Classification and molecular genetics

These disorders are much less common than the P-thalassaemias. In some cases, they result from deletions of the P- and S-globin genes (Figure 6.8), whereas in others there appears to have been

110 120

130 140

150 160 170

111 1

% HbF in

ß Thalassaemia

heterozygotes

Small deletions

0.2-6.9

1 Turkish

1.9-2.0

2 Filipino

1.0-9.1

3 UK Asian

3.2-4.7

4 Dutch

4-11

5 Australian

2.5-7.2

6 Southern Italian

9.0

§ß fusion

7 Hb Lepore

0.5-6.5

§ Thalassaemia

8 Corfu

1.1-2.8

yß fusion

9 Hb Kenya

5-10

Gy Ay (§ß)° Thalassaemia

10 Mediterranean

5.9-19.0

11 SE Asian

9.9-20.0

12 E European

13.0-24.0

13 Black

25.0*

14 Macedonian/Turkish

4.2-13.5

15 Indian

16.6

16 Spanish

5.0-13.0

17 Japanese

7.0-8.0

Gy (Ay§ß) " Thalassaemia

18 Black

4.0-16.5

19 Chinese

9.3-23.0

20 Belgian

14.2-23.0

21 Indian

9.7-18.1

22 Yunnanese

9.3-16.7

23 Malaysian 2

24 German

9.9-12.5

25 Turkish

10.0-13.5

26 SE Asian

17.2-22.9

27 Italian

?

Gy Ay(§ß) • HPFH

28 Black

18.6-31.0

29 Ghanaian

22.4-26.6

30 Indian

17.0-25.0

31 Italian 1

14.0-30.0

32 Italian 2

16.0-20.0

33 Vietnamese/SEA

14.1-26.6

34 Anglo-Saxon

35 Dutch

36 English <37 Scottish-Irish -<38 Hispanic 39 Mexican,

34 Anglo-Saxon

35 Dutch

36 English <37 Scottish-Irish -<38 Hispanic 39 Mexican,

Canadian, Yugoslavian

Figure 6.8 The deletions that underlie SP-thalassaemia and hereditary persistence of fetal haemoglobin. The upper arrows represent DNase I-hypersensitive sites (from Weatherall and Clegg 2001 with permission).

Figure 6.9 The mechanisms for the production of haemoglobin Lepore and related variants.

mispaired synapsis and unequal crossing over between the 8-and P-globin gene loci, with the production of 8P fusion genes (Figure 6.9). The latter produce 8P fusion chains, which combine with a-chains to form haemoglobin variants called the Lepore haemoglobins (Lepore was the family name of the first patient to be recognized with this disorder). Hence it is usual to classify this group of conditions into the (8P)0 thalassaemias and the Hb Lepore (8/5)+ thalassaemias.

The (8P)0 thalassaemias result from different length deletions of the P-globin gene cluster. In some cases these leave both the Gy and Ay genes intact, whereas in others the Ay genes are also involved, leaving only the Gy genes. Hence the disorders are called (8P)° or (Ay8P)0 thalassaemias (Figure 6.8). The deletions leave the y-globin genes active in adult life and, although their output is not as high as in the fetus, it is usually sufficient to make these conditions relatively mild. The Lepore haemoglobins are also heterogeneous, depending on the precise site of the abnormal crossover event and hence the structure of the 8P fusion variant (Figure 6.9). y-Chain production is not as high in these conditions and hence there is a more severe clinical phenotype.

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