AUTHOR=Mahungu Amokelani C. , Steyn Elizabeth , Floudiotis Niki , Wilson Lindsay A. , Vandrovcova Jana , Reilly Mary M. , Record Christopher J. , Benatar Michael , Wu Gang , Raga Sharika , Wilmshurst Jo M. , Naidu Kireshnee , Hanna Michael , Nel Melissa , Heckmann Jeannine M. 

TITLE=The mutational profile in a South African cohort with inherited neuropathies and spastic paraplegia

JOURNAL=Frontiers in Neurology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1239725

DOI=10.3389/fneur.2023.1239725

ISSN=1664-2295

ABSTRACT=Introduction: Limited diagnostics are available for inherited neuromuscular diseases (NMD) in South Africa and (excluding muscle disease) are mainly aimed at the most frequent genes underlying genetic neuropathy (GN), and spastic ataxias in Europeans. Here we used next generation sequencing to screen 61 probands with GN, hereditary spastic paraplegia (HSP) and spastic ataxias for a genetic diagnosis. Methods: After identifying four GN probands with PMP22 duplication and one spastic ataxia proband with SCA1, the remaining probands underwent whole exome (n=26) or genome sequencing (n=30). Curation of coding/splice region variants using gene panels was guided by allele frequencies from internal African-ancestry control genomes (n=537) and the Clinical Genome Resource's Sequence Variant Interpretation guidelines. Results: Of 32 GN probands, 50% had African-genetic ancestry and 44% were solved: PMP22 n=4; MFN2 n=3; one each of MORC2, ATP1A1, ADPRHL2, GJB1, GAN, MPZ and ATM. Of 29 HSP probands (six with predominant ataxia), 66% had African-genetic ancestry and 48% were solved: SPG11 n=3; KIF1A n=2; and one each of SPAST, ATL1, SPG7, PCYT2, PSEN1, ATXN1, ALDH18A1, CYP7B1 and RFT1. Structural variants in SPAST, SPG11, SPG7, MFN2, MPZ, KIF5A and GJB1 were excluded by computational prediction and manual visualization. Discussion: In this preliminary cohort screening panels of disease genes using WES/WGS data, we solved ~50% of cases which is similar to diagnostic yields reported for global cohorts. However, the mutational profile among South Africans with GN and HSP differs substantially from the Global North.