Genealogy of a cohort of South African families affected by fanconi anaemia, complemented by cytogenetic and melocular investigations

[摘要] English:Fanconi anaemia (FA) is a rare autosomal recessively inherited syndrome characterizedby various phenotypic abnormalities, which inevitably, eventuates in progressive bonemarrow failure. In the majority of cases a preliminary diagnosis of FA is based on theabove-mentioned two criteria. The lymphocytes show an increased sensitivity toclastogenic agents such as diepoxybutane (DEB) and mytomycin C (MMC), resulting inchromosomal aberrations. This analysis is mainly used for the verification of the clinicaldiagnosis and screening purposes to identify family members who are possibly affectedby FA. The incidence of FA children under 16 years of age related to the white Afrikaansspeaking(Afrikaner) South African population in the Orange Free State and NorthernCape provinces is 1:22 000. Among South African Black populations and the rest of theworld the approximate incidence is 1:400 000. A founder effect has been postulated asthe reason for the high incidence among the white Afrikaans-speaking population.In this study the clastogenic agent DEB was used and induced lymphocyte cultures wereevaluated for the presence of chromosomal instability in inherent FA affectedindividuals. These patients were selected from only those families in which the FAaffecteds were sensitive against DEB. Prior to the cloning of the FANCA gene, in whichcase if defective cause FA, a genealogical investigation was carried out on 12 FAfamilies to substantiate the hypothesis of a founder effect. This genealogical informationwas then compared to the results of the molecular analysis as soon as the FANCA genewas cloned and the Afrikaner mutations became known. An additional genealogicalinvestigation, relating to 13 supplementary FA parents known to be carriers of either thetypes I or II mutation, was used to verify the original genealogical investigation. The cytogenetic results obtained in this study showed that it was not possible todifferentiate between obligate carriers and the control group, however, homozygoteswere clearly distinguishable from heterozygotes using only 20 metaphase spreads perperson. Furthermore, when the DEB sensitivity of a patient was high, the number ofunaffected cells observed in these FA patients was low. The initial genealogical investigation pinpointed a French Huguenot couple, GuillaurneNel (or Néel) and/or his wife Jeanne de la Batt, as possible candidates of the founder(s)of FAin South Africa. If this couple is indeed one of the founders of FAin South Africa,the same mutation (autozygosity of a gene) causing FA is suspected to occur in all theirFA affected descendants. However, four mutations were present in the affecteddescendants, with one major mutation, a deletion stretching from exons 12 to 31 (type I),occurring on 63% of chromosomes analyzed. A hypothesis is put forward that the type Imutation is the original mutation, whereas the type II (deletion stretching from exons 11to 17) and III (339811A) mutations, with a frequency of respectively 14% and 18%, wereintroduced into the Afrikaner population at a later date. The second genealogical investigation once more confirmed the French Huguenotcouple Nel as possible founders of the type I Afrikaner mutation, however, the surnamedu Preez also featured prominently as a possible founder. As a result of numerousintermarriages, especially in the first few generations, it was not possible to distinguishbetween these two surnames as possible founders of the Afrikaner type I mutation.Genealogical investigations accentuated that either a VenterINel couple or an individualnamed JP du Plessis as possible founder of the type II mutation. The relationshipbetween Nel and Venter could explain the occurrence of at least two mutations amongthe affected descendants from the French Huguenot couple bearing the surname 'Nel'.

[发布机构] University of the Free State