bims-tyki2d 2026-05-31 papers

Issue of 2026–05–31
four papers selected by
Zoya Panahloo, UCB

Adv Clin Chem. 2026 ;pii: S0065-2423(26)00021-1. [Epub ahead of print]133 161-216

Marco Refrigeri, Alessandra Tola, Rosangela Mogavero, Maria Michela Pietracupa, Giulia Gionta, Roberto Scatena.

Mitochondrial myopathies comprise a heterogeneous group of disorders arising from structural or functional mitochondrial impairments that disrupt oxidative phosphorylation and cellular ATP production. The resulting energy deficit manifests not only in muscle but frequently leads to multi-systemic disease involving the brain, heart, kidneys, and endocrine system, creating a complex and often confounding clinical presentation. A critical, often overlooked aspect of their pathophysiology is that mitochondrial dysfunction extends far beyond bioenergetics. These organelles are vital hubs for biosynthetic pathways, calcium homeostasis, thermogenesis, apoptosis, and redox-sensitive signaling pathways that govern gene expression. The disruption of these integrated functions, whose molecular consequences are still being elucidated, is central to the disease's progression and heterogeneity. This clinical and molecular complexity contributes to significant diagnostic delay, with many remaining undiagnosed. Therefore, the development and strategic implementation of reliable biomarkers are essential. This review critically evaluates current and emerging biomarkers, proposing a diagnostic framework designed to improve diagnostic accuracy, limit unnecessary procedures, and ensure timely access to therapeutic interventions and genetic counseling.

Keywords: Biomarkers; Cell-free circulating mtDNA; Creatine; Diagnosis; Exercise intolerance; FGF21; GDF-15; Genetics; Mitochondrial disease; Mitochondrial medicine; Mitochondrial myopathy; Neurofilaments; Oxidative phosphorylation

DOI: https://doi.org/10.1016/bs.acc.2026.01.007

BMC Med Ethics. 2026 May 28.

Automating genomic reanalysis: perspectives of people living with, or impacted by, a genetic, rare or undiagnosed condition.

Fiona Lynch, Emily King, Savio Nona, Zornitza Stark, Danya Vears.

BACKGROUND: Reanalysis - the process of re-examining a person's existing genomic data based on new knowledge or technology - has the potential to greatly increase diagnostic yield for people living with a genetic, rare or undiagnosed condition. Routine reanalysis has not been widely implemented, largely because of the labour-intensive nature of doing this manually. Yet, the more genomes that undergo sequencing, the greater the likelihood that we are missing opportunities to reanalyse previously undiagnosable cases. Automating reanalysis of genomic data could increase efficiency and accuracy, subsequently providing an opportunity to increase the availability (and frequency) of reanalysis to all people living with an undiagnosed condition. Despite these significant potential benefits, concerns include a lack of transparency and accountability, bias, risk to data security, and the subsequent impact on trust in automated systems. However, the public's perspectives on these ethical issues are yet to be examined.
METHODS: Twenty-three Australians living with - or caring for a person with - a genetic, rare or undiagnosed condition participated in one of seven 1.5-hour focus groups conducted online. Focus groups explored participants' preferences and values regarding key characteristics of automated reanalysis of genomic data. Focus groups were recorded, transcribed and analysed using inductive content analysis.
RESULTS: Discussions demonstrated strong support among people living with, or impacted by, a genetic, rare or undiagnosed condition for the automation of genomic reanalysis, emphasising its potential to reduce both practical and psychological burdens associated with manual processes. Participants underscored the need for transparent communication and continued human oversight to build trust in automated systems. However, widespread misunderstandings about reanalysis, concerns around data privacy, and patient preferences for return of results remain significant barriers that must be addressed to ensure ethical and effective implementation.
CONCLUSIONS: Our findings suggest that people living with, and caring for someone with, a genetic, rare or undiagnosed condition perceive significant potential benefits of automated genomic reanalysis. Participants anticipated that automation could reduce some of the practical demands associated with initiating reanalysis and provide reassurance that their genomic data would continue to be reviewed as scientific knowledge evolves. However, successful implementation will require careful attention to governance frameworks, informed consent processes, transparent data practices, and sustained human oversight to maintain trust and ensure equitable access.

Keywords: Artificial intelligence; Australia; Focus groups; Genomics; Patient perspective; Qualitative

DOI: https://doi.org/10.1186/s12910-026-01493-5

J Genet Couns. 2026 Jun;35(3): e70235

Expanding African contributions to ClinVar through genetic counselor-led variant curation.

Nabeelah Peerbhai, Nolene Ramsunder, Tarin Europa, Jeannine Heckmann, Melissa Nel.

Global variant databases such as ClinVar are vital in linking genetic variation to clinical significance and enabling shared interpretation across laboratories. However, African genetic variants remain underrepresented, comprising under 2% of global ClinVar submissions. This gap reflects inequities in access to genome sequencing, workforce capacity, and data-sharing systems, which limit visibility, contextual interpretation, and re-evaluation of African genetic variation. We describe our experiences of genetic counselor-led variant curation, ClinVar submissions, and ongoing monitoring of germline genetic variants identified in African neuromuscular and amyotrophic lateral sclerosis research cohorts. Between March 2023 and August 2025, the Clinical Omics and Informatics Unit (University of Cape Town) submitted 93 DNA sequence variants to ClinVar spanning 58 genes, including 27 first-time submissions to the database. ClinVar submissions require valid Monarch Disease Ontology (Mondo) identifiers; gaps or inaccuracies were identified (n = 3) and updated, or Mondo disease entities were created to ensure gene-disease pairs were correctly represented. Using African Genome Variation Database frequencies to guide variant classification provided sub-regional context, highlighting population differences and refining interpretations. Furthermore, we maintained a structured follow-up of variant records using ClinVar's "follow" feature. This enabled passive monitoring of new submissions or classification changes, which were evaluated to assess whether reinterpretation or resolution of variants of uncertain significance or those with conflicting assertions were warranted. This work highlights the critical role that African genetic counselors can play as contributors to variant curation in an underrepresented geography, given their expertise in human genetics and clinical reasoning. By embedding African-specific frequency data and locally trained expertise into variant curation pipelines, a sustainable, equity-driven model for genomic knowledge production in Africa is developed. African-led ClinVar contributions can strengthen interpretative accuracy, foster collaborative curation, and position genetic counselors as active agents in global genomic data sharing and interpretation.

Keywords: African genomic data equity; ClinVar data sharing; amyotrophic lateral sclerosis; disease ontology; genetic counselor; genomics; neuromuscular diseases; variant curation

DOI: https://doi.org/10.1002/jgc4.70235

medRxiv. 2026 May 17. pii: 2026.05.06.26352483. [Epub ahead of print]

Not Forgotten: Patient Experiences with Genetic Variant Reclassifications.

Pankhuri Gupta, Min Seon Park, Eric Y Kao, Abbye E McEwen, Runjun D Kumar, Martha Horike-Pyne, Douglas M Fowler, Lea M Starita, Sarah Knerr, Andrew B Stergachis.

Purpose: Genetic variant reclassification is increasingly common in clinical genomics, yet limited data describe how patients experience re-contact and variant reclassification in routine clinical care.
Methods: We conducted semi-structured qualitative interviews with 20 adult patients who received a variant reclassification following routine clinical genetic testing. Interviews explored emotional responses, communication experiences, and perceived value of genetic testing. Data were analyzed using Template Analysis, a form of thematic analysis.
Results: Three overarching themes were identified. Participants identified a need for improved communication of reclassified results, particularly with respect to timing, modality, and contextualization (Theme 1). Experiences with reclassification also shaped perceptions of the value of genetic testing, with most participants viewing testing as worthwhile despite its evolving nature (Theme 2). Finally, many participants interpreted reclassification as evidence of personalized and ongoing care, reinforcing trust in genetic testing and biomedical research (Theme 3). Participants generally preferred to be informed of reclassified results regardless of reclassification type, although the direction of reclassification influenced emotional responses and preferred modes of communication. Downgrades from variants of uncertain significance to benign or likely benign were widely viewed as meaningful by participants.
Conclusion: Variant reclassification was experienced as a signal of personalized, ongoing care. Timely, contextualized, patient-centered re-contact practices may reduce uncertainty, strengthen trust, and help patients not feel forgotten.

DOI: https://doi.org/10.64898/2026.05.06.26352483