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

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. 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.

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). The 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 visualisation.

Discussion: 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.

Keywords: African; Charcot-Marie-Tooth disease; diversity and inclusion; equity; hereditary spastic paraplegia; whole exome sequencing; whole genome sequencing.

Figure 1

The genetic landscape of (A) genetic neuropathy (GN) and (B) hereditary spastic paraplegia (HSP) (including spastic ataxias) in a South African cohort of 61 probands. Novel variants (light grey) refer to variants that have not been previously associated with the disease.

Figure 2

Selected pedigrees (genotyping only performed in probands). (A) Family of proband (fam_006) with heterozygous MFN2 mutation. (B) Family of proband (fam_111) with novel PSEN1 mutation presenting with spastic paraparesis (SP) followed by progressive aphasia (PA).

Figure 3

Proband (ICGNMD_8) with a milder phenotype of RFT1-congenital disorder of glycosylation. Brain imaging at age 35 years. (A) Sagittal T1-weighted MRI-brain scan showing cerebellar atrophy. (B) An axial brain FLAIR MRI image showing widespread discrete high signal intensity lesions in the subcortical white matter. Apart from the RFT1-disorders known to have coagulation factor abnormalities, the patient had no other cardiovascular risk factors to account for these white matter abnormalities of presumed vascular origin. (C) Spontaneous painful lesions with subsequent ulceration, which occurred in the distal extremities (before anticoagulation). Since oral anticoagulants were started for possible clotting abnormalities as a cause, the lesions have disappeared in the forearms and are substantially less in the legs (age 49).