Gemma Casebook Experience

1. Gemma Casebook Experience • Background • PhD & postdoctoral research (7 years) • Clinical scientist 1997 • FRCPath Part 1 exam 2000 • Started thinking about options 2002 • First considered PhD option • relevant but too old (1994) • Next considered Papers option • 6 first author papers (pre-CS) – 1992-99 • Relevant (some too old)

2. Decision - Casebook • Each of 6 (pre-CS) papers as individual cases • Updating content & discussion • 7th case - paper reviewing an immunodeficiency service (work carried out as CS) • 8th case – interesting Wiskott-Aldrich syndrome family (work carried out as CS)

3. Casebook Proposal • Submitted proposal in 2003 • Short & simple - 1.5 pages long (< 1hr) • Stated that data from 7 papers presented & discussed in light of recent findings • Then listed 7 cases by their paper titles • Stated 8th case would cover an interesting immunodeficiency family • News proposal approved within few months

4. Casebook Title • “Molecular Analysis of the UGT1A1 TATA Box in a Gene Family Associated with Crigler-Najjar and Gilbert Syndrome and Genes associated with Wiskott-Aldrich and Hyper IGM Syndromes”

5. Cases (pre-CS) • Genetic variation in bilirubin UDP-glucuronosyltransferase gene promoter & Gilbert syndrome • UGT1A1 genotyping in a Canadian Inuit population • Gilbert syndrome is a contributory factor in the prolonged hyperbilirubinaemia of the newborn

6. Cases (2, pre-CS) • Localisation of a bile acid UDP-glucuronosyltransferase gene (UGT2B4) to chromosome 4 using PCR • Isolation of a human YAC contig encompassing a cluster of UGT2 genes & its regional localisation to chromosome 4q13 • Structure of the human UGT2B4 gene encoding a bile acid UDP-glucuronosyltransferase

7. Cases (3, work as CS) • Use of X-inactivation analysis to infer carrier status in a family with Wiskott-Aldrich syndrome • Review of the screening service for Hyper IgM at GOSH

8. Writing Casebook • The first 6 cases – mostly done by mid 2005 • 1 year maternity leave, returning mid 2006 • Unaware - must submit within 3 yrs of proposal accepted!! • Now 3.5 years later • Spoke to RCPath – allow 4 yr to submit (due to 1yr maternity) • Submitted at 4 yrs – 3-4 months -> PASS!

9. Things to note • 3 year deadline • Using papers as cases can be more work than expected if papers cover lot of work

11. PhD Option “Investigation of the molecular basis of Spinal Muscular Atrophy (SMA) in South African Patients”

12. Introduction & Aim • Pilot SMA study in S Africa • 65% black SMA patients homozygous SMNt gene del (95% in white) • Different molecular basis of SMA in population • Aim to investigate molecular basis of SMA in SA black population

13. Methods & Results • Dosage assay for SMNt del heterozygotes developed • Heterozygosity confirmed in 70% “non-homozygous del” black SMA patients • Carrier frequencies determined for black & white SA populations • SSCP, seq & blot ->to identify 2nd mutation

14. Methods & Results (2) • 3 seq variants, none functionally significant • Blot –no large scale rearrangements • Linked marker analysis (8 linked markers) • No common chromosomal background for 2nd mutation

15. Conclusions • SMA in South Africa more common than previously thought • Inclusion of SMNt dosage assay into service increases % of cases in which diagnosis can be confirmed • Allow carrier detection • Thought that a rearrangement of SMNt gene in black SMA population - unconfirmed

16. Initially... • PhD thesis already completed • Submitted an abstract to exams office to check suitability • No response from college despite repeated emails ..........

17. Then..... • Submitted • covering letter • 1 copy of thesis • Confirmation of award of the degree • CV • Update on new developments since thesis written (2003)

18. Update... • Disease / population specific updates • No further work had been carried out • Technical Advancements • MLPA for dosage • Technique explained & eg results given