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Background: We have investigated a strategy for identifying and counseling carriers of recessively inherited disorders in developing countries where consanguineous marriage is common. In such communities, gene variants are trapped within extended families, so that an affected child is a marker of a group at high genetic risk., Methods: Fifteen large Pakistani families, 10 with a history of a hemoglobin disorder and 5 without any such history (controls), were screened for beta-thalassemia and abnormal hemoglobins. All carriers and married couples consisting of two carriers received counseling, and eight families have been followed for two years., Results: In the control families, no carrier was found among 397 members tested. In the 10 families with an index case, 183 of 591 persons tested (31 percent) were carriers; carriers had a 25 percent risk of being in a marriage at risk for producing an affected child, and 17 of 214 married couples (8 percent) consisted of two carriers. No couple at risk was identified among 350 randomly selected pregnant women and their partners. All carriers reported that they have used the information provided in the testing and counseling process: carriers married to carriers with two or more healthy children have avoided further pregnancy, and most such couples with one or no healthy children have used prenatal diagnosis. Seven of eight new marriages and engagements are known not to be at risk., Conclusions: Testing of extended families is a feasible way of deploying DNA-based genetic screening in communities in which consanguineous marriage is common., (Copyright 2002 Massachusetts Medical Society)

A service for prenatal diagnosis of beta-thalassaemia was introduced in Pakistan in May 1994. Two renowned Islamic scholars, consulted before the service was introduced, ruled that a pregnancy can be terminated if the fetus is affected by a serious genetic disorder, and if termination is before 120 days (17 weeks) of gestation. During the first 3(1/2) years of the service 300 couples requested the test. Almost all the couples had been informed by their treating doctors. Most diagnoses were made between 10 and 16 weeks of gestation, and only 15 (5%) were reached after the 16th week. DNA analysis was by the amplification refractory mutation system (ARMS). A multiplex ARMS was developed in which three primer combinations identified the mutations in 91.5% of the couples. In 13 couples (4. 3%) linkage analysis was required for the fetal diagnosis. In 47/53 (88.7%) women carrying an affected fetus the pregnancy was terminated. In six cases it was declined principally on religious grounds. Postnatal confirmation of the prenatal diagnosis was possible in 117 unaffected children. One year after the start of the service, interviews with 141 couples with an affected child showed that 72% knew of the availability of prenatal diagnosis. Thirty-two of the informed couples had had a pregnancy, but only 18 (56%) used prenatal diagnosis. The main reasons for non-utilization of prenatal diagnosis were the cost of the test and fear of undergoing the test, though some gave no clear explanation. This study demonstrates that prenatal diagnosis is feasible and acceptable in a Muslim country such as Pakistan., (Copyright 2000 John Wiley & Sons, Ltd.)

Thalassaemia is the most common inherited disorder in Pakistan and there are very inadequate treatment facilities for over 4000 homozygotes born each year. Prevention of these disorders therefore forms an essential part of the management of this enormous health problem. We have characterized 1216 beta-thalassaemia alleles from the five major ethnic groups of Pakistan. The complete spectrum comprised 19 different mutations. There are important ethnic and regional differences in the prevalence of mutations. The five most common mutations, IVSI-5 (G-C) (37.3%), Fr 8-9 (+G) (25.9%), del 619 (7.0%), Fr 41-42 (-TTCT) (6.7%) and IVSI-1 (G-T) (5.4%), constitute 82.3% of the total. Fr 8-9 (+G) is the most common mutation in Northern Pakistan (41.3%), whereas IVSI-5 (G-C) is the most frequent mutation in Southern Pakistan (52.2%). Six subjects with transfusion-dependent thalassaemia major showed only a single mutant allele. One subject with transfusion-dependent thalassaemia major showed a novel 17 bp deletion involving Cd126-131. Our findings provide a comprehensive basis for carrying out prenatal diagnosis of thalassaemia in a geographical area where it is found in high frequency.

In a study of beta thalassaemia in the Asian Indian immigrant populations in the U.K., 23 out of 125 beta-thalassaemic chromosomes (18%) were of the Indian deletion beta type (600 bp deletion involving the 3' end). The individuals with beta thalassaemia had originated from various parts of India and Pakistan. However, all those individuals with deletion beta thalassaemia were from Sind and the adjacent area of Gujarat. Analysis of restriction fragment length polymorphisms in the beta globin gene cluster showed that all the 23 deletion beta thalassaemia chromosomes had an identical haplotype. These findings suggest a single origin for the Indian deletion beta thalassaemia.