British Human Genetics Conference 2001 Programme.

Monday 10 September 2001

08:00-10:00 CLINICAL GENETICS SOCIETY - Council Meeting - Room VO44 Vanbrugh College

10:00-12:30 Concurrent sessions

FUNCTIONAL SIGNIFICANCE OF SNPs ROLE IN COMMON DISEASE AND PHARMACOGENETICS

Central Hall

Chair: Dr Anneke Seller

10:00 (SP1)

Functional Significance of SNPs: Role in Common Disease and Pharmacogenetics-Dr Nigel Spurr (North Carolina)

10:30 (SP2)

Mutation detection techniques - Prof Egbert Bakker (Leiden)

10:50 (SP3)

The extent and distribution of linkage disequilibrium: problems for SNP mappers - Prof William Cookson (Oxford)

11:10 (SP4)

Gene: environment interactions in determination of risk of coronary artery disease - Dr David Flavell (London)

11:30 (SP5)

Functional significance of SNPs in cancer - Dr Ian Frayling (Cambridge)

11:50 (SP6)

Functional analysis of promoter SNPs - Dr Bastiaan Hoogendoorn (Cardiff)

12:10 (SP7)

Applications of electronic hybridisation - Dr Elaine Wiedenhammer (Nanogen)

QUALITY IN THE PROCESS OF GENETIC COUNSELLING

Exhibition Centre Room PX001 Chair: Prof Gerry Evers-Kiebooms

10:00 Introduction

10:10 (SP8)

Clinical outcomes: investigating adjustment - Ms Rhona MacLeod (Manchester)

10:40 (SP9)

Quality in the process of genetic counseling: an exploratory study of potential outcomes - Dr Barbara Biesecker (Bethesda)

11:10 (SP10)

Value of genetic counselling: a parent's view - Ms Arlene Smyth (Clydebank)

11:30 (SP11)

The evaluation of quality and outcome of genetic counselling. A personal view of a complex problem - Prof Gerry Evers-Kiebooms (Leuven)

12:00 Discussion

AUDIT IN PRACTICE

Exhibition Centre Room PL001 Chair: Dr John Barber

10:00 (SP12)

Clinical Governance and clinical audit: an overview - Aidan Halligan (DoH)

10:30 (SP13)

Uniparental disomy: UK collaborative study - Kim Smith & colleagues (Cambridge)

10:50 (SP14)

Changes in practice resulting from the Wessex Antenatally Detected Anomalies Register (WANDA) - Dr Diana Wellesley (Southampton)

11:10 (SP15)

Haematological Cytogenetics: Rationalising the workload - Helen Dickinson (Leeds)

11:30 (SP16)

National subtelomere screening audit update - Angela Fifer & colleagues (Nottingham)

11:50 (SP17)

High resolution cytogenetic analysis: a more cost effective approach to subtelomere screening? - Caroline Browne (Salisbury)

12:10 (SP18)

Problems with clinical audit - Eileen Roberts (Birmingham)

12:30 ASSOCIATION OF GENETIC NURSES AND COUNSELLORS - Business meeting Room PX001 Exhibition Centre

12:30-13:45 LUNCH AND POSTER VIEWING (Exhibition Centre)

12:30 Workshop: QF-PCR for rapid prenatals (Room V123 Vanbrugh College)

Poster presentations

1 - Clinical Genetics/Counselling

1.01 Audit of telephone cancer genetic risk assessment counselling - Elizabeth France, S Dougan, K Gamet

1.02 Genetic Counseling in Romania - an acute issue - Odette Gore, A Bobulescu, C Gore, M lsvoranu

1.03 Comparison of two screening strategies for haemochromatosis: A pilot study investigating uptake, feasibility and cost - Christine Patch, W Rosenberg, P Roderick

1.04 An audit of internet usage prior to genetic counselling in North West Thames- Louise lzatt, C Garrett, R Abrahams, H Williams

1.05 Rhabdomyosarcoma in familial Neurofibromatosis type I secondary to deletion of the gene- Anne Lampe, G Seymour, P Thompson, A Toutain, SA Lynch

1.06 The Changing Faces of the Fetal Anticonvulsant Syndromes- Usha Kini, J Clayton-Smith, A Fryer

1.07 Something for nothing: the West of Scotland database of families with structural chromosome abnormalities- Shelagh Joss, C Longman, F Be gum, R Morrison, J Colgan, JL Tolmie

1.08 General Practitioners' experiences of cancer genetics in the millenium: a study in Wales- Kate Stansfield, R Iredale, S Leeson, A Evans, J Gray

1.09 The value of cognitive behavioural therapy in genetics: A case presentation - Amy Silver

1.10 How are gynaecologists in Wales managing women at risk of familial ovarian cancer?- Simon Leeson, R Iredale, K Stansfield, A Evans, J Gray

1,11 Increasing life expectancy in Down syndrome: implications for counselling - Alan Bittles, EJ Glasson, BA Petterson, SG Sullivan, R Hussain, JF Hallmayer, PD Montgomery

1.12 Cranial magnetic resonance images in familial PEHO-like syndrome misleadingly suggest prenatal ischaemia- Cheryl Longman, J Tolmie, R McWilllam, A McLennan

1.13 Scanning For Dural Ectasia In Marfan Syndrome- Saba Sharif, R Lailt, J Clayton-Smith

1.14 Health and education of children with oculocutaneous albinism in Zimbabwe-Patricia Lund

1.15 Epidemiology of Idiopathic Congenital Talipes Equinovarus in the UK- Simon L Barker, D J Chesney, L Sharp, N Maffulli, Z Miedzybrodzka

1.16 Behcet disease in constitutional trisomy 8- Kristin Becker, LA Brueton, P Mainie, M Bannon

1.17 A longitudinal study examining emotions in patients attending a Regional Genetic Service: The first two data points- Amy Silver, J Brocki, L Hodges, L Kerzin-Storrar

1.18 Visual performance of children with oculocutaneous albinism in South Africa- Mashudu Raliavhegwa, AO Oduntan, DDD Sheni, PM Lund

1.19 Genetic Testing, Insurance and Huntington's Disease- Peter Harper

1.20 Familial Xp duplication - Case presentation with review of this previously unexplored area- Claire Dolling, R Newbury- Ecob, C Owen

1.21 Update from the Collaborative Study of Genetic Diagnosis for Skeletal Dysplasias- Saima Alam, B Newman, D Craufurd, D Donnai, R Elles, M Briggs, J Kennedy, M Wright

1.22 Langer mesomelic dysplasia and Leri-Weill dyschondrosteosis -novel SHOX mutations and clinical phenotypic spectrum-Deborah Shears, E Guillen-Navarro, M Sempere-Miralles, R Domingo-Jimenez, PJ Scambler, RM Winter

1.23 Chromosome 3p25 deletion - a distinct face - Meenakshi Bhat, J Paterson

1.24 Five years experience of fetal examination: a clinical audit- Kate Chandler, F Lalloo, B Kerr, KMetcalfe

1.25 Myotonic Dystrophy: Who Should Be Following-Up Patients? - Annelise Nehammer, D Mukherji, F Kavalier, J Berg

1.26 Fetal Carbimazole - Is there a face? - Wee Teik Keng, D FitzPatrick, F Stewart

1.27 Prenatal testing for Huntington's disease- a description of tests performed from 1993-1998: a European collaborative study-Sheila A Simpson, M Zoeteweij, G Evers-Kiebooms, K Nys, PS Harper, A Durrs, G Jacopini, C Yapijakis

1.28 Audit of Outcome of Pregnancies of Patients seen in Prenatal Genetic Clinic- Jane Fenton-May, SE Davies, D Robinson

1.29 Audit of the Respiratory Management in the South Wales Adult Muscle Clinic- Jane Fenton-May, PS Harper, AJ Clarke, MT Rogers, ME McEntagart

1,30 Benign Familial Infantile Convulsions - genetically heterogeneous, not always benign, and not always infantile- Shane McKee, AE Hughes

1.31 The relative contribution of mutations in the DFNB loci to congenital/early childhood non-syndromal sensorineural hearing impairment/ deafness - Nuria Navarro-Coy, TP Hutchin, HE Conlon, EL Coghill, A Middleton, JS Rowland, GR Taylor, T Bishop, RC Trembath

1.32 Neuropsychological profile of children with Velo-cardio-facial syndrome (VCFS)- Linda Elisabet Campbell, AF Stevens, R Morris, A Karmilof-Smith, E Simonoff, MJ Owen, DGM Murphy, KC Murphy

1.33 Evidence for genetic modifiers in FAP - Michael Crabtree, SV Hodgson, 1PM Tomlinson, RKS Phillips

1.34 Neuroanatomical Effect of FMR1 Gene mRNA in Premutation Carriers of Fragile X Syndrome- Caroline Moore, EM Daly, F Tassone, N Schmitz, P Hagerman, P Jacobs, K Davies, KC Murphy, DGM Murphy

1.35 Premutation expansion of CGG triplet repeats affects brain; a study of Male Carriers of Fragile X Syndrome- Eileen Daly, CJ Moore, N Schmitz, P Jacobs, K Davies, KC Murphy, DGM Murphy

1.36 5,1 0-methylenetetrahydrofolate reductase C677T common mutation may be a genetic risk factor for epilepsy in Northern Europeans-Surfraz Yousaf, A Osborne, S Joss, H Halley, N Haites, S Moore, J Dean

1,37 Ectodermal Dysplasia and the Eye - Cohn Willoughby, I Ellis, SB Kaye, A Fyrer, B Batterbury

1.38 A clinical and genetics study on 30 schizophrenia patients referred to Ebne Sina Hospital, Mashhad, Iran- Kazem Ghodsi, M Alavi, M Gorji H Tofani

1.39 Poland syndrome and Klippel Feil syndrome in an adult male-Alex Magee, FJ Stewart /

1.40 Withdrawn

1.41 Informed choice and prenatal screeing: comparison of same day vs return visit testing- Theresa Marteau, S Michie, E Dormandy

1.42 A family with Hypoparathyroidism, Deafness and Renal Anomaly Syndrome- Clinical and Molecular Studies- Angus Dobbie, EA Haan, MA Nesbit, M Bowl, RV Thakker

1.43 Malformation and developmental delay in a cohort of children exposed to anti-epileptic drugs in utero- John Dean, H Hailey, SJ Moore, D Campbell, PD Tumpenny, D Lloyd

1.44 A novel atypical 22q11.2 distal deletion in father and son - Sixto Garcia-Minaur, J Fantes, R Murray, MEM Porteous, L Strain, JP Warner

1.45 Lay Beliefs and the Disclosure of Personal Genetic Information to Family Members- Angus Clarke, K Featherstone, PA Atkinson

1.46 Knowledge of Cystic Fibrosis and its Inheritance Amongst Adult Patients and Their Adult Siblings- Jo Haydon, DES Stable forth, RE Cullen, CM McKeown

1.47 A New Zealand European family with an autosomal dominant Noonan-like disorder- Kate Gibson, A Kidd, L Porteous

1.48 The North Cumbria Community Genetics Project - Public Support For A DNA Bank- Diana S Chase, EJ Tawn, P Jonas, L Parker, J Killip, J Burn

1.49 The risk of head and neck paragangliomas in SDHD mutation carriers - Jan C Oosterwijk, JC Jansen, EM van Schothorst, KH Zwinderman, AGL van der Mey, P Devilee, CJ Comelisse

2. Cytogenetics

2.01 Patient Mosaic for Two Structural Rearrangements of Chromosome 9-Richard Hall, AK Anderson, JW Taylor, V Murday

2.02 Tetraploidy in an acardiac twin - Lisa Reali, JA Sibbald, E Roberts, MD Kilby, N Ostojic, EV Davison

2.03 A Case of Childhood ALL with two TEL/AML 1 Fusions in a Hyperdiploid Karyotype- Kalliroi Stergianou, ML Whitehouse

2.04 Localisation of a Novel Region of Amplification in Follicular Lymphoma Tumours to a 24cR Region of Human Chromosome 13- Nicola Foot, M Neat, M Jenner, L Goff, I Dunham, M Ross, J Fitzgibbon, TA Lister

2.05 Screening for gene dosage alterations in subtelomeric DNA by fluorescent Multiplex Amplifiable Probe Hybridisation- John Armour, EJ Hollox, T Atia, T Parkin

2.06 A complex rearrangement of chromosomes Y,10,15 and 22 previously interpreted as an unbalanced t(Y;10) translocation- Ian Cross, SA Zwolinski, SA Lynch

2.07 Screening for Cryptic Chromosome Rearrangements using subtelomeric probes: The experience of a UK diagnostic cytogenetics laboratory - Deborah Morrogh, N Friend, R Palmer

2.08 Low oestriol levels associated with STS deletion - a case history and recommendations for prenatal screening- Jo Russell, PL Campbell, C Fear, SN Mohammed

2.09 Amplification of DEFB2 confirmed by MAPH in euchromatic variants of 8p23.1- John Barber, EJ Hollox, JAL Armour

2.10 M-FISH in routine diagnostic cytogenetics: practical and analytical aspects- Kath Smith, PJ Talley

2.11 The Use of Interphase FISH to detect Aneuploidies of Chromosomes 13, 18, 21, Y and Y in Products of Conception (POC) and Fetal Tissues (FT) following culture failure- Rachel Millener, T Davies, D Delmege

2.12 A Rare Case of Centric Fission Involving Chromosome 8- Jill Williams

2.13 Deletions of the subtelomeric region of the long arm of chromosome 9: a case report- Catherine Delmege, P Tumpenny

2.14 An audit of solid tumour referrals to the North Trent Cytogenetics Service 1995-2000, and a comparison with referrals to otherUK laboratories- Jill Elliott

2.15 A case of trisomy 18q with an unexpected phenotype- Karen Marks, MA Patton

2.16 Clinical and Cytogenetic Study on 30 Meningioma Patients Referred to Ghaem Hospital, North East of Iran- Kazem Ghodsi, A Birjandi, M Anvari, M Gorji

2.17 Chromosome Abnormalities detected in Bladder Cancer Cell Lines by Multi-plex FISH- Jon Strefford, M Steggall, D Lillington, A Nouri, BD Young, RTD Oliver

2.18 Short stature, asymmetry and limitation of movement at the elbow in a patient with a mosaic marker karyotype resulting in partial trisomy 8q24-qter- Laura Yates, I Cross, J Brummit, SA Lynch

2.19 Recurrent trisomy 21 resulting from gonadal mosaicism- Carol English, A L Hammersley, A Jackson, S Stenhouse, IE Cross

2.20 A novel duplication of the short arm of chromosome 8: a case report- Helen Stewart, C Giblin, H Elliott, M Green, D Donnai

2.21 c-MYC amplification in a CMML patient with double minutes- Joan Cunningham, K Asakura, M Sales, NR Pratt

2.22 46,XY/46,XX chimerism shown by cytogenetics and DNA polymorphism in a phenotypically normal male- Lynsey Didcock-Bayer, F McKay, D Baty, NR Pratt

2.23 A familial t(3;13) with cryptic chromosome 16 involvement- Graham Fews, SA Larkins, J Morton, EV Davison

2.24 A case of bilateral retinoblastoma due to a familial t(13;14)(q13.3q21.2;q12q13)- Graham Fews, K Britton, SM Hill, SA Larkins, T Cole, EV Davison

2.25 Aneuploidy testing using QF-PCR: development of a rapid prenatal NHS service- Kathy Mann, SP Fox, Z Docherty, C Mackie Ogilvie

2.26 A complex karyotype involving stable dicentric chromosomes and a jumping translocation- Sarah Ryley, ST Mountford, F Muntoni, CM Campbell

2.27 Detection of subtle subtelomeric rearrangements in clinical cytogenetics by MAPH- Tarek Atia, M Suri, JAL Armour, G Cross, JA Raeburn, T Parkin

2.28 Mosaic sex chromosome anomalies detected by rapid aneuploidy FISH- Rosalind Hastings, A Barnicoat, J Kelly

2.29 Coexistence of two separate unbalanced structural chromosome abnormalities, mosaic tetrasomy 8p and deletion 22q11.2, in a female infant with heart abnormality- Karen Marshall, DP Duckett, T Kontou, MJ Parker

2.30 Triple Philadelphia Chromosomes During Accelerating Phase of Chronic Myeloid Leukemia- Said Abdou, H Abdel Aziem, M Al-Ansary

2.31 Unexpected biphenotypic presentation (AML and CLL) in a diagnosed CLL case - the value of karyotyping from unstimulated cultures- Claire Fletcher, J Sadler

2.32 Two cases of prenatally detected duplications involving 8p23.1- Tracy Boyle, C Cooper

2.33 MLL gene rearrangement as an additional event to a t(10;11)(p14;q21) observed in a five month old patient with B cell ALL- Claire Fletcher, J Sadler

2.34 Development and validation of a QF-PCR assay for sex chromosome aneuploidy- Angharad Roberts, C Mackie Ogilvie, K Mann

2.35 A simple method for performing FISH on formaldehyde-fixed, paraffin-embedded tissue- Carol English, IE Cross, C Wright, S Tijani, S McKenzie

2.36 Comparison of three BCR/ABL FISH probe systems for quantitative interphase analysis- Samantha Connors, G Cuthbert, N Bown, M Cole

2.37 Specific breakpoint delineation using FISH may reduce the empiric risk associated with de novo rearrangements- Paul Campbell, C Mackie Ogilvie, C Fear

2.38 Mosaicism for double trisomy detected prenatally in cultured amniotic fluid cells - Richard Ellis, HE Harvey-Smith, KS Waters

3. Molecular Genetics

3.01 Novel mutations in the BRCA1 and BRCA2 gene in Iranian women with early-onset Breast Cancer - Vahid Reza Yassaee, S Zeinali, I Harirchi, MA Mohagheghi, DP Hornby, A Dalton

3.02 A mosaic APC gene mutation in an FAP affected patient detectable by the protein truncation test (PTT) but not by direct sequendng - David Bourn, D Cairns, J Lewis, F Macdonald, R Mountford, Y Wallis

3.03 Our experience of using the Elucigene CF20 ARMS assay - Kim Hampson, P Tarpey, J Whittaker

3.04 Mutation Analysis of the Fanconi Anaemia Group A, C, E, F and G Genes in Sporadic Acute Myeloid Leukaemia - Marc Tischkowitz, NV Morgan, SV Hodgson, C Eddy, S Ball, S Langabeer, I Vorechovsky, D Grimwade, C Mathew

3.05 Localisation of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43 - Afrina Alam, S Bevan, M Churchman, E Barclay, K Barker, EEM Jaeger, IM Leigh, RS Houlston, IPM Tomlinson

3.06 Preimplantation Genetic Diagnosis of Huntington's Disease - Cheryl Black, S Pickering, H Bickerstaff, J Caller, A Lashwood, P R Braude

3.07 A practical approach to the diagnosis of hereditary non polyposis colon cancer - Gail Norbury, DC Jones, A Lucassen, G Crawford, L Jones, IP Tomlinson

3.08 Primary open-angle glaucoma - GLC1A mutation testing in clinical practice - Laura Baumber, MA Aldred, A Hill, K Goh, W Karwatowski, RC Trembath

3.09 A comparative genome-based study of minority ethnic populations in PR China - Alan Bittles, M Black, T Baric, S Di Grandi, W Wang

3.10 Identification of RS6PKA3 gene mutations in patients with Coffin Lowry syndrome - Andrew Curtis, S Cliff, E McCarthy, A Jackson, S Lindsay, A Curtis

3.11 X inactivation status in a manifesting female carrier of X-linked myotubular myopathy - Fiona Macdonald, JB Winer, AN Norman, S Liechti-Gallati, IJ Sutton

3.12 Mutation detection protocol for STK11 mutations in patients with Peutz-Jeghers syndrome-Andrea Kay, I Ellis, A Ellis, R Mountford

3.13 Pseudoxanthoma Elasticum: Identification of mutations in the ABCC6 gene, encoding multidrug resistance protein 6- Claire Hamer, MF Pope, C Shaw-Smith, J Xavier, F Macdonald, DP Germain

3.14 Diagnostic service for X-linked retinoschisis: the first year - Rebecca Treacy, D Trump, J Whittaker

3.15 Prothrombotic genotypes do not predispose to pre-eclampsia or gestational hypertension - E Rona Morrison, ZH Miedzybrodzka, DM Campbell, NE Haites, B Wilson, MS Watson, M Greaves, MA Vickers

3.16 Screening of British CADASIL families for NOTCH 3 mutations - Michael Simpson, N Ali, YB Dong, J Powell, R Martin, A Crosby, H Markus

3.17 Genes for autosomal recessive cerebellar ataxia: order from chaos? - Andrea H Nemeth, E Dunne, P Bomont, M Moreira, E Bochukova, SM Huson, AMR Taylor, M Koenig

3.18 An investigation of the role of DNA variants of the XRCC2 and XRCC3 genes in sporadic breast cancer - Saeed Rafli, G Xinarianos, M Meuth, P O'Regan, J Thacker, I Azmy, M Reed, A Cox

3.19 The application of microplate array diagonal gel electrophoresis (melt-MADGE) to high throughput inexpensive BRCA1 mutation analysis - Mohammed Aldahmesh, E Spanakis, INM Day, DM Eccles

3.20 The Use of the Protein Truncation Test for the Analysis of Meta-PCR Products - Andrea Haworth, A Wallace, J Short, R Taylor

3.21 A Recurrent Mutation in the BRCA1 Gene Identified in Three British Families Originating fron the Indian Subcontinent - Andrea Haworth, J Short, S Cottrell, A Ardern-Jones, S Gaff, R Eeles, T Homfray, R Taylor

3.22 Epigenetic inactivation of the RASSF1A 3p21.3 tumour suppressor gene in both Clear Cell and Papillary Renal Cell Carcinoma-Catherine Morrissey, A Martinez, M Zatyka, T Kishida, M Yao, P Schraml, F Richards, F Latif, E Maher

3.23 Detection Of Whole Exon Deletions Of The PAH Gene In PKU Patients - Mary Gable, A Stephenson, A Wingate, M Williams, L Tyfield

3.24 Development of QF-PCR for the detection of common aneuploidies in uncultured amniocytes - Jane Diack, C Clark, S J Imrie, N Haites

3.25 Oculopharyngeal muscular dystrophy: not all mutations are pure (GCG) expansions - Julie Sillibourne, DO Robinson

3.26 Three year audit of referrals of suspected cystic fibrosis - Geraldine Malone, MJ Schwarz, J Cheshire, J Rawson, L Jarvey, N Andrew, M Super

3.27 Diagnostic service for von Hippel-Lindau disease: a progress report- Treacy Rebecca, E Maher, J Whittaker

3.28 Epigenetic inactivation of the RASSF1A tumour suppressor gene in Wilms' tumour- Kate Wagner, WN Cooper, RG Grundy, R Wadey, F Latif, ER Maher

3.29 100% Detection of FXI mutations by dHPLC - Pip Patel, M Mitchell, MP Smith, GF Savidge

3.30 Incontinentia pigmenti in a 46XY male patient due to somatic mosaicism for the common NEMO deletion - Sue Kenwrick, G Shuttleworth, H Woffendin, E Mayer, L Greenhalgh

3.31 Three years in the life of a diagnostic service for epidermolysis bullosa simplex - David Baty, B Lane, I McLean

3.32 Microdeletion detection of the PTCH gene by dosage analysis - Harjeet Rai, J Bell, C Hardy, P Farndon

3.33 A search for genes for congenital bilateral isolated ptosis - David Robinson, TFW McMullan, AG Tyers, JA Crolla, N Carter

3.34 A Diagnostic Screening Strategy for Cystinosis - Marlene Attard, H Middleton-Price, W van't Hoff, M Town

3.35 Mutation detection in HMSN/HNPP patients. Five years experience - Maggie Williams, L.A. Tyfield, P Guldberg, G.A Morris

3.36 Targeted Diagnostic Testing for Fragile X Syndrome - Sarah Warburton, J Waters, V Davison

3.37 Genotype/phenotype correlation of Rett syndrome patients following dHPLC analysis of the MeCP2 gene - David Bunyan, G Farrell, J Harvey

3.38 DHPLC versus gel based SSCP/Heteroduplex: a comparative analysis for high throughput screening of the HNPCC genes - Claire Curtis, P Duncan, D Bunyan, D Eccles, J Harvey

3.39 DHPLC analysis of FAP: a rapid sensitive screen of the APC gene - Philippa Duncan, C Curtis, D Bunyan, D Eccles, J Harvey

3.40 A karyotypically normal male with an apparently unstable normal FRAXA allele - William Wakeling, W King, R Hall, K Stopps, S Cottrell, R Taylor

3.41 Chemiluminescence detection offers a safe, effective and convenient alternative to radioisotopic labelling of probes for detecion of Fragile X syndrome and other single gene disorders - William Wakeling, W King, R Taylor

3.42 The pattern of biallelic APC mutations in colorectal tumours suggests a model for different categories of growth advantage - Jeremy Cheadle, M Krawczak, MW Thomas, AK Hodges, N AI-Tassan, N Fleming, JR Sampson

3.43 A Diagnostic Mutation Database - Graham Taylor, M Aldred, S Heath, W King, WP Logan, S Patton, Y Wallis

3.44 Severe digital abnormalities in a patient heterozygous for mutations in both HOXD13 and HOXA13 - Chiara Bacchelli, FR Goodman, P Debeer, JP Fryns, PJ Scambler

3.45 The involvement of transcriptional repressor proteins in Huntington's disease - Lesley Jones, J Duce, L Elliston, PS Harper

3.46 Evaluation of software systems for heterozygote detection in a high-throughput screening system for familial breast/ovarian cancer Karen Young, C Watson, A Wallace, G Wieringa, R Elles

3.47 An APC allele harbouring both Y159X and E1317Q in a large family with attenuated familial adenomatous polyposis - Nada Al-Tassan, J Maynard, N Fleming, DR Davies, JR Sampson, JP Cheadle

3.48 Neurofibromatosis-Noonan Syndrome (NFNS)- A molecular and clinical study- Diana Baralle, C Mattocks, M Lees, C ffrench-Constant, J Whittaker

3.49 The role of MUCL1 in sporadic leiomyomas and leimyosarcomas - Karen Barker, S Bevan, R Wang, A Alam, I Tomlinson, J Shipley, R Houlston

3.50 Y Microdeletion Analysis for Male Infertility Patients: 4 Years Experience In A Service Laboratory - Hilary Sawyer, M Gable, J Harrison, AP Gardner, L Tyfield

3.51 CTLA-4 gene polymorphisms and susceptibility to coeliac disease - Alistair L King, JS Fraser, SJ Moodie, D Curtis, E Reid, AM Dearlove, PJ Ciclitira

3.52 Exclusion of the candidate gene Uroplakin III in primary vesicoureteral reflux - Sean Ennis, C Bermingham, H Kelly, A Yoneda, S Kelly, D Shields, C Molony, AJ Green, P Puri, DE Barton

3.53 Mutation detection in Osteogenesis Imperfecta patients - Robert McMahon, A Dalton, S Olpin, N Bishop

3.54 Screening for BRCA1 exon deletions and duplications using QF-PCR: Identification of a BRCA1 compound heterozygote - David Ellis, S Trivers, SC Yau, SV Hodgson, SJ Abbs

3.55 A Novel Linkage Genome Marker Set Covering the Whole Human Genome - Natalie Robinson, CA Guiver, NJ Lench, AH Carey, RM Edwards, BM Dechairo

3.56 Evaluation of PCR enzyme related parameters affecting Denaturing High Performance Liquid Chromatography - Joanne Walter, H Lamb, C Griffiths, K Hecker, M Robinson, M Daniels, P Krause, D Gjerde, P Taylor

3.57 No evidence for a role for the angiotensin II, type 2 receptor in primary vesicoureteral reflux - Akihiro Yoneda, S Kelly, D Shields, C Molony, AJ Green, P Puri, DE Barton

3.58 Genetic linkage in a large multigenerational family with vasculitis - Steve Bevan, JL Rosbotham, PS Mortimer, VA Hill, R Houlston

3.59 Mitochondrial DNA mutations in Leigh syndrome - Carl Fratter, P Bignell, A Seller, J Poulton, G Brown

3.60 Mutation And Biochemical Analysis In Carnitine Palmitoyl Transferase Type II (CPTII) Deficiency Suggests Complex Genotype/Phenotype Interactions - Amal Afifi, SE Olpin, A Dalton, JV Leonard, J Land, F Muntoni, PJ Lee

3.61 Development of a Diagnostic Service for Neurofibromatosis Type 1 Facilitated by Automated Data Analysis - Chris Mattocks, D Baralle, C ffrench-Constant, P Tarpey, M Bobrow, J Whittaker

3.62 A clinical and genetic analysis of a three generation pedigree with dominantly inherited cataract and microcomea - Colin Willoughby, AE Shafiq, I Ellis, M Priston, SB Kaye, A Chandna, AL Vincent, G Billingsley, E Heon

3.63 Study of prevalence and phenotypic expression of genes associated with genetic haemochromatosis (GH) in male blood donors in Trent - Karren Palmer, MS Tanner, DC Gleeson, A Dalton

3.64 Application of DHPLC to the analysis of germline and somatic mutations in the NF1 gene - Song Han, DN Cooper, M Upadhyaya

3.65 New CFTR gene mutation confuses both OLA and ARMS - Shu Yau, V Nihalani, M Schwarz, SJ Abbs, EP Green

3.66 High throughput sequence-based mutation scanning in NF2: A rapid and improved test based on Meta-PCR - Carolyn Watson, K Young, A Wallace, G Wieringa, R Elles

3.67 Analysis of Nucleic Acid Modification Enzyme Reactions Using IP RP HPLC - Mark Dickman, DP Hornby

3.68 Clinical and laboratory service implications arising from MECP2 mutation detection - David Ravine, S Whatley, N Mason, A Clarke

3.69 Characterisation of an erythroid-specific domain of histone acetylation across the a-globin locus - Colin Johnson, E Anguita, DR Higgs, M Turner

3.70 Mapping of loci for a distinct syndrome of autosomal dominant cleft lip and palate in two families - Natalie Prescott, M Lees, P Winter, S Malcolm

3.71 Hemifacial Microsomia: progress in understanding the genetic basis of a multifactorial condition - Jess Tyson, D Kelberman, A Brady, C Garrett, M Botma, J Lim, M Calvert, R Gorlin, S Malcolm, RM Winter, M Bitner-Glindzicz

3.72 Progress in genetic counselling and prenatal diagnosis of maternally inherited mtDNA diseases - Joanna Poulton, DR Marchinglon, C Fratter, A Seller, S Kennedy

SP1

Functional Significance Of SNPs: Role In Common Disease And Pharmacogenetics

Nigel Spurr

Discovery Genetics-US, GlaxoSmithKline Pharmaceuticals

The past year has seen the completion of the draft Human Genome sequence and the announcement of the identification of over 1.4 million SNPs. The identification of DNA based variants such as single nucleotide polymorphisms (SNPs) are becoming key in both the discovery and characterisation of molecular targets in drug discovery. They are an important component in the identification, characterisation and validation of drug targets. Genetic variation may give us an insight into differences in the binding or selectivity of small molecules of drug targets, as well as their role as markers of variation in individuals and populations for association and quantitative trait studies. In addition, the use of SNPs in studying adverse events in-patients on drug therapy and in studying differences in response to therapy is becoming possible. SNPs are probably going to have wide-ranging impact on medicine from re-defining molecular pathology to understanding the role of variation response to drugs (pharmacogenetics). This t alk will focus on the identification and use of SNPs in drug discovery and discuss the future applications of these markers in Drug Discovery and Development

nks9632@gsk.com

SP2

Mutation detection techniques

Egbert Bakker, Rolf Vossen, Patrick Dieltjes, Peter de Knijif, Johan den Dunnen

University of Leiden, Institute of Anthropogenetics

Now (nearly) the whole human sequence is known, rapid detection of mutants and/or genetic variations is one of the main technical challenges. Approaches to detect genetic variants or mutants usually are divided into, the so-called scanning techniques and screening techniques. Scanning techniques are used to detect an yet unknown mutant in a gene or part of a gene while screening techniques are used test for the presence or absence of known mutants. For larger genes one often starts with a pre-scan by using heteroduplex analysis techniques such as DGGE or HPLC to identify mismatches. For the detection of known variants techniques as standard techniques as restriction digestion, ASO and OLA. As soon as large sets of patient/individual samples have to be tested newer assays are used based on the fluorescent-energy transfer techniques such as Taqman or Lightcycler assays or other techniques which enable high-throughput screening. Chips etc. A more recent development is Pyrosequencing which is a high-throughput re al-time sequencing technique. We have used Pyrosequencing n molecular genetic diagnosis: CF mutation detection (alternative for ASO), detection of somatic mosaics for point mutations for the APC gene in sporadic cases. In the forensic molecular testing: for Y-chromosome SNP-haplotyping (population studies) and for identification studies. In research to detect gene copy numbers in transgenic animals. In our hands the Pyrosequencing technique is a useful addition to the standard techniques in a molecular genetic laboratory which allows not only the detection of a sequence variant in its sequence context but also allows quantification of the sequence variant.

e.bakker@lumc.nl

SP3

The Extent and Distribution of Linkage Disequilibrium:

problems for SNP mappers

William Cookson

University of Oxford, Wellcome Trust Centre for Human Genetics

SNP mapping has been proposed as a method for identifying genes underlying complex disorders as well as genes modifying individual responses to pharmaceutical agents. My group have developed quite dense SNP maps of several chromosomal regions. Although linkage disequilibrium (LD) can extend for hundreds of kilobases the distribution of LD is highly irregular. The distribution of LD and the statistical difficulties of dealing with multiple tests of significance provide a serious hurdle to be overcome before genome-wide SNP mapping becomes an effective tool. wocc@well.ox.ac.uk

SP4

Gene:environment interactions in determination of risk of

coronary artery disease

David Flavell [1], PJ Talmud [1], NM Day [2], G Miller [3], SE Humphries [1]

(1.) Centre for Cardiovascular Genetics, BHF Laboratories, Dept of Medicine, Royal Free and University College London Medical School,

(2.) Wessex Human Genetics Institute, Southampton University,

(3.) MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive Medicine, The Medical College of St Bartholomew's Hospital

Risk of coronary artery disease (CAD) is determined by a combination of genetic and environ mental factors and their interactions. We have examined factors determining CAD risk in the Second Northwick Park Heart Study (NPHS2), a prospective study of 3000 healthy middle aged UK men followed for 8 years so far. To date there have been 189 ischemic heart disease events (acute Ml, silent Ml or coronary surgery) which are associated with the traditional risk factors of smoking, hypertension, plasma cholesterol and fibrinogen concentrations and body mass index. We have taken a candidate gene approach to examine risk associated with common variation in genes known to play a role in plasma lipid concentrations, inflammation and vessel wall biology. The majority of genetic variants examined do not show a significant effect on risk of CAD. However variants in several genes show a significant interaction with smoking status on risk of CAD, including lipoprotein lipase (LPL), apolipoprotein E (apoE), stromelysin/MMP3 and interleukin 6 (IL-6). Such interactions highlight important biological mechanisms in the pathogenesis of CAD and may help to enable the identification of subgroups with dramatically higher risk of CAD leading to more effective targeting of preventative strategies.

rmhadfl@ucl.ac.uk

SP5

Functional significance of SNPs in cancer

Ian Frayling

Department of Medical Genetics, Addenbrooke's Hospital, Cambridge

Pharmacogenetics is the study of genetic variation in, mostly, drug-metabolizing enzyme (DME) genes and thus variation in response to and handling of drugs. DMEs evolved to metabolise naturally occurring xenobiotics, and hence DME variation has a direct bearing on carcinogen activation and deactivation, and thus cancer risk. While much of the variation in DMEs is due to SNPs, variation in other non-DME genes also has a bearing on cancer risk. The major challenge is how to determine the functional significance ('pathogenicity') of such SNPs in relation to cancer risk. SNPs may lie in and affect protein coding sequence, or lie in gene controlling regions, e.g. promoters, or be in linkage disequilibrium with a pathogenic variant. Complementary approaches can and have been taken in identifying functionally significant SNPs. Candidate genes can be screened for variation in groups of affected individuals. Modifying genes amongst families with known single-gene disorders can also be studied. Finally, SNPs that have been identified in candidate genes can be tested for significance in large association studies. This latter approach ideally requires very large well defined data sets. However, it is unlikely any one SNP or other common gene variant will confer a large increase (or decrease) in risk, and overall risk will be determined by a complex combination of gene variants and environmental factors. Furthermore, subtypes of common cancers are being increasingly recognised, e.g. colorectal tumours with or without microsatellite instability. Factors predisposing to one subtype may not predispose to others. Having established functional significance, i.e. what to test for and why, the challenge will then be who to test and how, and by whom.

ian.frayling@addenbrookes.nhs.uk

SP6

Functional analysis of promoter SNPs.

Bastiaan Hoogendoorn, K Smith, SL Coleman, C Guy, PR Buckland, MC O'Donovan

Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN U.K

Single nucleotide polymorphisms (SNPs) in the regulatory regions of genes may affect transcription by altering binding or recognition sites for transcription factors or RNA polymerase. Consequent variation in gene expression may be implicated in inherited psychiatric disorders. We have developed a rapid and simple method for detecting promoter activity of putative gene promoters and for comparing the effect of promoter region polymorphic variants on the expression of genes. To date, we have selected 1050 putative gene promoters identified from a variety of publicly available databases. To date, we have designed PCR primers for 630 of these promoters. The primer pairs spanned the DNA sequence 500bp immediately upstream of, and including, the start of transcription. POR conditions were optimised for 400 of the 630 promoters, which were subsequently amplified from DNA of 16 unrelated subjects. Amplimers were screened for heteroduplex formation by DHPLC. To date, 207 out of 400 promoters were found to be polymorp hic. SNPs were confirmed and characterised by sequencing. Allelic pairs of promoters were cloned into a modified pGL3 luciferase expression T-vector, and transfected into 3 cultured cell lines (HEK293T, TE671, JEG3) before measuring levels of luciferase by luminometry. By utilising 96 well plate technology and an internal control plasmid expressing secreted alkaline phosphatase, each of these allele pairs can be tested for relative promoter activity in each of three cell lines. Significant differences in activity were detected between alleles in many of the pairs assayed. This work is ongoing and the relevant numbers are likely to change considerably.

hoogendoornb@cardiff.ac.uk

SP7

Applications of electronic hybridisation

Elaine M Weidenhammer

Nanogen, Inc., 10398 Pacific Center Court, San Diego, CA 92109, USA

Nanogen, Inc. has developed semiconductor microarrays that use electric field control to drive the transport and concentration of a nucleic acid sample to specific locations within the array, facilitating hybridization of targets with complementary probes. The NanoChip[TM] microarrays are currently available for scoring SNPs and other genetic variants; a number of additional applications are being developed, including a method for targeted gene expression profiling. Because each site on the electronic microarray can be individually controlled using the Nanogen Molecular Biology Workstation, direct analysis of a set of targets from different samples can be analyzed side-by-side on the same array. This aspect represents a particular strength of electronic hybridization for gene expression monitoring, allowing great flexibility in assay configuration while reducing experimental variation arising from between-chip comparisons. The expression levels of mRNAs derived from different cell or tissue types, or from sim ilar cell or tissue types in different physiological or pathological states, can be queried on a single NanoChip[TM] cartridge, using sequential electronic hybridizations. A method for quantitatively monitoring differential gene expression profiles of specific target mRNAs from multiple samples using electronic hybridization will be described. Inclusion of an exogenous control gene within each sample preparation allows relative levels of the cellular targets of interest to be compared between different samples. The accuracy and flexibility provided by the Nanogen arrays will provide a valuable tool for targeted gene expression profiling; in addition, the microelectronic array system allows different genetic assays, such as SNP scoring and gene expression profiling, to be performed on a single NanoChip[TM] cartridge.

eweidenhammer@nanogen.com

SP8

Clinical Outcomes: Investigating Adjustment

Rhona MacLeod

Dept of Medical Genetics, St Mary's Hospital Manchester

Most definitions of genetic counselling include helping patients adjust to their genetic situation as a key aim of clinical practice (e.g. Fraser, 1974). In comparison to other domains of genetic counselling such as comprehension of risk, adjustment has been least investigated to date. If adjustment is considered to be a favourable outcome of genetic counselling, the question arises as to what it is, and how do we measure it? Indeed there has been some debate as to whether adjustment should be considered as a state or a process (Brennan, 2001). One way forward is to look at other healthcare specialties where the same challenge exists, to see how they have explored adjustment in their patients. The literature from three specialties, general practice, oncology and psychotherapy, has been looked at to see how the following issues have been tackled: 1. the impact of communication between practitioner and counselee. 2. the 'merging' of process and outcome research 3. the extent to which research has been used to i nform clinical practice. Whilst it is acknowledged that each specialty will have characteristics unique and separate from the others in question, the literature would suggest not only an overlap of concern, but also shared ideas for conducting profitable research.

rmacleod@central.cmht.nwest.nhs.uk

SP9

Quality in the process of genetic counseling: an exploratory study of potential outcomes

Barbara Biesecker

Medical Genetics Branch NHGRI/NIH, Bethesda, MD 20892

Enhancing the quality of the process of genetic counseling depends upon arriving at consensus on its goals. Historically, studies of genetic counseling outcome have focused on client recall of information, reproductive decisions and satisfaction. While each of these outcomes is a related by-product of the process of genetic counseling, none offers a comprehensive desirable measure. Results from a small exploratory study using three qualitative approaches, in-depth interviews with experienced US genetic counselors, a focus group of US counselors and interviews with genetic counseling clients will be presented along with discussion of future research needs. Genetic counselors seem primarily focused on meeting client needs and rely on clients to make those needs known during the process. Counselors cite educating and supporting their clients as particularly important outcomes. Clients on the other hand often describe not knowing what to expect from genetic counseling. They often noted how surprised and appreciat ive they were of the discussion of their emotional needs during genetic counseling. This study noted that counselors and clients alike describe a positive interpersonal connection as a measure of success. These results imply that empirical research aimed at assessing desirable outcomes of genetic counseling may benefit from additional descriptive research to develop appropriate outcome measures.

SP 10

barbarab@nhgri.nih.gov

Value of genetic counselling a parent's view

Arlene Smyth

Turner Syndrome Support Society (UK)

Following the diagnosis of a genetic condition parent's experience many different fears and emotions. It is important that all should be offered the opportunity to have genetic counselling as soon after the diagnosis as possible. The understanding and answering of the many questions that go through your mind can be the first step to coming to terms with the conditions, especially the rare ones such as Turner Syndrome. The isolation felt when you think you are the only family in the area can increase anxiety about the condition. During the workshop I would like to speak to the delegates about why genetic counselling is important and discuss the various stages in ones life it can benefit both the individual affected and their family. I speak from personal experience when my daughter was born with Turner Syndrome.

TurnerSynd@aol.com

SP 11

The evaluation of quality and outcome of genetic counselling. A personal view on a complex problem.

Gerry Evers-Kiebooms

Psychosocial Genetics Unit, Center for Human Genetics, Leuven, Belgium

The education model and the counselling model are two basic approaches to genetic counselling with their own strengths and limitations. Notwithstanding the fact that the skills needed for the two approaches differ so vastly that only unusually gifted and flexible professionals are able to combine them in short term interactions, it is important for the profession to combine them (to find a good balance). A team approach involving professionals from different disciplines may result in a better type of combination. The evaluation of "success" and "quality" of genetic counselling is complex for several reasons. The value and limitations of four different outcome measures are discussed: - knowledge and retention of information - reproductive plans and reproductive behaviour - patient satisfaction with the process of genetic counselling - perceived personal control. For studying genetic counselling inspiration has been sought in the study of other medical consultations. These studies suggest a framework involving the "input" to counselling, the "process" of counselling - in a genetic counselling context sufficient attention should hereby be paid to the adequate measurement of (non) directiveness- and the "outcomes" of counselling. Within this framework it is important to delineate the role of input and process variables as predictors of outcomes. So far the results are rather limited. Evaluating and improving the quality of the process of genetic counselling is a continuing challenge...

Gerry.Kiebooms@med.kuleuven.ac.be

SP12

Clinical Governance and Clinical Audit

Aidan Halligan

NHS Clinical Governance Support Team

The NHS Clinical Governance Support Team (CGST) runs a series of unique programmes to support the implementation of clinical governance 'on the ground'. Clinical governance is the framework which helps NHS organisations provide safe and high-quality care. Fundamental to making this happen is creating and enabling a cultural change within the NHS. Through its innovative programmes, the CGST enables a wide variety of NHS organisations to involve staff and patients in improving services. Clinical governance is about changing the way people work, demonstrating that leadership, teamwork and communication is as important to high-quality care as risk management and clinical effectiveness. The CGST has developed a challenging strategy that involves implementing clinical governance at a number of levels through: A general Clinical Governance Development Programme. This covers more than 300 NHS organisations to date. This works through a 5-day, results-focused, task-oriented programme for multi-disciplinary teams. Set over nine months, this programme helps frontline staff bridge the 'knowing-doing' gap. A 'strategic leadership' programme for NHS Boards to facilitate 'whole systems' quality improvement programmes - taking a 'top down' and 'bottom up' approach. Wider work with NHS regions and health economies. One of the aims of this work is to ensure capability is provided within these organisations. The use of 'protected time' pilots to allow whole organisation as well as health economy implementation of clinical governance and spread of best practice. Specific specialty programmes around implementing clinical governance best practice. Other CGST objectives include: Improving awareness and understanding of clinical governance amongst NHS organisations, healthcare professionals and patients. Disseminating the lessons learned to enhance and accelerate quality improvement and modernisation across the NHS.

aidan.halligan@ncgst.nhs.uk

SP13

Uniparental Disomy: UK Collaborative Study

Kim Smith

T Boyle

D Morgan

CA Parkin

Association of Clinical Cytogeneticists (ACC) Working Party on UPD

Fifteen UK cytogenetics laboratories responded to an ACC questionnaire on both prenatal and postnatal referrals and cytogenetic findings when uniparental disomy (UPD) investigations were instigated. PRENATAL: Fetal UPD 15 was confirmed in two cases of trisomy 15 confined to the placenta (CPM) and one case of apparent trisomy 15 pseudomosaicism in amniotic fluid. Fourteen cases with a supernumerary marker derived from 15 and 12 cases with a parent carrier of a Robertsonian translocation involving 15 were investigated and all showed biparental inheritance.

Fifty prenatal cases of a parent carrying a Robertsonian translocation involving chromosome 14 (24 cases maternal and 26 cases paternal) all showed biparental inheritance. There were no cases of UPD7 or UPD6 detected. UPD16 was confirmed in a single case of trisomy 16 CPM. POSTNATAL: UPD14 was confirmed in a female with precocious puberty, a carrier of a balanced Robertsonian translocation involving 14 and in conjunction with trisomy 14 mosaicism. Four referrals for Silver-Russell syndrome/short stature showed UPD7 and one case of transient neonatal diabetes mellitus showed UPD6. UPD was found associated with either structural rearrangements or mosaicism for chromosomes 6, 7 and 9.

kim.smith@addenbrookes.nhs.uk

SP14

Changes in Practice resulting from the Wessex Antenatally Detected Anomalies Register (WANDA)

Diana Wellesley

NR Dennis

Wessex Clinical Genetics Service

Congenital Anomaly Registers are increasingly recognised as a useful prevalence tool but undervalued as a vehicle for communication and clinical change. WANDA commenced in 1994 as a regional register. In order to facilitate early change and ongoing communication the basis for its data collection has always been regular local WANDA meetings, one to three monthly, in each of the contributing districts. Thus when new findings or worrying trends are observed, immediate action can be instituted. This is particularly useful in the changing field of ultrasound 'soft markers'. Directly as a result of the WANDA data analysis, significant changes have occurred in the management of patients throughout the region whose fetuses are found on scan to have echogenic bowel, ventriculomegaly, pyelectasis or choroid plexus cysts. In addition, the use of warfarin in early pregnancy was also amended following the detection of 2 cases of warfarin embryopathy soon after a change in anti-coagulant policy within the Wessex Cardiothor acic Centre. Further details of these cases will be presented illustrating the value of congenital anomaly registers as an integral part of fetal medicine.

dgw@soton.ac.uk

SP15

Haematological Cytogenetics - Rationalising The Workload

Helen Dickinson

Cytogenetics Lab, St James' Hospital, Beckett St, Leeds. LS9 7TF

Since September 98 the Leeds Cytogenetics lab has collaborated with HMDS, a regional haemato-pathology unit to rationalise the tests performed on bone marrow samples referred for a suspected haematological disorder. We have agreed with our local clinicians that chromosome analysis is inappropriate unless there are distinct haematological indications and we are undertaking a policy of targeted testing. With the exception of patients entered into clinical trials where a different approach may be justified, we have drawn up a joint protocol balancing the use of conventional karyotyping with FISH or PCR techniques. Chromosome analysis is the most versatile technique, able to detect the majority of common abnormalities but relies on successful culture of the abnormal clone, is labour intensive, has less sensitivity, and is more expensive than FISH or PCR. In the lymphoid neoplasms interphase FISH or PCR may be the technique of choice to identify the markers which have independent prognostic significance. The major ity of follow-up samples can be monitored by PCR techniques if an informative abnormality is present at diagnosis. This has led to over 40% of samples not having conventional cytogenetic analysis resulting in a smaller backlog, decreased turnaround time, higher abnormality rate, and improvements in patient management.

helen.dickinson@gw.sjsuh.northy.nhs.uk

SP16

National subtelomere screening audit update

Angela Fifer

N Smith

K Martin

Department of Cytogenetics, City Hospital, Nottingham, NG5 1PB

Subtelomeric rearrangements have been reported to be responsible for 7.4% of moderate to severe cases of idiopathic mental retardation (Knight S and Flint J, Journal of Medical Genetics 2000:37:401-409). With the introduction of commercial subtelomere multi-probe systems many clinical cytogenetic laboratories have introduced a screening service. Data from a national audit of subtelomere screening was presented at the Association of Clinical Cytogeneticists Spring Meeting 2001 in Nottingham. The aims of this audit were firstly to combine screening data from all participating laboratories to establish detection rates of subtelomeric rearrangements, secondly to produce an anomaly map of the subtelomeric regions and thirdly to establish the range of the referral guidelines in operation around the country. An update of this audit will be presented and any changes to the screening service made as a result of the initial audit will be discussed.

amfifer@yahoo.com

SP17

High resolution cytogenetic analysis: a more cost effective approach to subtelomere screening?

Caroline Browne [1], NR Dennis [2], IK Temple [2], CA Joyce [1]

(1.) Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, UK, (2.) Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, SO16 5YA

A subtelomeric FISH screen undertaken in our laboratory on 200 developmentally delayed patients revealed no cryptic rearrangements. One patient carried a subtle terminal rearrangement identified by high resolution G-banded analysis prior to FISH screening. Subsequently we have continued to offer FISH subtelomere screening only for referrals through a Clinical Geneticist and following repeat high resolution analysis. Amongst 18 patients referred by a Clinical Geneticist no cryptic rearrangements were found. However, one of these patients was found to have a subtle terminal rearrangement on re-analysis prior to FISH screening. For a trial period a new cytogenetic approach was instigated involving concentrated analysis of the subtelomeric regions in a prometaphase cell in all developmentally delayed patients, the aim being to determine the feasibility of substituting FISH subtelomere screening with higher resolution cytogenetic analysis. Of 420 patients analysed using this protocol, 20 (4.1%) carried an unbalanc ed structural rearrangement, 6 of which (30%) were subtle and required subtelomeric FISH for confirmation. The frequency of 4.1% in this trial period was slightly higher than in the previous 5 years (range 2.3-3.7). However the number of subtle unbalanced rearrangements detected had increased in recent years from 7/148(4.7%) (Aug 95-July 98) to 19/165 (11.5%) (Aug 98-May 01). Our data suggests that high resolution G-banded analysis focused on subtelomeric regions may be the most cost effective approach of detecting cryptic terminal rearrangements. Indeed, 11(42%) of the 26 subtle rearrangements detected in our laboratory since 1996 had previously been reported as cytogenetically normal.

wessex.genetics@dial.pipex.com

SP18

Problems with Clinical Audit

Eileen Roberts, LJ Reali, EV Davison

Regional Genetics Laboratories, Birmingham Women's Hospital NHS Trust, Edgbaston, Birmingham B15 2TG

Clinical Governance places a responsibility on all NHS staff to be quality focussed and accountable for their actions. A crucial part of this is leaming from errors and problems that arise during patient treatment or investigations. A number of recent publications have highlighted the need for the NHS to move towards a 'safety' culture rather than a 'blame' culture, thereby focussing on areas for improvement and changes in practice. We routinely monitor problems that arise during laboratory genetic investigations of patients and a problems log detailing all such problems is maintained. The log is separate from the Trust incident reporting procedure and is an internal document only. We have recently audited the problems encountered over a 17-month period (approximately 19,500 cytogenetic samples received) to determine their impact (if any) on patient management and whether changes in practice are warranted. Recording and auditing of problems in this way raises a number of issues relevant to clinical audit, inc luding the application of standards, and actual practice compared to perceived practice. This presentation will use the problems log audit as an example to highlight these issues and to look at how we have attempted to overcome problems associated with clinical audit.

eileen.roberts@bham-womens.thenhs.com

SP19

Artificial Chromosomes: Progress and Prospects

Howard Cooke, Jose de Las Heras, Ming Hong Shen

MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU

It is now 4 years since the first mammalian artificial chromosomes were produced. Since then there have been a number of developments and new approaches but the mechanisms behind the formation and function of these chromosomes remains obscure. The debate about the role of DNA sequence versus epigenetic determinants continues in the absence of the sequence conservation seen at telomeres. Can artificial chromosomes throw some light on this question? Different methods exist for the production from naked DNA of chromosomes with kinetochores which function but the methods all have common features in terms of the DNA content of the input and its multimerisation in the chromosomes formed. The opposite approach of chromosome engineering in the cell can provide complementary information. What are the prospects of their providing a platform for the development of gene delivery systems? Where do the different approaches have advantages and disadvantages? What future developments are needed?

Howard.Cooke@hgu.mrc.ac.uk

SP20

Large-Scale chromatin structure and function in the Major Histocompatibility Complex

Denise Sheer, E Volpi, S Beck, R Horton, R Donev

Imperial Cancer Research Fund, London, & The Sanger Centre, Cambridge

We recently showed that giant chromatin loops carrying the Major Histocompatibility Complex (MHC) on chromosome 6 are rapidly induced when MHC gene expression is up-regulated with interferon-gamma (J.Cell Sci, 2000,113:1565-1576). Since the nuclear matrix has been suggested to play a role in chromatin folding, we mapped the consensus matrix attachment regions (MARs) in the MHC. A subset of these which are adjacent to the TAP/LMP gene cluster were then shown experimentally to bind to the nuclear matrix. Furthermore, several of these MARs were found to associate with specific proteins involved in transcriptional and regulation and mRNA processing when gene expression was upregulated. These findings will be discussed in relation to current models of large-scale chromosome organisation.

sheer@icrf.icnet.uk

SP21

Packing and unpacking of DNA in sperm

Rod Balhom, M Corzett, C Dolan, LR Brewer, J Lee, MJ Allen

Lawrence Livermore Nat Lab, Livermore, CA USA

balhorn2@llnl.gov

SP22

Chromosomes, gene control and new therapies for human disease

Alan Wolfe

California

Abstract not submitted

SP23

Mutations in the gamma2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis.

Edward Blair [1], C Redwood [1], H Ashrafian [1], M Oliveira [1], J Broxholme [2], B Kerr [3], A Salmon [4], Ostman-Smith [5], H Watkins

(1.) Department of Cardiovascular Medicine, University of Oxford, (2.) Wellcome Trust Centre for Human Genetics, University of Oxford, (3.) Royal Manchester Childrens Hospital, UK (4.) Southampton General Hospital, UK, (5.) Paediatric Cardiology, John Radcliffe Hospital, Oxford

Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known disease-genes are not found in up to one third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in the gamma2 subunit of AMP-activated protein kinase (AM PK) in two families with severe hypertrophic cardiomyopathy and with aberrant conduction from atria to ventricles in some affected individuals (pre-excitation; Wolff-ParkinsonWhite syndrome). The mutations, one missense and one in-frame single codon insertion, occur in highly conserved regions. One of the mutations occurs in an equivalent site to a skeletal myopathy causing mutation in the pig gamma 3 subunit of AMPK. Neither mutation is seen in a control population of chromosomes. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, we propose that these data substantiate energy compromise as a unifying abnormality in all forms of HCM. This conclusion should radically redirect thinking about this disorder and also, by establishing energy depletion as a cause of myocardial dysfunction, should be relevant to the acquired forms of heart muscle disease that HCM models.

Ed.Blair@orh.nhs.uk

SP24

Nail Patella Syndrome: Expanding the clinical phenotype

Elizabeth Sweeney [1], AE Fryer [1], RC Mountford [2], AJ Green [3], McIntosh [4]

(1.) Merseyside and Cheshire Clinical Genetics Department, Royal Liverpool Children's Hospital, Alder Hey, Liverpool, (2.) Merseyside and Cheshire Molecular Genetics Laboratory, Liverpool Women's Hospital, Crown Street, Liverpool, (3.) National Centre for Medical Genetics, Our Lady's Hospital for Sick Children, Crumlin, Dublin (4.) Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA

Nail Patella Syndrome (NPS) is an autosomal dominant condition affecting the nails, skeletal system, kidneys and eyes. Skeletal features include absent or small patell", elbow abnormalities, talipes and iliac horns on x-ray. Kidney involvement may lead to renal failure and there is also a risk of glaucoma. There is marked inter- and intra-familial variability. We present the results of a British study involving 123 NPS patients and suggest that gastrointestinal and neurological symptoms may also be part of the NPS phenotype. We also present the first data on the incidence of glaucoma in NPS. 98% of patients had fingemail changes. 75% of patell were hypoplastic and 9% absent. There was loss of extension in 70% of elbows and 12% of patients had pterygia. 19% had congenital talipes. 68% had iliac homs on X-ray. Renal involvement was present in 25% of patients (33% in [greater than] age 40) with an average age at detection of 22 years (1-51). Only 2% had developed renal failure. 7% had…