DECIPHERING DEVELOPMENTAL DISORDERS IN CENTRAL AFRICA

Developmental Disorders (DD) is a group of disorders characterized by a failure to achieve developmental milestones, with or without departing from the normal morphology, and present before the age of 18 years. These include developmental delay, intellectual disability (ID), birth defects, and certain psychiatric or neurological disorders. About 1 to 3% of children aged ≤5 are affected worldwide. Little is known in the African population where both the genomic diversity and interethnic morphological variation are great. To date, the genomic basis for many DD has not been elucidated. Several categories of genomic variants or mechanisms may escape current strategies applied for the clinical interpretation of genomic data such as Mendeliome or Whole Exome Sequencing (WES). For instance, imprinting disorders may escape routine filtering strategies.

This study's aim is to perform in-depth phenotypic and genotypic studies in a cohort of Congolese individuals with an unexplained Developmental disorder, thus contributing to our knowledge on DD in Central Africa, and improving the diagnosis and guidance of individuals with a DD.

This study is conducted in the Democratic Republic of Congo. We collaborate with specialized institutions and tertiary hospitals throughout the country, where we have to recruit 150 patients with unexplained developmental disorders.

After systematic clinical phenotyping (including detailed family and personal history and a clinical examination using a standardized scheme), Clinical information will be annotated using the Human Phenotype Ontology. Data will be uploaded to the DECIPHER database. Clinical pictures will be taken, stored in Face2Gene, and used for clinical review by a geneticists' multicentric team. Those pictures will facilitate the implementation of this tool in the syndromic analysis of African populations.

DNA will be extracted (from white blood cells) at the Human Genetics Centre of UNIKIN using the salting out procedure, and the samples will be transferred to the Sanger Institute for Whole Exome Sequencing (WES). The high-quality bioinformatics pipelines, previously established at the Sanger Institute for the DDD project, will be applied for this study to call different types of variants including CNVs, SNVs, and indels. I will perform variant filtering and interpretation. Variant classification will follow the ACMG guidelines.

This will result in a cohort of African patients with DD and an established genetic diagnosis in known or novel genes. The pathogenic variants found will be correlated with phenotypic data to phenotypically redefine the known genetic syndromes, and to determine possible new phenotype-genotype associations.

In unsolved families, we will pursue further studies to identify novel genes for DD: 1) Exploration for imprinting disorders by designing and applying a filtering algorithm for the mechanisms of imprinting disorders able to identify relevant variants and uniparental disomy (UPD) from WES data; 2)  For the families where at least two boys are affected, I will do an in-depth analysis of Regions of Homozygosity (ROH): I will find the degree of inbreeding, and for parents who will appear to be more closely related, I will calculate the genomic kinship coefficient of consanguineous parents with the children affected based on the length of ROHs or using the known toolsets as IBDelphi. This analysis will allow determining structural variants and conditions of autosomal recessive disorders including pathogenic variants shared on two alleles (case of composite heterozygous); 3) Novel candidate genes will also be searched by investigating the LoF intolerance and Knock Out intolerance using data generated through this study and companion studies on reference Congolese patients and MATCHMAKER will be used to identify other patients carrying variants in these novel candidate genes.