1. Human FADD deficiency Alexandre Bolze PhD director: Pr. Jean-Laurent Casanova St. Giles Laboratory of Human Genetics of Infectious Diseases Rockefeller University, New York 10065, NY January 18, 2011

2. Clinical Presentation - Fatal Invasive pneumoccocal disease - Functional Hyposplenism - Severe viral infections - Cardiac malformations

3. Hypothesis We Hypothesized that this new syndrome would segregate as an autosomal-recessive trait. Linkage analysis and whole-exome sequencing

4. Genetic analysis Total number of reads24,989,074 Total variants called23,146 Substitutions Total (novel)21,224 (1796) Synonymous9,936 Nonsense71 Missense8,121 Splice ‐ site 37 Non ‐ coding RNAs 58 Indels1,922 chromosome 11 region Total (novel)67 (8) Synonymous (novel) 26 (1) Nonsense (novel)0 (0) Missense (novel)15 (1) Splice ‐ site (novel) 0 (0) Indels0 Chromosome 18 region Total (novel)14 (0) Synonymous (novel) 6 (0) Nonsense (novel)0 (0) Missense (novel)8 (0) Splice ‐ site (novel) 0 (0) Indels0

5. FADD C105W

6. Fas-Associated Death Domain protein (FADD) Tourneur et al. TREIMM, 2010

7. Decreased protein expression level

8. Impaired Fas-FADD interaction FADD DD Fas DD C105W

9. Impaired antiviral immunity (1) VSV infection in EBV-B cells. MOI=1

10. Impaired antiviral immunity (2) VSV infection in EBV-B cells.

11. Impaired spleen architecture?

12. ALPS ?

13. Biological features of ALPS - Increased number of CD4-CD8-TCRαβ+ T cells - Increased serum levels of FasL and IL-10. - Impaired lymphocyte apoptosis in vivo and in vitro on EBV-B cells

14. Conclusions and Questions -Whole-exome sequencing and whole-genome sequencing are great ways to find new immunodeficiencies and will probably redefine the immunology pathways in the near future. - C105W FADD homozygous mutation in humans leads to: - impaired anti-viral immunity - fatal invasive pneumococcal disease - functional hyposplenism - biological features of ALPS but no clinical phenotypes Questions remaining: - mechanism and role of FADD in the spleen architecture - How to explain that the patients do not have splenomegaly or lymphadenopathy? - Role of FADD in the development of the heart

15. New York: Jean-Laurent Casanova Minji Byun Avinash Abhyankar Paris: Anne Puel United Kingdom: David McDonald Neil V Morgan Chris M Bacon Eamonn Maher Sophie Hambleton San Diego: Lakshmanane Premkumar Stefan J Riedl Singapore: Jean-Pierre Abastado Alessandra Nardin Charlene Tow