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

English:Fanconi anaemia (FA) is a rare autosomal recessively inherited syndrome characterized by various phenotypic abnormalities, which inevitably, eventuates in progressive bone marrow failure. In the majority of cases a preliminary diagnosis of FA is based on the above-mentioned two criteria. The lymphocytes show an increased sensitivity to clastogenic agents such as diepoxybutane (DEB) and mytomycin C (MMC), resulting in chromosomal aberrations. This analysis is mainly used for the verification of the clinical diagnosis and screening purposes to identify family members who are possibly affected by 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 Northern Cape provinces is 1:22 000. Among South African Black populations and the rest of the world the approximate incidence is 1:400 000. A founder effect has been postulated as the reason for the high incidence among the white Afrikaans-speaking population. In this study the clastogenic agent DEB was used and induced lymphocyte cultures were evaluated for the presence of chromosomal instability in inherent FA affected individuals. These patients were selected from only those families in which the FA affecteds were sensitive against DEB. Prior to the cloning of the FANCA gene, in which case if defective cause FA, a genealogical investigation was carried out on 12 FA families to substantiate the hypothesis of a founder effect. This genealogical information was then compared to the results of the molecular analysis as soon as the FANCA gene was cloned and the Afrikaner mutations became known. An additional genealogical investigation, relating to 13 supplementary FA parents known to be carriers of either the types 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 to differentiate between obligate carriers and the control group, however, homozygotes were clearly distinguishable from heterozygotes using only 20 metaphase spreads per person. Furthermore, when the DEB sensitivity of a patient was high, the number of unaffected cells observed in these FA patients was low. The initial genealogical investigation pinpointed a French Huguenot couple, Guillaurne Nel (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 their FA affected descendants. However, four mutations were present in the affected descendants, 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 I mutation is the original mutation, whereas the type II (deletion stretching from exons 11 to 17) and III (339811A) mutations, with a frequency of respectively 14% and 18%, were introduced into the Afrikaner population at a later date. The second genealogical investigation once more confirmed the French Huguenot couple Nel as possible founders of the type I Afrikaner mutation, however, the surname du Preez also featured prominently as a possible founder. As a result of numerous intermarriages, especially in the first few generations, it was not possible to distinguish between these two surnames as possible founders of the Afrikaner type I mutation. Genealogical investigations accentuated that either a VenterINel couple or an individual named JP du Plessis as possible founder of the type II mutation. The relationship between Nel and Venter could explain the occurrence of at least two mutations among the affected descendants from the French Huguenot couple bearing the surname 'Nel'.