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

Abstract

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

Hematological consequences of a FANCG founder mutation in Black South African patients with Fanconi anemia

“…In the present South African cohort, all patients were referred to Pediatric Hematology/Oncology Clinics already manifesting symptoms of significant bone marrow disease, with only a single patient referred on the basis of a physical anomaly-unusual skin pigmentation. Unfortunately, a previous evaluation of the physical phenotype of the present cohort did not highlight specific features, which could be easily identified by practitioners servicing primary health care facilities and which could alert them to the possible diagnosis of FA and the need for tertiary referral [17]. Although recommendations have been made to expedite referral of patients with growth deficiency and/or pigmentary anomalies (shown to be the most common physical features of FA in Black South African patients) for pediatric or medical geneticist evaluation, most Black patients with FA in South Africa will not be diagnosed prior to the onset of hematological symptoms which suggest severe cytopenia [17].…”

“…A modified International Fanconi Anaemia Registry (IFAR) score, using the physical criteria of growth retardation (height for age Z-score b − 2SD of the mean), birthmarks (N2 pigmentary anomalies, including café au lait macules, hyper-and hypopigmented streaks and macules), microphthalmia (palpebral fissure length b− 2 SD of the mean for age), thumb and radius abnormalities (hypoplastic/absent radius, thumb or first metacarpal) and kidney and urinary tract abnormalities was calculated for each patient, using data previously collected during a physical phenotype study in the same patient cohort [17]. The total was scored out of five.…”

“…The physical phenotype of Black patients with FA, homozygous for the FANCG founder mutation, has been reported previously [17].…”

Founder Haplotype Analysis of Fanconi Anemia in the Korean Population Finds Common Ancestral Haplotypes for a FANCG Variant

“…The majority of Dutch FA patients and a Canadian Manitoba Mennonite kindred (de Vries et al, 2012) belong to complementation group FA-C, with c.67delG being the predominant mutation. Furthermore, sub-Saharan Africans (Morgan et al, 2005;Wainstein et al, 2013;Feben et al, 2014), Germans (Demuth et al, 2000), Turks (Demuth et al, 2000), and Japanese (Yagasaki et al, 2003) carry founder mutations in the FANCG gene. Founder mutations of FANCA and FANCG account for the majority of Korean FA (Park et al, 2013) and Japanese FA cases (Tachibana et al, 1999;Yagasaki et al, 2003;Yagasaki et al, 2004).…”

Fanconi anaemia in black South African patients heterozygous for the FANCG c.637-643delTACCGCC founder mutation

“…[15] An additional study indicated that there were no particular features of the FANCG phenotype in black patients that would allow prediction regarding the prognosis of affected individuals. [16] The FANCG gene maps to chromosome 9p13, is 6kb in length comprising 14 exons and encoding a 2.5kb mRNA transcript. [17] This is translated into a 622 amino acid polypeptide with a molecular weight of 68kDa.…”