doi: 10.1111/j.1469-1809.2006.00338.x Carrier Frequency of a Nonsense Mutation in the Adenosine Deaminase (ADA) Gene Implies a High Incidence of ADA-deficient Severe Combined Immunodeficiency (SCID) in Somalia and a Single, Common Haplotype Indicates Common Ancestry Juan J. Sanchez 1, * , Gemma Monaghan 2 , Claus Børsting 1 , Gail Norbury 2 , Niels Morling 1 and H. Bobby Gaspar 3 1 Department of Forensic Genetics, Institute of Forensic Medicine, University of Copenhagen, DK-2100 Copenhagen, Denmark 2 Regional Molecular Genetics, Great Ormond Street Hospital NHS Trust, Great Ormond Street, London WC1N 3JH, United Kingdom 3 Molecular Immunology Unit, Institute of Child Health, 30 Guilford Street London WC1N 1EH, United Kingdom Summary Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that causes immunodeficiency, varying from severe combined immunodeficiency (SCID) in the majority of cases to a less severe form in a small minority of patients. Five patients of Somali origin from four unrelated families, with severe ADA-SCID, were registered in the Greater London area. Patients and their parents were investigated for the nonsense mutation Q3X (ADA c7C>T ), two missense mutations K80R (ADA c239A>G) and R142Q (ADA c425G>A), and a TAAA repeat located at the 3 ′ end of an Alu element (AluVpA) positioned 1.1 kb upstream of the ADA transcription start site. All patients were homozygous for the haplotype ADA-7T /ADA-239G/ADA-425G/AluVpA7. Among 207 Somali immigrants to Denmark, the frequency of ADA c7C>T and the maximum likelihood estimate of the frequency of the haplotype ADA-7T/ADA-239G/ADA-425G/AluVpA7 were both 0.012 (carrier frequency 2.4%). Based on the analysis of AluVpA alleles, the ADA c7C/T mutation was estimated to be approximately 7,100 years old. Approximately 1 out of 5 – 10000 Somali children will be born with ADA deficiency due to an ADA c7C/T mutation, although within certain clans the frequency may be significantly higher. ADA-SCID may be a frequent immunodeficiency disorder in Somalia, but will be underdiagnosed due to the prevailing socioeconomic and nutritional deprivation. Keywords: ADA deficiency, SCID, Q3X, multiplex PCR, Somalis. Introduction Inherited adenosine deaminase (ADA) deficiency is a rare metabolic disorder that causes immunodefi- ciency, varying from severe combined immunodefi- ∗ Corresponding author: Juan J. Sanchez, Department of Forensic Genetics, Institute of Forensic Medicine, University of Copen- hagen, 11 Frederik V’s Vej, DK-2100 Copenhagen, Denmark. Tel: +45 35 32 62 87. Fax: +45 35 32 61 20. Email: jj.sanchez@mju.es ciency (SCID) in the majority of cases to a less se- vere form in a small minority of patients. ADA de- ficiency accounts for approximately 15% of all SCID cases and one-third of autosomal recessive SCID cases (Hershfield, 2003). ADA-SCID patients suffer from se- vere recurrent infection and failure to thrive, and of- ten die within the first year of life if the disease is not treated by haematopoietic stem cell transplanta- tion (HSCT) (Antoine et al. 2003), enzyme replacement therapy (Hershfield, 1995) or gene therapy (Aiuti et al. 2002). The frequency of the condition is not known and 336 Annals of Human Genetics (2006) 71,336–347 C  2006 The Authors Journal compilation C  2006 University College London