Screening for Fragile X Syndrome (Murray et al.) - NIHR Journals ...

GeneticsTABLE 6 Haplotypes occurring more frequently in families affected by fragile X syndrome: results from 13 studies in different populationsPopulation Marker † Haplotype Controls Affected families(Study)Tested Present (%) Tested Present (%)Australian 1–2 AF 202 12 (6) 134 42 (31)Richards & Sutherland, 1992Finnish I 2–3 153-196 34 1 (3) 26 19 (73)Oudet et al, 1993aFrench 2–3 155-204 153 2 (1) 102 14 (14)Oudet et al, 1993bDutch-Belgian 3 204 134 1 (1) 68 25 (37)Buyle et al, 1993Swedish 2–3 147-194 28 1 (4) 28 8 (29)Malmgren et al, 1994Czech 2–3 149-204 20 1 (5) 15 4 (27)Malmgren et al, 1994British I 3–1–2 6-4-4 188 8 (4) 44 7 (14)Macpherson et al, 1994Japanese 1–2 DB 142 18 (13) 40 8 (20)Richards et al, 1994bFinnish II 3–2 196-153 135 11 (8) 60 48 (80)Haataja et al, 1994Caucasian I 1–4–5 D-A-A 172 10 (6) 97 45 (46)Kunst & Warren, 1994Caucasian II 3 196 50 8 (16) 64 22 (34)Snow et al, 1994British II 1–3 D6 102 2 (2) 70 17 (24)Hirst et al, 1994Italian 1–3 C-3 235 0 137 12 (9)Chiurazzi et al, 1996British III 3–2–1 7-1-3 154 0 44 3 (7)Eichler et al, 1996† Microsatellite markers used include, 1 = FRAXAC1, 2 = FRAXAC2, 3 = DSX548, 4 = FMRa, and 5 = FMRb.16to this, Chen and colleagues (1995) suggest thatthe repair mechanism by which slippage structuresare normally excised may be impaired.TimingThe expansion in repeat size might take placeeither during oogenesis or in early embryonicdevelopment, but three types of study suggest thatit is likely to be a post-zygotic event. First, observationson methylation status during early developmentshow that although the foetal tissue maybe methylated the chorionic villi are hypomethylated,indicating that methylation is acquiredafter fertilisation. Expansion is a separate processthat appears to precede methylation, as evidencedby the observation of fully expanded, hypomethylatedchorionic villi in an affected foetus.Second, if expansion took place before celldifferentiation in the foetus there would besomatic homogeneity, whereas individuals withan FM display mosaicism among and betweentissues. Moreover, in vitro studies have shownthat cells carrying the FM exhibit clonal stability(Wöhrle et al, 1993), suggesting that somaticvariation is restricted to a period during earlyfoetal development. Lastly, expansion may occurafter the twinning event since monozygotic twinsdiscordant for repeat size and methylation statushave been observed (Malmgren et al, 1992; Devyset al, 1993; Kruyer et al, 1994).