Neil A. Hanchard, M.B.B.S., D.Phil.

The CCDGS is a translational genomics research lab using human genetics and genomics to better understand the pathophysiology of childhood diseases, particularly in diverse populations. Traditionally, genomic studies in children have focused on rare Mendelian phenotypes; however, the unique developmental context and reduced environmental exposure of children over time, provides fertile ground for genetic discovery and therapeutic investigation. At the same time, there is a general lack of diversity among genomic studies, with populations of African ancestry being particularly underrepresented, despite harboring an abundance of genomic diversity and unique clinical presentations. Our approach is to start with epidemiological evidence for differences between individuals and formulate plausible genetic models of disease. We then work with global and national collaborators to recruit well-phenotyped cohorts, to which we apply genomic, epigenomic, and transcriptomic technologies alongside population and quantitative genetics to identify the genes and gene-pathways that drive disease. Newly discovered genes are then validated, and the underlying mechanisms probed. This approach facilitates our ultimate goal of translating mechanistic understanding into therapeutic strategies – providing personalized medicine by going from bedside to bench and back.

Severe Acute Malnutrition (SAM)

Approximately two million children worldwide under the age of five become severely malnourished every year – an estimated 20-30% of whom do not survive. Classically, severe acute malnutrition is described as being either non-edematous (NESAM or marasmus) or the systemically deleterious edematous (ESAM, kwashiorkor, or marasmic-kwashiorkor) form. Despite decades of study, the reason some children develop ESAM and others NESAM remains unanswered, and molecular differences in the pathophysiology of the two types remain largely unexplored. We are applying our multi-’omics’ approach to cohorts from populations of diverse ancestries where ESAM and SAM remain prevalent. Through this we hope to better understand and inform the etiologic and pathophysiologic differences between ESAM and NESAM.

Childhood-onset Essential Hypertension (COEH)

Childhood-onset essential hypertension – in which there is elevated blood pressure in childhood without an obvious cause - affects 1-2% of all children, accounting for about 40% of all hypertension in children, and is found more often among populations of African- or Hispanic ancestries. Children with COEH are harder to diagnose, but have a strong family history of hypertension. These observations suggest a role for genetics in the development of the disease; however, it is unclear whether this genetic risk mirrors that observed in adults (multiple genes all with small effects) or is more consistent with rare Mendelian diseases that are more striking in childhood (single genes with large effects). Crucially, the treatment of CEOH mirrors that of adults, partly because the underlying pathophysiology is assumed to be the same. We are using next-generation sequencing to explore the model of Mendelian and rare variant contributions to COEH, following up promising candidates with functional characterization and consideration of existing pharmaceutical interventions. We are working alongside national collaborators to expand our COEH cohort and better characterize the vascular and clinical phenotype of gene variant carriers.

Sickle Cell Disease (SCD)

Sickle Cell Disease (SCD) is a recessive disorder of hemoglobin and one of the most common single gene disorders in the world. Despite being caused by a single pathogenic variant in the beta-globin gene and being the first described ‘molecular disease’, there is incredible variability in the consequences and manifestations of the disease that remain understudied. We are using genomics to explore the genetic factors contributing to variability in the response to red blood cell transfusions and the expression of beta-globin genes.

We are a part of a multi-national project funded by the NIH, Wellcome Trust, and African Academy of Sciences (AAS) known as the Human Health and Heredity in Africa (H3Africa) Consortium. The goals of the consortium are to establish and grow genomics and genetics technologies and expertise in Africa for the purposes of advancing human health and disease (www.h3africa.org; @H3Africa). Our project – the Collaborative African Genomics Network (CAfGEN; @CAfGEN1) is based in Botswana and includes clinical and/or research sites in Botswana, Uganda, eSwatini, and the United States. The main focus of the consortium is pediatric HIV/AIDS, which affects more than 1 million children in Africa under the age of 15 and imposes a significant health burden on affected countries. Collectively, the project seeks to use genetics and genomics to better understand the molecular drivers of the progression from HIV infection to AIDS and to improve the diagnosis of active tuberculosis disease in African children. These research aims also provide opportunities for training and development of genomics knowledge in the host countries. CAfGEN is using transcriptomics and genomics to describe the genetic ancestry and variation within African genomes and using the resulting information to refine the genes, pathways, and environmental influences involved in disease progression.