Loss-of-Function GRHL3 Variants Detected in African Patients with Isolated Cleft Palate.

In contrast to the progress that has been made toward understanding the genetic etiology of cleft lip with or without cleft palate, relatively little is known about the genetic etiology for cleft palate only (CPO). A common coding variant of grainyhead like transcription factor 3 ( GRHL3) was recently shown to be associated with risk for CPO in Europeans. Mutations in this gene were also reported in families with Van der Woude syndrome. To identify rare mutations in GRHL3 that might explain the missing heritability for CPO, we sequenced GRHL3 in cases of CPO from Africa. We recruited participants from Ghana, Ethiopia, and Nigeria. This cohort included case-parent trios, cases and other family members, as well as controls. We sequenced exons of this gene in DNA from a total of 134 nonsyndromic cases. When possible, we sequenced them in parents to identify de novo mutations. Five novel mutations were identified: 2 missense (c.497C>A; p.Pro166His and c.1229A>G; p.Asp410Gly), 1 splice site (c.1282A>C p.Ser428Arg), 1 frameshift (c.470delC; p.Gly158Alafster55), and 1 nonsense (c.1677C>A; p.Tyr559Ter). These mutations were absent from 270 sequenced controls and from all public exome and whole genome databases, including the 1000 Genomes database (which includes data from Africa). However, 4 of the 5 mutations were present in unaffected mothers, indicating that their penetrance is incomplete. Interestingly, 1 mutation damaged a predicted sumoylation site, and another disrupted a predicted CK1 phosphorylation site. Overexpression assays in zebrafish and reporter assays in vitro indicated that 4 variants were functionally null or hypomorphic, while 1 was dominant negative. This study provides evidence that, as in Caucasian populations, mutations in GRHL3 contribute to the risk of nonsyndromic CPO in the African population.

Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations.

Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10(-3)), 8q24 (rs987525, P = 1.22 × 10(-3)), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp and p.Lys426IlefsTer6) in ARHGAP29 In conclusion, the authors have shown evidence for the association of many loci with NSCL/P and NSCPO. To the best of this knowledge, this study is the first to demonstrate any of these association signals in any African population.

Prognostic significance of biochemical markers in African Burkitt's lymphoma.

BACKGROUND AND PURPOSE Endemic Burkitt's lymphoma (eBL) remains the prevalent form of paediatric cancer in tropical Africa with subtle pathological differences. This calls for intensified efforts to validate the global prognostic markers within local settings for improved cancer treatment and survival. This study proposes prognostic markers for enhanced eBL treatment and management. PATIENTS AND METHOD One hundred and eighty histologically and/or clinically diagnosed BL patients at Komfo Anokye Teaching Hospital, Kumasi, Ghana were eligible for this cross-sectional eight-year retrospective study. Biochemical, clinical and demographic data, before chemotherapy administration, were documented and examined for their progression-free (PFS) and overall survival (OS) significance. RESULTS A mean age of 6 (SD=2.7, range: 1-16) years was observed with general male dominance (M:F=1.69:1). Total serum lactate dehydrogenase (HR=2.04; 95% CI, 1.25-3.32; log rank=8.3; p=0.004), serum creatinine (HR=3.59; 95% CI, 1.62-7.98; log rank=15.4; p=0.002) and St. Jude stage (HR=1.74; 95% CI, 1.11-2.73; log rank=8.0; p=0.015) were important independent prognostic biochemical markers for both PFS and OS. Age, serum calcium, uric acid, potassium, sodium and phosphorus were non-prognostic. CONCLUSION The better monitoring of these prognostic indices coupled with risk-stratification treatment may improve patients' survival, especially in resource-limited settings.

Clinical and epidemiological characterisation of Burkitt's lymphoma: an eight-year case study at Komfo Anokye Teaching Hospital, Ghana.

Endemic Burkitt's lymphoma (BL) is a juvenile malignant neoplasm of B-lymphocyte origin, markedly affected by climate, vegetation and geographical location. This real country-based, cross-sectional, retrospective study reviews all out-patient clinical records of patients histologically and/or clinically diagnosed with BL from January, 2000 to December, 2007 at the Komfo Anokye Teaching Hospital, Ghana, a country within the malaria and lymphoma belts of the world. The aim of the study is to clinically and epidemiologically characterise all cases of BL over an eight-year period to ascertain the most common form of BL demographically prevalent. A mean age of 6.9 +/- 2.7 (range: 1-16) was observed. Males generally dominated in incidence (M:F=1.43:1, P<0.001) and significantly with facial presentation (P<0.05). Females weakly dominated in abdominal tumour presentation (P>0.05). The age range 4-8 years was the high risk range (P<0.001) for both sexes. Males were affected early in life (4-7 years) compared to their female counterparts (6-11 years). Of the 551 cases reviewed, 48.3%, 32.7%, 15.8% and 3.3% involved the face, abdomen, combined facial and abdominal and either facial or abdominal with central nervous system (CNS) involvement (usually paraplegia), respectively. An intriguing observation was evident between facial and combined facial and abdominal cases which exhibited reversed trends in incidence. Three regions within the forest zone showed significantly higher (P<0.001) incidences compared to the seven cohorts from the coastal and savannah agro-ecological zones of Ghana. No region was explicitly associated with any particular clinical presentation. The study has shown that although BL can present with demographic patterns in prevalence within a given geographical location, no clinical characterisation is associated with such patterns.