Precision medicine for developmental and epileptic encephalopathies in Africa-strategies for a resource-limited setting.

Purpose: Sub-Saharan Africa bears the highest burden of epilepsy worldwide. A presumed proportion is genetic, but this etiology is buried under the burden of infections and perinatal insults in a setting of limited awareness and few options for testing. Children with developmental and epileptic encephalopathies (DEEs) are most severely affected by this diagnostic gap in Africa, because the rate of actionable findings is highest in DEE-associated genes.

Current practice in diagnostic genetic testing of the epilepsies.

Epilepsy genetics is a rapidly developing field, in which novel disease-associated genes, novel mechanisms associated with epilepsy, and precision medicine approaches are continuously being identified. In the past decade, advances in genomic knowledge and analysis platforms have begun to make clinical genetic testing accessible for, in principle, people of all ages with epilepsy. For this reason, the Genetics Commission of the International League Against Epilepsy (ILAE) presents this update on clinical genetic testing practice, including current techniques, indications, yield of genetic testing, recommendations for pre- and post-test counseling, and follow-up after genetic testing is completed.

Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.

More than two decades ago, a recessive syndromic phenotype affecting kidneys, eyes, and ears, was first described in the endogamous Afrikaner population of South Africa. Using whole-exome sequencing of DNA from two affected siblings (and their carrier parents), we identified the novel RRM2B c.786G>T variant as a plausible disease-causing mutation.

Cascade Testing for Fragile X Syndrome in a Rural Setting in Cameroon (Sub-Saharan Africa).

Fragile X Syndrome (FXS), an X-linked dominant monogenic condition, is the main genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD). FXS is associated with an expansion of CGG repeat sequence in the Fragile X Mental Retardation gene 1 (FMR1) on chromosome X. Following a neuropediatric assessment of two male siblings who presented with signs of FXS that was confirmed with molecular testing, we provided cascade counselling and testing to the extended family.

Noonan Syndrome in South Africa: Clinical and Molecular Profiles.

Noonan Syndrome (NS) is a common autosomal dominant multisystem disorder, caused by mutations in more than 10 genes in the Ras/MAPK signaling pathway. Differential mutation frequencies are observed across populations. Clinical expressions of NS are highly variable and include short stature, distinctive craniofacial dysmorphism, cardiovascular abnormalities, and developmental delay.

C9orf72 repeat expansions in South Africans with amyotrophic lateral sclerosis.

The hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic variant found in individuals with sporadic amyotrophic lateral sclerosis (ALS), occurring at a frequency of between 7 and 11% in cohorts of European ancestry. While limited data suggest that C9-expansions (>30 repeats) are less frequent in African-Americans with ALS, there is no data on the frequency of C9-expansions among ALS subjects residing in Africa. We therefore investigated the frequency of this expansion mutation (using repeat-primed PCR) in a cohort of 143 South Africans (SA) with ALS.

Dravet syndrome in South African infants: Tools for an early diagnosis.

Purpose: Dravet syndrome (DS) is a well-described, severe genetic epileptic encephalopathy with an increased risk of SUDEP. The incidence and genetic architecture of DS in African patients is virtually unknown, largely due to lack of awareness and unavailability of genetic testing. The clinical benefits of the available precision medicine approaches to treatment emphasise the importance of an early, correct diagnosis.

Skin cells for use in an alternate diagnostic method for Duchenne muscular dystrophy.

The importance of molecular diagnosis and identification of disease-associated variants for Duchenne muscular dystrophy (DMD) is evident in the age of gene-based therapies and personalised medicine. Detection of the causative DMD variant and determination of its effects on dystrophin expression is best achieved by analysis of RNA extracted from muscle biopsy material. However, this is not done routinely, as the procedure can be traumatic, especially to young children, and carries risk of complications related to the use of anaesthetic.

Clinical Application of Epilepsy Genetics in Africa: Is Now the Time?

Over 80% of people with epilepsy live in low- to middle-income countries where epilepsy is often undiagnosed and untreated due to limited resources and poor infrastructure. In Africa, the burden of epilepsy is exacerbated by increased risk factors such as central nervous system infections, perinatal insults, and traumatic brain injury. Despite the high incidence of these etiologies, the cause of epilepsy in over 60% of African children is unknown, suggesting a possible genetic origin.

Caution regarding the interpretation of homoallelism in polyglutamine multiplex assays: a recommendation for confirmatory testing of homozygous alleles.

Spinocerebellar ataxia type 7 (SCA7) is an inherited dominant neurodegenerative disease caused by the expansion of a CAG repeat within the ATXN7 gene. Standard molecular diagnostic testing for SCA7 involves amplification of the region surrounding the CAG repeat via end-labeled PCR and subsequent capillary electrophoresis. In addition, multiplex methods exist that may be used to test for multiple polyglutamine spinocerebellar ataxias in a single assay.