Medical Genetics Branch National Human Genome Research Institute National Institutes of Health

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1 What I Know Best: Holoprosencephaly Max Muenke Medical Genetics Branch National Human Genome Research Institute National Institutes of Health Bethesda, Maryland, USA mamuenke@mail.nih.gov Second European Course in Clinical Dysmorphology Rome, March 28-29, 2008

2 Clinical Projects Holoprosencephaly QuickTime and a TIFF (LZW) decompressor are needed to see this picture. ADHD QuickTime and a TIFF (LZW) decompressor are needed to see this picture. Muenke syndrome

3 Holoprosencephaly (HPE)

4 Nodal and Hedgehog Signaling NODAL SHH Low Cholesterol CDO TDGF1 DISP1 PTC GLI2 TGIF FOXH1 SIX3 ZIC2

5 Sonic Hedgehog, Cholesterol, Brain Development, and Prematurity

6 Holoprosencephaly l (HPE) Midline Defect of the Developing Forebrain and Face Prevalence: 1 in 250 Early Embryos 1 in 10,000 Live-born Infants less than 1:100,000 over 1 Y/O Etiology: Extremely Heterogeneous

7 Alobar HPE Semilobar HPE

8 Holoprosencephaly p The Face Predicts the Brain

9 Holoprosencephaly Gene Carriers

10 Causes of HPE Cytogenetic Anomalies Gene Mutations Defects of Cholesterol Biosynthesis Gene/Environment Interactions ti

11 Causes of HPE Cytogenetic Anomalies Gene Mutations Defects of Cholesterol Biosynthesis Gene/Environment Interactions ti Low maternal cholesterol? Maternal diabetes? Alcohol exposure? Retinoic acid exposure?

12 Cytogenetic Anomalies in HPE

13 Positional Cloning of HPE Genes HNF3β? β TGIF ZIC2 SHH SIX3 DISPATCHED

14 Microdeletion Detection by Multicolor FISH Dispatched : 1q41 SIX3 : 2p21 SHH : 7q36 ZIC2 : 13q32 TGIF : 18p11 HNF3 β : 20p11

15 Microdeletion of TGIF ,XY.ish del(18)(p11.3p11.3)(tgif-)

16 Microdeletion Detection Multicolor FISH qpcr MLPA acgh

17 Familial Holoprosencephaly p

18 Positional Cloning of HPE Genes SHH

19 Sonic Hedgehog Cleavage and Modification Palmitate Cholesterol

20 Sonic Hedgehog Cleavage C25S and Modification C198X generates Shh-N without cholesterol or C-terminus Palmitate Cholesterol

21 Sonic Hedgehog Cleavage and Modification Human Hedgehog Acyltransferase (HHAT) Palmitate Cholesterol

22 SHH Signaling

23 SHH Signaling

24 Nodal and Hedgehog Signaling NODAL SHH Low Cholesterol CDO TDGF1 DISP1 PTC GLI2 TGIF FOXH1 SIX3 ZIC2

25 Two Mutations in HPE Patients

26 SHH Mutations in Families with SCI

27 Cholesterol biosynthesis and holoprosencephaly Background: Pertubations of cholesterol homeostasis are an important factor in HPE pathogenesis in animal models Purpose: Are alterations in cholesterol bio- synthesis are associated with HPE in humans? Methods: In vitro loading test using 14 C-acetate as a substrate which identifies C27 sterols in lymphoblasts and comparison with GCMS

28 Cholesterol biosynthesis and holoprosencephaly Results: 22 of 230 patients (9.6%) with various HPE phenotypes had abnormal sterol profiles that were different from known defects Conclusion: Impaired cholesterol biosynthesis contributes to the etiology of HPE in humans Future studies: Analysis of enzyme defects that t lead to the abnormal sterol patterns in HPE patients

29 Summary: Causes of HPE Cytogenetic Anomalies:~50-60% Gene Mutations: ~10-15% 15% Defects of Cholesterol Biosynthesis: ~ 5% Gene/Environment Interactions: ~30-40% (?)

30 Holoprosencephaly Does the Face Predict the Cause? With few exceptions: NO

31 Facial findings in children with HPE and ZIC2 mutations

32 Facial findings in children with pituitary anomalies and GLI2 mutations

33

34 Brain Development and Cholesterol Maternal cholesterol in early embryogenesis is crucial for normal craniofacial and brain development.

35 Statins Cholesterol Biosynthesis Modifiedd from C.C. Hui

36 First Trimester Statins CNS Anomalies HPE, NTD Limb Reduction Defects VACTERL

37 Brain Development and Cholesterol Pilot study of cholesterol in the parents and children with isolated HPE Result: significantly lower cholesterol l in mothers

38 Brain Development and Cholesterol HPE in patients with Smith-Lemli- Opitz Syndrome (SLOS)

39 Acknowledgements Holoprosencephaly p Clinicians around the world Erich Roessler, NIH Kenia El-Jaick, NIH, now UFRJ J.P. Karkera, NIH Claude Bendavid, NIH, U. Rennes Maia Ouspenskaia, NIH Ben Feldman, NIH Jeff Ming, CHOP/Penn, now Merck Bassem Haddad, Georgetown U. Cholesterol Robin Edison, NIH Kate Berg, NIH Alan Remaley, NIH Roger Stevenson, Greenwood Genetics Ctr Jean Golding, U. Bristol, UK Richard Kelley, KKI/JHU