Recent evidence suggests that stochasticism is important for generating cell type diversity. We have identified a novel stochastic fate choice as part of the mechanism by which Delta/Notch (Dl/N) signaling specifies R7 fate in the Drosophila eye. The equivalence of R1/R6/R7 precursors is normally broken by the activation of N, which specifies the R7 fate. The orphan nuclear hormone receptor Seven-up (Svp) is necessary and sufficient to direct R1/R6/R7 precursors to adopt the R1/R6 fate. A simple model, therefore, is that N represses Svp, which otherwise prevents adoption of the R7 fate. However, we have found that R1/R6s lacking svp stochastically adopt either the R7 or the R8 fate with equal likelihood. We show that N specifies the R7 fate by a novel branched pathway: N represses Svp expression, thereby exposing an underlying stochastic choice between the R7 and R8 fates, and then tips this choice towards the R7 fate.

Background. Germline pathogenic mutations in cancer susceptibility genes result in inherited cancer syndromes. In the Afrikaner population of South Africa (SA), three founder mutations in the BRCA genes that lead to hereditary breast and ovarian cancer syndrome (HBOCS) have been identified. Objectives. To investigate the uptake and type of molecular testing performed on patients for HBOCS, to determine the prevalence of the three Afrikaner founder BRCA mutations as well as non-founder BRCA mutations in the study population, and to analyse the utility of two mutation prediction models (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and Manchester scoring method) in assisting with the decision for the most cost-effective testing option. Methods. A retrospective file review was performed on counsellees of self-reported Afrikaner ancestry from Johannesburg, SA (2001 -2014), with a personal or family history of breast and/or ovarian cancer. Demographic and family history information was recorded and Manchester and BOADICEA scores were calculated for each patient. Results. Of 86 unrelated counsellees whose files were reviewed, 54 (62.8%) underwent BRCA genetic testing; 18 (33.3%) tested positive for a mutation, and 14 of these (77.8%) for an Afrikaner founder mutation. Twelve counsellees had the BRCA2 c.7934delG mutation. Four non-founder mutations were identified. BOADICEA scores were significantly higher in counsellees who tested positive for a mutation than in those who tested negative. Conclusions. Founder mutation testing should be performed as a first-line option. BOADICEA is very useful in identifying counsellees at high risk for a BRCA mutation and also assists with the decision to pursue further testing following a negative founder mutation result. These findings assist in guiding an informed genetic counselling service for at-risk individuals with an Afrikaner background.

This review highlights molecular genetic studies of monogenic traits where common pathogenic mutations occur in black families from sub-Saharan Africa. Examples of founder mutations have been identified for oculocutaneous albinism, cystic fibrosis, Fanconi anemia, and Gaucher disease. Although there are few studies from Africa, some of the mutations traverse populations across the continent, and they are almost all different from the common mutations observed in non-African populations. Myotonic dystrophy is curiously absent among Africans, and nonsyndromic deafness does not arise from mutations in GJB2 and GJB7. Locus heterogeneity is present for Huntington disease, with two common triplet expansion loci in Africa, HTT and JPH3. These findings have important clinical consequences for diagnosis, treatment, and genetic counseling in affected families. We currently have just a glimpse of the molecular etiology of monogenic diseases in sub-Saharan Africa, a proverbial "ears of the hippo" situation.

BackgroundThe timeous and accurate diagnosis of rare genetic disorders is critical, as it enables a better understanding of patient management, prognosis and more personalized treatment. A confirmed genetic diagnosis also enables accurate genetic counselling for affected individuals and their relatives by offering options for prenatal and cascade testing. In a resource-constrained environment such as the South African State healthcare system, the challenge is to design appropriate and cost-effective assays that will enable accurate genetic diagnostic services in patients of African ancestry across a broad disease spectrum. Next-generation sequencing (NGS) has transformed testing approaches for many Mendelian disorders, but this technology is still relatively expensive to implement. The paucity of baseline genetic data on African populations adds to the complexity of implementing an appropriate NGS-based service and interpretation of results.ResultIn the current study, the approach taken aimed at balancing NGS cost, efficiency, data quality as well as diagnostic utility of results. As a proof of concept, we describe a feasible diagnostic strategy for genetic disorders frequently seen in our genetics clinics (RASopathies, Cornelia de Lange syndrome, Treacher Collins syndrome, CHARGE syndrome and other phenotypically overlapping syndromes. The custom-designed targeted NGS gene panel enabled mutation screening for these disorders that range in incidence from 1 in 1000 to 1 in 100 000 newborns. Samples were batched during sequencing and analyzed selectively based on the clinical phenotype. This study had an overall diagnostic yield of 54.5%. ConclusionThe strategy employed is cost-effective as it allows batching of samples from patients with different diseases in a single run, an approach that can be utilized with rare and less frequently ordered molecular diagnostic tests. The subsequent selective analysis pipeline allowed for timeous reporting back of patients results. This is feasible and can be employed for the molecular diagnosis of a wide range of rare monogenic disorders in resource-constrained environment.