Genetics of CCHS

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Congenital Central Hypoventilation Syndrome. Rare disorder of respiratory controlHirschsprung's disease (15%)tumours of neural crest origin (<3%)symptoms of diffuse ANS dysfunction:decreased HRV

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Genetics of CCHS

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1. Genetics of CCHS Martin Samuels

2. Congenital Central Hypoventilation Syndrome Rare disorder of respiratory control Hirschsprung’s disease (15%) tumours of neural crest origin (<3%) symptoms of diffuse ANS dysfunction: decreased HRV & response to exercise oesophageal dysmotility / severe constipation less perception of anxiety / discomfort profuse sweating pupillary abnormalities decreased body temperature

3. Neurocristopathies Neural crest gives rise to following tissues: Neuronal Endocrine Craniofacial Pigmentary Conotruncal cardiac

4. Evidence for Genetics Most cases are sporadic familial recurrence – MZ twins siblings women with CCHS and 4 affected children Milder ANSD in relatives (56 cases, 2353 relatives) Mother of CCHS child had neuroblastoma as child Analysis of genes known to be related to Hirschsprungs & NC: EDN3, RET, GDNF, HASHI Study moved to those with role in embryological development of ANS: PHOX2b

5. PHOX2b SW Regional Genetics Lab Southmead Hospital Dr Peter Lunt, Geneticist Theresa Patrick, Scientist 1st National CCHS Family Day

6. PHOX2b Analysis by: Dr Peter Lunt SW Regional Genetics Lab Southmead Hospital Bristol Scientist: Theresa Patrick Presented at 1st National CCHS

7. PHOX2b on chromosome 4p12 “encodes a highly conserved homeobox domain transcription factor” activates neuronal differentiation & regulates noradrenergic phenotype activity in hindbrain, eg nucleus tractus solitarius, nucleus ambiguous and medulla involved in embryo enteric neuroblasts

8. PHOX2b essential for development of neural crest in mice homozygous deficiency leads to fetal death due to absence of noradrenergic neurons heterozygous PHOX2b mice develop normally after birth, but have abnormal apnoea germline mutations have been found in familial neuroblastoma +/- HSCR / CCHS 1st genetic mutation to predict tumour

9. Paris Amiel J, Trang H, et al, 2003 18 / 29 (62%) CCHS children had heterozygous expansion mutations in a polyalanine tract (PHOX2b) 8 parents tested: all negative

10. Chicago Weese-Meyer et al, 2003 65 / 67 cases (97%) (2 m – 22 y) had 1 expanded allele (25-33 alanines) 1 normal allele (20 alanine repeats) 0 / 67 controls 2 cases had other adjacent mutations Commonest was 5-7 repeats 8-13 repeats had Hirschsprung’s, tumour of neural crest origin mutation length <-> number of ANSD symptoms & daily hrs ventilated

11. Chicago 97 parents: 4 had same expansions as children (~ 10% of families), but lighter signals, ie somatic mosaicism 36 sibs: all normal alleles 4 parent-infant pairs (affected adult): all 3 symptomatic infants had same expansion mutations as mother

12. Genotype – Phenotype Matera et al, J Med Genet 2004 27 patients, incl 3 sibling pairs and 3 late-onset CHS 25 (93%) showed 5-13 polyalanine expansions detected in 2 asymptomatic parents none of 120 controls AD inheritance with reduced penetrance longest expansions in phenotypically most severe cases: awake hypoventilation / HSCR mildest, including LOCHS, had 5 alanine repeats

13. Vertical Transmission somatic mosaicism in 10% parents if –ve, could have germline mosaicism (up to 50%) with CCHS infant, advise parental testing if parents affected, transmission AD mutation is meiotically stable “mutation likely to occur through misrepairing during replication followed by unequal crossing over, not through a strand slippage mechanism”

14. Autonomic Function – Gozal 05 19 CCHS patients + 24 controls 31 parents + 15 controls sympathetic challenges: cold pressor test, sighs, brachial art occlusion Pulse arterial tonometry CCHS children showed lower rises Parents of CCHS cases same as control adults confirms ANSD in children with CCHS and occurs as de novo mutation

15. PHOX2b & SIDS prevalence of SIDS high in CCHS families ? PHOX2b candidate gene for SIDS not found in 93 + 22 SIDS cases

16. New Findings 3 parents diagnosed with late onset CHS had PHOX2b mutation: 1 had 2 daughters with LO-CHS and same mutation (US) 1 with child & same mutation (Aus) 1 had daughter-son both with CCHS and same mutation (UK)

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