Introduction to consanguinity, clinical impact and need for diagnostic testing

1. Introduction to consanguinity, clinical impact and need for diagnostic testing Dr Peter Corry Neurodisability paediatrician, Bradford

2. Aims • Outline situation in Bradford • Discuss consanguinity • Highlight some issues • Report on progress • The future

3. Bradford • Population 360,000 • Children (up to 18) 106,000 • Annual births 5,500-6,000 • Pakistani origin births approx 50% High rates of consanguinity and endogamy These figures exclude Airedale

4. Ethnicity of pregnant women • Pakistani 47 % • White British 37 % • Bangladeshi 4 % • Indian 3 % • Other white 2 % Data on first 674 pregnant women enrolled (2007) to Born in Bradford

5. Autosomal recessive conditions • Typical district probably has 15-25 different AR conditions in children (e.g. Cyst Fibrosis) • Blackburn reported 83 in 2004 (1) • Pakistani children x 12 times • Bradford 157 (1) Benson and Korwariwalla

6. Give me a letter! Any letter of the alphabet, please except Q and Y.

7. Neurodegenerative conditions • 1986 8 children • 1999 45 children Pakistani 39 White British 5 Arabic 1

8. BPSU study since 1997 • Progressive Intellectual and Neurological Deterioration, case reports by monthly “orange card”. United Kingdom 902 children Bradford postcode 72 children (8% of UK total) British Paediatric Surveillance Unit Bulletin Oct 2006

9. Microcephaly • 44 children • 35 congenital, 9 postnatal • Congenital: 27 Pakistani 7 White British 1 Bangladeshi Corry P, 2002 Community Genet.

10. Cerebral Palsy in Bradford • Prevalence (Asian) 5.48/1,000 • Prevalence (Non-Asian) 3.18/1,000 • 8 out of 29 Asian children had close relative with same type of cerebral palsy Sinha G, 1997 Dev Med Child Neuro

11. International evidence Saudi Arabia Odds ratio for cerebral palsy: 14.52 with affected sibling, 2.31 for consanguinity Turkey Odds ratio: 3.2 for consanguinity, 16% had relative with cerebral palsy Al-Rajah S, 1991, Dev Med Child Neuro Tuzun EH, Eker L, EMCPDM Congress 2002

12. Australian study • 10,000 people taking part in a University of Adelaide study: to identify whether genetic factors make women more vulnerable to environmental risks that affect the brain of their newborn child Science Daily 2 July 2008

13. The global distribution of consanguineous marriage

14. Cousins and clans • First cousin marriage is most popular • Some are double first cousins (i.e. your cousin partner’s mother and father are both blood relatives) • Even if not cousins, many marriages are within the biraderi or clan. These may show a founder effect (c.f. Amish)

15. Risk of having a child with disability • Unrelated parents 2 % • First cousins 4 % • Double first cousins 6 % • BUT also increased with maternal age, smoking, drinking, drugs, poor nutrition, poor obstetric/healthcare

16. Risk of having a child with disability • Risk for first cousins is doubled but still low (i.e. 4% instead of 2%, so 96% have healthy children) • Risk for the community is an extra 2% incidence (i.e. with 2,000 consanguineous births each year, an extra 40 children with autosomal recessive [AR] conditions)

17. Added risks - community customs • Child of random first cousins has risk that 6% (1/16) of genes are homozygous • Child of first cousins from UK communities preferring consanguinity has risk that 11% of genes are homozygous Woods C G, 2006 (Am J Hum Genet)

18. Family Tree

19. It’s not all due to cousin marriage • Endogamy • Limited understanding of genetics • Poor access to information? • Early pregnancy may be spent abroad • Barriers to antenatal testing • Limited spread of genetic knowledge through wider family

20. Down’s syndrome • Maternal age 20 1 in 1724 • Maternal age 35 1 in 365 • Maternal age 40 1 in 109 Hook and Chambers 1977

21. Tobacco and Alcohol

22. Clinical and genetic issues • Many different and unusual conditions • Increased prevalence • Language, cultural, religious issues • May have limited health/genetic knowledge • Limited information about relatives abroad • Large numbers may need counselling

23. What can we do? • Collect good data • Fund and improve services, clinical and genetic • Identify gene mutations • Clinical understanding and treatments • Improve community understanding

24. Data collection • Clinical groupings: e.g. BPSU study, metabolic register • Congenital anomalies register • Born in Bradford

26. Improving services • Payment by results • Centres of excellence • Networks • Transcultural genetics • IT

27. Work on gene mutations • Local work: • Primary Microcephaly • Aicardi-Goutières syndrome • Deafness • Cerebral palsy • And much more!

28. Benefits from genetic knowledge • More specific genetic advice for family • Carrier testing • Antenatal diagnosis • More to offer consanguineous community

29. Theories of brain development arose from microcephaly genes identified in Bradford Child Development Centre (Microcephalin and ASPM) (Image - National Geographic) Homo floresiensis (Hobbit)

30. Juvenile Sandhoff Disease 11 existing case reports (one reported 2 siblings) We reported 9 children from Pakistani families in West Yorkshire and described different presentations Mutations in HEXB reported Hendriksz C 2004, Wang SZ et al 2008

31. Improving community awareness • Individual work with families • Using consanguineous families as a resource? (Aamra Darr) • PCT and Children’s Centre meetings • Providing accurate information in non-judgemental way • Links with other areas?