Pathogenic Variant Filtering for Mitochondrial Genome Haplotype Reporting

Abstract

Given the enhanced discriminatory power of the mitochondrial DNA (mtDNA) genome (mitogenome) over the commonly sequenced control region (CR) portion, the scientific merit of mitogenome sequencing is generally accepted. However, many laboratories remain beholden to CR sequencing due to privacy policies and legal requirements restricting the use of disease information or coding region (codR) information. In this report, we present an approach to obviate the reporting of sensitive codR data in forensic haplotypes. We consulted the MitoMap database to identify 92 mtDNA codR variants with confirmed pathogenicity. We determined the frequencies of these pathogenic variants in literature-quality and forensic-quality databases to be very low, at 1.2% and 0.36%, respectively. The observed effect of pathogenic variant filtering on random match statistics in 2488 forensic-quality mitogenome haplotypes from four populations was nil. We propose that pathogenic variant filtering should be incorporated into variant calling algorithms for mitogenome haplotype reporting to maximize the discriminatory power of the locus while minimizing the reveal of sensitive genetic information.

Mitochondrial DNA variation in Parkinson’s disease: Analysis of “out-of-place” population variants as a risk factor

“…Notably, four of our study participants carried mtDNA variants previously confirmed to be associated with LHON or deafness. This is in line with findings from previous studies that have reported these and other pathogenic mtDNA variants in the general population at varying levels of heteroplasmy (4.4–100.0%) ( Elliott et al, 2008 ; Venter et al, 2019 ; Marshall et al, 2020 ). To the best of our knowledge, none of the individuals carrying these mtDNA variants were affected by either of these conditions, reinforcing the well-accepted notion that additional genetic (i.e., mtDNA and nDNA backgrounds) and environmental factors [e.g., exposure to aminoglycoside antibiotics that induce non-syndromic deafness in carriers of the m.1555A > G variant ( Ou et al, 2018 )] may play a role in the expression of a mtDNA-associated disease phenotype ( Khan et al, 2017 ; Wei et al, 2017 ).…”

A cost–benefit analysis for use of large SNP panels and high throughput typing for forensic investigative genetic genealogy

“…The limitation, however, with the use of microarrays, in addition to requiring a large amount of input DNA, is that they contain potential genetic data with reasonable positive predictive power that could expose personal, privacy information about an individual. Budowle et al, [ 86 ] and Marshall et al [ 87 ] recommended (for whole mitochondrial genome sequence data) those SNPs that may provide such information could be filtered so only SNPs with little or no predictive power are reported. However, the raw data would still contain the SNPs which some jurisdictions and stakeholders might consider a risk to privacy.…”

The time is now for ubiquitous forensicmtMPSanalysis

“…There are potential ethical issues concerning genetic privacy, such as health‐related mutations in the coding region (Brandhagen et al, 2020; Marshall, Sturk‐Andreaggi, Ring, et al, 2020). While forensic laboratories are not focused on studying genes linked to the predisposition of a disease, this information can be found in mitogenome mtMPS data.…”

“…To overcome this, laboratories will need to develop policies on how to deal with the unintended discovery of medical information (Scudder et al, 2018). Marshall, Sturk‐Andreaggi, Ring, et al (2020), used the MitoMap database to identify 92 mtDNA coding region variants with confirmed pathogenicity. They then searched for the pathogenic variants in EMPOP and found that the frequency of the variants is quite low.…”