bims-tyki2d 2026-07-26 papers

Issue of 2026–07–26
three papers selected by
Zoya Panahloo, UCB

Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261469197

Patients' lived experience of thymidine kinase 2 deficiency: the online survey-based assessment of TK2d patient perspectives study.

Amel Karaa, Asha Hareendran, Katie Waller, Philip Yeske, Alexandra Morrison, Marnie Ross, Cristy Balcells.

Background: Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial disease characterized by progressive myopathy.
Objectives: To understand patient experiences and the impact of TK2d on patient quality of life (QoL), and to explore support needs.
Design: A cross-sectional international online survey.
Methods: The survey for the Assessment of TK2d Patient Perspectives (ATP) study, co-created with patient advocates, included multiple-choice questions, verbal rating scales, and open free-text questions. Patients of all ages with a self-reported genetic diagnosis of TK2d were eligible to participate, either directly or through a caregiver proxy. The patient, caregiver proxy, or bereaved caregiver proxy answered questions on demographics, signs/symptoms, impacts on health-related QoL (HRQoL), support needs, healthcare resource use, and overall experience of living with TK2d. Quantitative data were summarized with descriptive statistics. Qualitative data were analyzed using inductive thematic analysis.
Results: Responses for 32 patients (24 patient and 8 caregiver proxy responses) were collected between September 2023 and February 2024. All patients experienced myopathic symptoms. The most frequently reported impact of TK2d was on patients' ability to perform basic activities of daily living (26/32), including difficulties in walking (22/32), eating/swallowing (19/32), and breathing (25/32). The proportions of patients reporting a moderate or severe impact of breathing and walking difficulties on HRQoL, and the proportions requiring medical devices, were higher for those with an earlier age of TK2d symptom onset (⩽2, vs >2 to ⩽12, or >12 years). For most patients, TK2d also had a negative impact on mood, social and leisure activities, and employment/education. Progressive loss of abilities, increasing dependency on others, and medical equipment use contributed to mental and emotional burdens.
Conclusion: These quantitative and qualitative analyses of patients' lived experiences highlight the substantial, progressive, and wide-ranging burden of TK2d.

Keywords: burden; patient experience; quality of life; thymidine kinase 2 deficiency

DOI: https://doi.org/10.1177/26330040261469197

Arch Med Res. 2026 Jul 24. pii: S0188-4409(26)00114-1. [Epub ahead of print]57(8): 103492

Variant Curation and Classification in Rare Disease Genomics: Standards and Emerging Tools for Single-Nucleotide Variant Analysis.

Jimena Barraza García, Marta García, Leire Echepare Olivera, Carlos Iván Rivera Pedroza, Víctor Del Nogal Soler.

The widespread adoption of next-generation sequencing (NGS) for rare disease diagnosis has transformed clinical genomics. Multiple approaches have been proposed to standardize and improve the analysis, classification, interpretation, and reporting of genetic variants in clinical settings. This review provides a focused, practical overview of variant curation and current classification frameworks, particularly for single-nucleotide variants (SNVs) and small insertions/deletions within coding regions. These variant types remain the most frequent findings in clinical sequencing and are the primary targets of existing classification guidelines. While highly relevant, other variant types and analytical approaches fall outside the scope of this focused review and are addressed elsewhere in the literature and within this special issue. We distinguish between three related yet conceptually distinct processes: variant curation, defined as the systematic collection and evaluation of evidence; variant classification, defined as the standardized assignment of pathogenicity categories according to established guidelines; and clinical interpretation, which contextualizes a classified variant within an individual patient's phenotype to inform medical decision-making. We will examine advances in the field of variant classification that contribute to improving molecular diagnosis of rare diseases, highlighting the achievements, limitations, and challenges present in each aspect addressed. Key developments in variant classification are reviewed, including the 2015 guidelines and subsequent refinements, population databases, computational predictors, multiplexed functional studies, reanalysis efforts, and collaborative initiatives. Many challenges remain to be addressed, such as the interpretation of non-coding variants, the transition to updated classification frameworks, the diversity in population databases, and the development of new predictors, among others.

Keywords: ACMG/AMP guidelines; Pathogenicity predictors; Rare diseases; Variant classification

DOI: https://doi.org/10.1016/j.arcmed.2026.103492

EClinicalMedicine. 2026 Aug;98 104073

Recommendations for the use of clinical outcome assessments in rare disease drug development.

LifeArc Accelerating Rare Disease Trials (ARDT) centreaf

There are over 10,000 rare diseases collectively affecting an estimated 250-450 million people globally. While these diseases are rare individually, their cumulative impact on patients, families, healthcare systems, and society is substantial. The incorporation of clinical outcome assessments (COAs) in clinical trials can facilitate patient-focused drug development and treatment evaluation by generating meaningful evidence on how patients feel and function. This work was conducted in three phases: a targeted literature review (searched Aug 2025; updated Feb 2026), a multistakeholder workshop (online, Sept 2025) and, finally, an online survey to ratify final recommendations (responses by March 3, 2026). Of 43 individuals invited, 35 (81%) attended the virtual workshop: 11 researchers (including clinical trialists); 12 patients/caregivers; seven industry experts; four individuals from regulatory agencies and one HTA expert. All were based in the UK or USA. Across three sessions, the workshop explored stakeholder perspectives on considerations and appropriate methodological approaches to COA assessment for rare disease drug development to facilitate the generation of recommendations for future use. A threshold of at least 70% votes was chosen, a priori, for inclusion in the final set of recommendations. Here, we describe the potential benefits of COAs, summarise the key challenges, and provide recommendations to facilitate their effective and consistent integration in drug development for rare diseases.

Keywords: Clinical outcome assessment; Clinical trials; PRO; Patient-focused drug development; Patient-reported outcome; Rare diseases

DOI: https://doi.org/10.1016/j.eclinm.2026.104073