A. El-Harith

Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene

Familial thrombosis (FT) has been described as a rare autosomal‐dominant disorder, mostly caused by activating mutations of the thrombopoietin gene (THPO). Other cases of FT have been linked to one of two different germline mutations in the myeloproliferative leukaemia virus oncogene gene (MPL), which codes for the thrombopoietin receptor MPL. We studied an Arab family with two siblings with severe thrombocytosis by linkage analysis and obtained evidence for linkage to MPL. Sequencing revealed homozygosity for the novel MPL germline mutation p.Pro106Leu (c.317C > T) in the two siblings. Subsequently, homozygosity for p.Pro106Leu was identified in six further FT patients from three other Arab families. Of 18 heterozygous carriers, 14 had normal platelet counts, while four had mild thrombocytosis. Strong support for association of the novel MPL mutation p.Pro106Leu with development of familial thrombocytosis has been obtained. Overall, p.Pro106Leu was absent on 386 alleles of 193 healthy German controls and present on 14 of 426 alleles (3·3%) of 213 unrelated Arabs, which was statistically significantly different (P < 0·001, Fisher’s exact test). We assume that p.Pro106Leu is a frequent MPL mutation in the Arab population, leading to severe thrombocytosis in homozygotes and occasionally to mild thrombocytosis in heterozygotes. In the families described the mode of inheritance could be regarded as autosomal‐recessive with possible mild heterozygote manifestation rather than autosomal‐dominant with high penetrance as usually seen in FT.

Novel and characteristic CFTR mutations in Saudi Arab children with severe cystic fibrosis.

More than 600 different CFTR (cystic fibrosis transmembrane conductance regulator) gene mutations have been identified so far that are considered to cause the fatal genetic disorder cystic fibrosis (CF). We have investigated 15 Arab children from 12 families, who were diagnosed as having CF, for mutations in the coding region and in the flanking intron sequences of the CFTR gene. Six different CFTR mutations were identified including two novel mutations, 1548delG in exon 10 and 406-2A-->G in intron 3. Prominent mutations were the splice mutation 3120 + 1G-->A (intron 16) followed by N1303K (exon 21) and 1548delG (exon 10). Most CF children were homozygotes who presented with a severe form of the disease including failure to thrive, recurrent chest infections, particularly with Pseudomonas aeruginosa, and frequent hospital admissions. Identification of the CFTR mutations facilitates molecular investigation of the disease and better understanding of its pathophysiology in Arab children, among whom CF is probably an underdiagnosed disease.

Familial thrombocytosis as a recessive, possibly X-linked trait in an Arab family

Familial thrombocytosis (FT) has previously been described as an autosomal‐dominant disorder with manifestations similar to those of sporadic essential thrombocythaemia. We studied an Arab family consisting of four brothers, aged 4–8 years, who had either sustained markedly elevated (> 1000 × 109/l) or moderately elevated (> 500 × 109/l) platelet counts, two healthy sisters and their parents who had normal platelet counts. The four brothers with FT had normal plasma thrombopoietin levels and are currently not presenting with any thrombotic or haemorrhagic complications. Mutation analysis at the thrombopoietin gene (THPO) of the affected family members failed to detect the intron 3 G→C splice mutation that had been described as causing FT. In addition, segregation analysis using a polymorphic CA marker revealed completely discordant THPO alleles among the affected brothers. We postulate the existence of a new locus for FT whereby the disease is transmitted as a recessive, possibly X‐linked trait.

Identification and clinical presentation of beta thalassaemia mutations in the eastern region of Saudi Arabia.

Editor—The autosomal recessive disease β thalassaemia is a common single gene disorder that poses a serious health problem in many parts of the world. According to the Human Gene Mutation Database (http://www.uwcm.ac.uk/uwcm/mg/hgmd.html) and the β-Globin Gene Server (http://globin.cse.psu.edu) about 300 sequence variants in the β globin gene have been identified up to the present. Mutations in the β globin gene have been found at carrier frequency rates ranging from 1% in some areas of Saudi Arabia to 15% in others.1 Both β° and β+ thalassemia have been reported.2 Studies on the molecular pathogenesis of β thalassaemia have shown that the mutations encountered in Arab countries close to the Mediterranean basin are the same as those reported in other Mediterranean populations.3 In the Gulf region, in Saudi Arabia, UAE, and Iraq, the Asian pattern of mutations seems to be prevalent.4 5 The precise genetic changes prevalent in the different regions of the large country of Saudi Arabia and analysis of the genotype/phenotype relationship of the disease in Saudi patients still remain inadequately studied. The present study aimed to investigate the mutational pattern of the β globin gene and to explore the relationship between these mutations and disease presentation in a group of patients with β thalassaemia major from the eastern region of Saudi Arabia. For this purpose, 31 children diagnosed with β thalassaemia major who over the past two years had regularly attended the paediatric clinics of Qatif Central Hospital or Dammam Maternity and Children Hospital were selected. Within this group of patients there were four pairs of sibs and one pair of first cousins. The whole β globin gene of all patients was amplified using standard PCR techniques and six specially designed different primers for …