A common Fanconi anemia mutation in black populations of sub-Saharan Africa

Morgan, Neil V.; Essop, Fahmida; Demuth, Ilja; Ravel, Thomy de; Jansen, Stander; Tischkowitz, Marc; Lewis, Cathryn M.; Wainwright, Linda; Poole, Janet; Joenje, Hans; Digweed, Martin; Krause, Amanda; Mathew, Christopher G.

doi:10.1182/blood-2004-10-3968

Cited by 56 publications

(59 citation statements)

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“…Complementation analysis was not performed on these individuals to confirm that the mutation is the sole source of the FA as this testing is not available diagnostically in South Africa. However, Morgan et al, 9 in elucidating the founder mutation, performed a complementation analysis in their cohort and established that the FANCG protein was undetectable in all cell lines tested. The deletion mutation produces a truncated protein of 217 amino acid residues and is thought to be pathogenic.…”

Section: Methodsmentioning

confidence: 99%

“…The deletion mutation produces a truncated protein of 217 amino acid residues and is thought to be pathogenic. 9 Altogether, 35 unrelated black patients, homozygous for the founder mutation on molecular testing, were included. In cases of affected sibling pairs, only the elder sibling was chosen to participate to reduce the possible influence of familial shared physical characteristics.…”

Section: Methodsmentioning

confidence: 99%

“…On the basis of the mutation frequency found in this population group, the incidence of FA is predicted to approximate 1/40,000. 9 Notwithstanding advances in standards of care, the health-care system in South Africa remains underdeveloped and is largely based on semi-urban and rural primary health-care clinics that are predominantly staffed by nurses. Despite the severity of FA, it has previously been postulated that only a small percentage of affected patients are recognized in these local and regional health-care institutions and referred for tertiary management 9,10 although the reasons for this remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation

Feben

Kromberg

Wainwright

et al. 2014

Genetics in Medicine

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Purpose: Fanconi anemia is a genotypically and phenotypically heterogeneous condition, characterized microscopically by chromosomal instability and breakage. Affected individuals manifest growth restriction and congenital physical abnormalities; most progress to hematological disease including bone marrow aplasia. Black South African Fanconi anemia patients share a common causative founder mutation in the Fanconi G gene in 80% of cases (637_643delTACC-GCC). The aim of this study was to investigate the genotype-physical phenotype correlation in a cohort of individuals homozygous for this mutation.Methods: Thirty-five black patients were recruited from tertiary level hematology/oncology clinics in South Africa. Participants were subjected to a comprehensive clinical examination, documenting growth, congenital anomalies, and phenotypic variability.Results: Descriptive statistical analysis showed significant growth abnormalities in many patients and a high frequency (97%) of skin pigmentary anomalies. Subtle anomalies of the eyes, ears, and hands occurred frequently (≥70%). Apart from malformations of the kidney (in 37%) and gastrointestinal tract (in 8.5%), congenital anomalies of other systems including the cardiovascular and central nervous systems, genitalia, and vertebrae were infrequent (<5%). Conclusion:The diagnosis of Fanconi anemia in black South African patients before the onset of hematological symptoms remains a clinical challenge, with the physical phenotype unlikely to be recognized by those without dysmorphology expertise.Genet Med advance online publication 26 December 2013

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation

Feben

Kromberg

Wainwright

et al. 2014

Genetics in Medicine

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“…FA-A is the most common group world-wide, but there are population-specific differences as a result of founder mutations. Thus, for example, most Ashkenazi Jewish patients are from group C and are homozygous for a splice-site mutation (IVS4 þ 4A>T) in FANCC (Whitney et al, 1993), and other examples have been identified in Afrikaners, Spanish gypsies and subSaharan Africans (Tipping et al, 2001;Callen et al, 2005;Morgan et al, 2006).…”

Section: Genetics Of Famentioning

confidence: 99%

Fanconi anaemia genes and susceptibility to cancer

2006

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Fanconi anaemia (FA) is a rare recessive disorder associated with chromosomal fragility, aplastic anaemia, congenital abnormalities and a high risk of cancer, including acute myeloid leukaemia and squamous cell carcinomas. The identification of 11 different FA genes has revealed a complex web of interacting proteins that are involved in the recognition or repair of DNA interstrand crosslinks and perhaps other forms of DNA damage. Bi-allelic mutations in BRCA2 are associated with a rare and highly cancer-prone form of FA, and the DNA helicase BRIP1 (formerly BACH1) is mutated in FA group J. There is little convincing evidence that FA heterozygotes are at increased risk of cancer, but larger studies are needed to address the possibility of modest risk effects. Somatic inactivation of the FA pathway by mutation or epigenetic silencing has been observed in several different types of sporadic cancer, and this may have important implications for targeted chemotherapy. Inhibition of this pathway represents a possible route to sensitization of tumours to DNA crosslinking drugs such as cisplatin.

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“…Prevalence studies on certain common chromosomal disorders showed that Down syndrome occurs in approximately one in 525 births in the whole population (A. Christianson, personal communication 2010), fragile X in one in 4,000 males (Goldman et al 1997), trisomy 18 in one in 10,000 Morgan et al 2005 births and trisomy 13 in one in 25,000 births (Parrott 1997 (Mqoqi et al 2004). The various factors that increase the risk of a child being born with a birth defect include: advanced maternal age, consanguineous marriage, teratogens, unplanned pregnancy and possibly teenage pregnancies.…”

Section: Congenital and Genetic Disease Burdenmentioning

confidence: 99%

Genetic services and testing in South Africa

2012

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South Africa is a developing middle-income country with a population of over 49 million people. It has a health system, based on national, provincial and private health programmes, which is in transition. There are well organised but small genetic services, based mostly in academic centres, provincial health departments and the National Health Laboratory Service. Trained medical geneticists, genetic counsellors and medical scientists are available to deliver the service. Funding for this service is limited, due partly to the extensive demands made by the rampant HIV/AIDS epidemic (which has lead to a falling life expectancy, and increasing maternal, child and infant mortality rates) and partly due to some ignorance, among both health professionals and the public, concerning the benefits of genetic counselling and testing in affected families. There are four academic human genetics departments across the country providing counselling (7,313 cases were counselled in 2008), testing services (16,073 genetic tests were performed in 2008) and professional training. They also undertake research. Only one tenth of the required staff, according to the WHO recommendations, is available at present to provide these services, and further employment opportunities are urgently required. However, training of professionals continues, comprehensive genetic testing facilities are available, research on many of the genetic conditions of specific concern to the country has been and is being undertaken, and patients from all over Southern and Central Africa make use of these services.

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A common Fanconi anemia mutation in black populations of sub-Saharan Africa

Cited by 56 publications

References 10 publications

Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation

Phenotypic consequences in black South African Fanconi anemia patients homozygous for a founder mutation

Fanconi anaemia genes and susceptibility to cancer

Genetic services and testing in South Africa

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