Preliminary genealogical evidence for the Plakophilin-2 gene, PKP2 c.1162C>T founder mutation in cases with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive form of inherited heart muscle disease characterized by ventricular arrhythmias and sudden cardiac death. Often the pathogenesis is linked to deleterious mutations in the desmosomal gene plakophilin-2 (PKP2). We extended investigations of the pathogenic PKP2 c.1162C>T founder mutation which had previously been reported to occur within four 'unrelated' probands (6.2%) who selfidentified as Afrikaners and who also carried a common haplotype. Common evolutionary history suggests common haplotypes are linked to a common founder and today the Afrikaner populations are a unique ethnic group in South Africa identified with various founder effects for a range of heritable disorders. Aim: This study aimed to identify the common founder using genealogical and molecular methods for the PKP2 c.1162C>T mutation in ARVC families of Afrikaner descent in South Africa. Methods and results: DNA was collected from 46 participants (7 probands and 39 relatives) from the ARVC Registry of South Africa. Probands and relatives were screened for the PKP2 c.1162C>T mutation using High Resolution Melt and Sanger sequencing. The genetic results indicated that 65.2% (30/46) of the family members harbored this mutation. High Resolution Melt, Sanger sequencing and microsatellite typing were used to create a haplotype which encompassed the c.1162C>T mutation and three microsatellite markers (M1, D12S1692 and M2) spanning the PKP2 gene. A common haplotype emerged that segregated amongst all of the affected members of the seven Afrikaner families. Genealogical tracing went back, through multiple generations, into the implicated ancestral lines of the present day Afrikaner families. Four of the seven families attained their 17th century progenitors. Through genealogical analyses of the two largest families, ACM 19 and ACM 38, we identified 116 couples which we reduced to ten candidate South African founder couples who were then subjected to further analyses. After the ACM 12 family was added to the analysis there were five candidate founder couples. Unfortunately, the ACM 71 family did not progress past the 20th century due to tracing difficulties associated with poor record keeping of mixed ancestry data in South Africa and hence, could not be linked back to any other family tree without finding ACM71.5's grandparents. Additionally, ACM 8 and 57 families were recent finds and completion of their genealogical tracing still has to done. Conclusions: Our genetic data showed that not only were 30/46 individuals positive for the PKP2 c.1162C>T mutation but that all 30 individuals also shared the same common haplotype. Our preliminary genealogy tracing data suggests that the PKP2 c.1162C>T mutation segregates at a higher frequency in the Afrikaner population possibly due to a founder effect. The genealogical evidence supports the hypothesis that the PKP2 c.1162C>T mutation is a founder mutation and that descendants of the common founders are at risk of developing ARVC. At least three more families need to be recruited to make a clear conclusion and achieve genealogical evidence based saturation, ideally, a common founder.

Grantor dc:publisher.institution

Department of Paediatrics and Child Health

Year dc:date.issued

2016

Author dc:creator

• Machipisa, Tafadzwa

Advisors dc:contributor.advisor

• Shaboodien, Gasnat
• Mayosi, Bongani M

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/23420

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/23420