Junctophilin 3 (JPH3) expansion mutations causing Huntington disease like 2 (HDL2) are common in South African patients with African ancestry and a Huntington disease phenotype

Abstract

Huntington disease (HD) is a progressive autosomal dominant neurodegenerative disorder, characterized by abnormal movements, cognitive decline and psychiatric symptoms, caused by a CAG repeat expansion in the huntingtin (HTT) gene on chromosome 4p. A CAG/CTG repeat expansion in the junctophilin-3 (JPH3) gene on chromosome 16q24.2 causes a Huntington disease-like phenotype (HDL2). All patients to date with HDL2 have some African ancestry. The present study aimed to characterize the genetic basis of the Huntington disease phenotype in South Africans and to investigate the possible origin of the JPH3 mutation. In a sample of unrelated South African individuals referred for diagnostic HD testing, 62% (106/171) of white patients compared to only 36% (47/130) of black patients had an expansion in HTT. However, 15% (20/130) of black South African patients and no white patients (0/171) had an expansion in JPH3, confirming the diagnosis of Huntington disease like 2 (HDL2). Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many cases, although the average age of onset and diagnosis in HDL2 is 5 years later than HD and individual clinical features may be more prominent. HDL2 mutations contribute significantly to the HD phenotype in South Africans with African ancestry. JPH3 haplotype studies in 31 families, mainly from South Africa and North America, provide evidence for a founder mutation and support a common African origin for all HDL2 patients. Molecular testing in individuals with an HD phenotype and African ancestry should include testing routinely for JPH3 mutations.

The Frequency of Huntington Disease and Huntington Disease-Like 2 in the South African Population

“…It is likely that this is a result of poor access to specialist medical services; however, underlying genetic variation may be a key factor [14,16,17] . This variation may provide an explanation for the lower estimated disease frequency of HD in the black South African population, as has been indicated for East Asian populations [18,19] .…”

“…A high number of HDL2-affected individuals has been identified in South Africa [14] . The presence of a shared haplotype highlights its significance, both in African populations and those with African ancestry.…”

“…Subsequent testing for the JPH3 mutation revealed that approximately one third of black South African patients clinically diagnosed with HD, in fact had HDL2 [12,14] . To date, HDL2 has been confirmed only in individuals of African or probable African ancestry (all of whom share a common haplotype) and the largest patient cohort known worldwide, is clustered in South Africa [14] .…”

“…To date, HDL2 has been confirmed only in individuals of African or probable African ancestry (all of whom share a common haplotype) and the largest patient cohort known worldwide, is clustered in South Africa [14] .…”

Understanding the genetic diversity of South Africa’s peoples

“…Individuals with HDL2 share many clinical features with individuals with HD and are clinically indistinguishable in many individual cases, although the average age of onset and diagnosis in HDL2 is approximately 5 years later than HD and individual clinical features may be more prominent. [16] While mutations at…”