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=14

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=<sec><title>Introduction</title><p>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. In this study, we used next-generation sequencing to screen 61 probands with GN, hereditary spastic paraplegia (HSP), and spastic ataxias for a genetic diagnosis.</p></sec><sec><title>Methods</title><p>After identifying four GN probands with <italic>PMP22</italic> duplication and one spastic ataxia proband with SCA1, the remaining probands underwent whole exome (<italic>n</italic> = 26) or genome sequencing (<italic>n</italic> = 30). The curation of coding/splice region variants using gene panels was guided by allele frequencies from internal African-ancestry control genomes (<italic>n</italic> = 537) and the Clinical Genome Resource's Sequence Variant Interpretation guidelines.</p></sec><sec><title>Results</title><p>Of 32 GN probands, 50% had African-genetic ancestry, and 44% were solved: <italic>PMP22</italic> (<italic>n</italic> = 4); <italic>MFN2</italic> (<italic>n</italic> = 3); one each of <italic>MORC2, ATP1A1, ADPRHL2, GJB1, GAN, MPZ</italic>, and <italic>ATM</italic>. Of 29 HSP probands (six with predominant ataxia), 66% had African-genetic ancestry, and 48% were solved: <italic>SPG11</italic> (<italic>n</italic> = 3); <italic>KIF1A</italic> (<italic>n</italic> = 2); and one each of <italic>SPAST, ATL1, SPG7, PCYT2, PSEN1, ATXN1, ALDH18A1, CYP7B1</italic>, and <italic>RFT1</italic>. Structural variants in <italic>SPAST, SPG11, SPG7, MFN2, MPZ, KIF5A</italic>, and <italic>GJB1</italic> were excluded by computational prediction and manual visualisation.</p></sec><sec><title>Discussion</title><p>In this preliminary cohort screening panel 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 that in the Global North.</p></sec>