Athens, Greece

Cochaux, Brussels, Belgium Lucotte, College de France

Collins, U Michigan, USA Malcolm, ICH-London, England

Coskun, Hacettepe U, Turkey Malik, Basler-Basel, Switzerland

Coutelle, East Berlin Mao, Collab Res, USA

Cutting, Johns Hopkins, USA McIntosh, WGH-Edinburgh, Scotland

Dallapiccola, Roma, Italy Morel, Lyon, France
De Arce, Dublin, Ireland Morgan, McGill, Canada

de la Chapelle, Helsinki, Finland Nukiwa, Tokyo, Japan

Dean, NCI Frederick, USA Ober, U Chicago, USA

Desnick, Mount Sinai, New York, USA Olek, U Bonn, West Germany

Edkins, Perth, Australia Orr, U Minnesota, USA

Edwards, Oxford, England Pignatti, U Verona, Italy

Efremov, Skopje, Yugoslavia Ramsay, SAMIR, South Africa

Elles, St Mary's-Manchester, England Richards, GeneScreen, USA

Erlich, Cetus, USA Romeo, Gaslini-Genoa, Italy

Estivill, Barcelona, Spain Rowley, Rochester, USA

Ferec, Brest, France Rozen, Montreal Children, Canada

Ferrari, Milano, Italy Scheffer,UGroningen,The Netherlands

Gerard, Harvard, USA Schmidtke, IHG, Berlin

Gilbert, Cornell, New York, USA Schwartz, U Copenhagen, Denmark

Godet, Villeurbanna, France Sebastio, Naples, Italy

Goossens, Creteil, France Seltzer, U Colorado, USA

Graham, Belfast, N Ireland Spona, Vienna, Austria

Halley, Rotterdam, The Netherlands Super, Royal Manchester, England

Harris, Guy's-London, England Thibodeau, Rochester, USA

Higgins, Birmingham, England Tümmler, Hannova, West Germany

Highsmith, NC Mem Hosp, USA Verellen-Dumoulin,Bruxelles,Belgium

Hood, California Inst Tech, USA Willems, U Antwerp, Belgium

Horst, Münster, West Germany Williamson,St Mary'sLondon,England

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FROM: LAP-CHEE TSUI TOTAL NUMBER OF PAGES: 8

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NEWSLETTER #28, November 5, 1990

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1. There are 4 new mutations reported to the Consortium in the last month:

a. M. Dean, M.B. White, and B. Gerrard report 2 mutations in exon 6a; the first is 852del22 (a 22 bp deletion which is the largest found so far) and the other is H199Q (see attached letter);

b. F. Chevalier-Porst, M. Mathieu and J. Godet report a nonsense mutation in exon 4 (Y122X) (see attached letter);

c. M. Goossens, N. Ghanem, P. Fanen and M. Vidaud report a splice site mutation after exon 23 (4374+1G->A).

2. The following is a synopsis of the discussions during the last consortium meeting held on October 4, 1990, at the International CF Congress in Arlington, Virginia, USA.

a. Lap-Chee Tsui made a brief report about the consortium: There is a total of 80 groups on the membership list; 4 members withdrawn from the consortium; 10 applications were refused by the Steering Committee. The total number of CF mutations reported is 59, together with 12 sequence variations (polymorphisms) and 2 corrections. The exon/intron boundary sequences for all 27 exons were reported to the consortium. The number of pages published for the last 27 issues of Newsletter is 227 (average of 8.4 pages per issue). The cost for the FAX transmission is about $500 (Canadian dollars) per month.

b. One additional member has been added to the Steering Committee; it now consists of Art Beaudet, Francis Collins, Michel Goossens, Lap-Chee Tsui and Bob Williamson.

c. Some guidelines have been established for acceptance of members to the consortium in the future. A successful application should convince members of the Steering Committee that the applicant will make useful contributions to the consortium; for example, there should be some preliminary data on mutation identification and/or population frequencies for some of the published mutations.

d. Information about the CF mutations may be provided (on a one-time basis) to investigators whose main interest is not in the area of mutation identification or screening, but rather in related fields that hold promise to provide useful insight about the structure and function of CFTR. To be qualified for the latter catagory, the investigator should provide a short summary of the proposed study, including some background information about the research topic. The investigator will also agree to respect the usual guidelines of the consortium and agree to report any interesting findings to the consortium before publication.

e. Members who are not active in contributing data to the consortium may be asked to withdraw from the consortium; the minimal requirement is one mutation or screening report every 6 months.

f. Future Newsletters will continue to be sent by FAX to all consortium members; however, the number of pages will be limited to 5-6. Large tables and other large-volume materials will be distributed by regular (air) mail. Also, since there have not been too many "simultaneous discoveries" so far, it is decided that the "10-day rule" (see previous quidelines) is unnecessary and that future Newsletters will be published monthly (in the first week of each month).

g. When reporting mutations, consortium members are asked to note the amino acid and the nucleotide changes, using the the numbering system of Riordan et al (1989); the report should contain information about the method of detection, population frequency, and, haplotype (if any), all in one page (if possible). Since the report will be transmitted by FAX, clarity of the original copy is essential.

h. It is generally agreed that association between clinical phenotype and genotype, especially for the less common mutations, is not straightforward. A test case (for G551D) is being conducted by Garry Cutting. Proposals to test any other hypotheses in the future should be submitted to the Newsletter; data collection will be the responsibity of the investigator making the proposal.

i. There is a suggestion that the Consortium should publish a report about the population frequencies of some of the more common non-[[Delta]]F508 mutations, in the same format as for [[Delta]]F508.

j. There was a suggestion that the Consortium should have a logo but the response was poor. Nevertheless, designs are welcome.

k. There are 3 possibilities for the location of the Consortium meeting in 1991:

(1) The North American CF Conference (October 2-5, 1991, Dallas, Texas);

(2) The European Cystic Fibrosis Conference (June 17-21, Copenhagen); and

(3) The Annual meeting of the American Society of Human Genetics (October 6-11, Washington, D.C.); any other suggestions?

3. A compile copy of the back issues of Newsletter #14-#26) was distributed through regular mail at the beginning of October. If you have not received it, please drop me a note. A copy of the compiled Newsletter #1-13 was included for those members who join after April 5, 1990.

Best regards,

Lap-Chee Tsui

Summary of population screening data

# CF chrom. # CF chrom.

Name Total (*) w/ mut'n Name Total (*) w/ mut'n

1. [[Delta]]F508 15802 10805 31. Y913C 218 1

2. [[Delta]]I507 4093 26 32. R553Q 674 1

3. 2566insAT 1168 1 33. S549R(A->C) 665 1

4. F508C (var?) 1039 5 34. P574H 292 1

5. I506V (var) 595 2 35. 1154insTC 346 1

6. G551D 5981 231 36. 1214delT 243 1

7. S549N 2995 15 37. 3659delC 175 3

8. R553X 5365 115 38. 556delA 387 1

9. A559T 944 1 39. 621+1G->T 1214 44

10. G542X 4243 210 40. E1371X 430 1

11. S549R(T->G) 1384 3 41. G85E 154 1

12. R560T 1243 21 42. R851X 283 1

13. A455E 1814 16 43. 711+1G->T 54 1

14. Q493X 202 1 44. G179R 61 1

15. R117H 2248 12 45. 2909delT 111 1

16. D110H 1338 1 46. 2522insC 179 1

17. R347P 3095 25 47. R1162X 125 1

18. S1255X 1512 1 48. Q1291H 638 2

19. W1282X 1217 26 49. Q39X 14 1

20. W1316X 352 1 50. G1244E 627 1

21. 444delA 1616 1 51. Y1092X 52 1

22. 3821delT 333 1 52. 3662delA 125 1

23. R334W 2101 16 53. 1677delA 393 1

24. S549I 1678 1 54. V520F 721 3

25. G458V 778 3 55. 3732delA 125 1

26. G1349D 574 2 56. 2789+5G->A 13 1

27. W846X 227 2 57. C524X 662 1

28. 1717-1G->A 752 12 58. 129G->C var? 117 3

29. N1303K 1421 30 59. 3850-3T->G

30. Y563N 346 1 60. 1784delG

61. Q552X

(*) The numbers include a rough estimate of [[Delta]]F508 screened for each of the non-[[Delta]]F508 mutations.

Standardized population screening report to the consortium

From (Name of principal investigator): ___________________________

Patient population (Location / ethnic origin):

# CF chrom. # CF chrom.

Name Total (*) w/ mut'n Name Total (*) w/ mut'n

1. [[Delta]]F508 ______ ______ 31. Y913C ______ ______

2. [[Delta]]I507 ______ ______ 32. R553Q ______ ______

3. 2566insAT ______ ______ 33. S549R(A->C)______ ______

4. F508C (var?)______ ______ 34. P574H ______ ______

5. I506V (var) ______ ______ 35. 1154insTC ______ ______

6. G551D ______ ______ 36. 1214delT ______ ______

7. S549N ______ ______ 37. 3659delC ______ ______

8. R553X ______ ______ 38. 556delA ______ ______

9. A559T ______ ______ 39. 621+1G->T ______ ______

10. G542X ______ ______ 40. E1371X ______ ______

11. S549R(T->G)______ ______ 41. G85E ______ ______

12. R560T ______ ______ 42. R851X ______ ______

13. A455E ______ ______ 43. 711+1G->T ______ ______

14. Q493X ______ ______ 44. G179R ______ ______

15. R117H ______ ______ 45. 2909delT ______ ______

16. D110H ______ ______ 46. 2522insC ______ ______

17. R347P ______ ______ 47. R1162X ______ ______

18. S1255X ______ ______ 48. Q1291H ______ ______

19. W1282X ______ ______ 49. Q39X ______ ______

20. W1316X ______ ______ 50. G1244E ______ ______

21. 444delA ______ ______ 51. Y1092X ______ ______

22. 3821delT ______ ______ 52. 3662delA ______ ______

23. R334W ______ ______ 53. 1677delA ______ ______

24. S549I ______ ______ 54. V520F ______ ______

25. G458V ______ ______ 55. 3732delA ______ ______

26. G1349D ______ ______ 56. 2789+5G->A______ ______

27. W846X ______ ______ 57. C524X ______ ______

28. 1717-1G->A______ ______ 58. 129G->C var?_____ ______

29. N1303K ______ ______ 59. 3850-3T->G ______ ______

30. Y563N ______ ______ 60. 1784delG ______ ______

61. Q552X ______ ______

(*) In order to have a more useful number for comparison among the different populations, please include the number of [[Delta]]F508 screened for the non-[[Delta]]F508 mutations, even though you might not have done so.