Genetics in Medicine最新文献

Purpose: Genetic testing commonly yields a plethora of variants of uncertain significance (VUS) that can lead to ongoing uncertainty for patients and their caregivers. While all VUS hold uncertainty, some VUS have more evidence in support of pathogenicity while others have more evidence of a benign role. Sharing these nuances can help guide the investment in follow-up clinical and research investigations and may, at times, influence medical decision-making despite appreciated uncertainty.

Methods: Four clinical laboratories have been subclassifying VUS to help prioritize investigation and guide reporting decisions. Each laboratory developed a distinct approach for how these subclasses are used in their laboratories and, in some cases, displayed on reports. We examined the composition of each laboratory's VUS subclasses and the likelihood variants from each subclass were reclassified towards pathogenic or benign.

Results: We found that variants in the lowest subclass of VUS were never reclassified as likely pathogenic (LP) or pathogenic (P), while those in the highest subclass were much more likely to be reclassified as P/LP.

Conclusion: Given that forthcoming professional guidance in variant classification will advise the use of VUS subclasses, the experience of our laboratories in using VUS subclasses can inform future practices.

Purpose: Heterozygous pathogenic variants in SPTAN1 cause a diverse spectrum of neurogenetic disorders ranging from peripheral and central nervous system involvement to complex syndromic presentations. We set out to investigate the role of SPTAN1 in genetically unsolved hereditary myopathies.

Methods: Through international collaboration we identified 14 families with distal weakness and heterozygous SPTAN1 loss-of-function variants. Clinical data, electrophysiology, muscle CT or MRI and muscle biopsy findings were collected and standardized. SPTAN1 protein, mRNA expression analysis and cDNA sequencing was performed on muscle tissue from two participants.

Results: Five families showed autosomal dominant mode of inheritance, while in nine patients the variant was shown to be de novo, including 2 pairs of monozygotic twins. In two families, further segregation analysis was not possible. All affected participants presented with early childhood onset distal weakness and foot abnormalities. Muscle MRI or CT in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes in 7 patients. Finally, we provide proof for nonsense mediated decay in muscle tissue derived from two patients.

Conclusion: We present evidence linking heterozygous SPTAN1 loss-of-function variants to childhood-onset distal myopathy in 14 unrelated families.

Purpose: To systematically evaluate the diagnostic yield and clinical utility of genome and exome sequencing (GS and ES; genome-wide sequencing [GWS]) in pediatric patients with rare and undiagnosed genetic diseases.

Methods: We conducted a meta-analysis to evaluate studies published between 2011 and 2023. To address study heterogeneity, comparative analyses included within-cohort studies only using random effects models.

Results: We identified 108 studies including a total of 24,631 probands with diverse clinical indications. The pooled diagnostic yield among within-cohort studies (N=13) for GWS was 34.2% (95% CI: 27.6, 41.5; I2: 86%) vs. 18.1% (13.1, 24.6; I2: 89%) for non-GWS, with 2.4-times odds of diagnosis (1.40, 4.04; p<0.05). The pooled diagnostic yield among within-cohort studies (N=3) for GS was 30.6% (18.6, 45.9; I2: 79%) vs. 23.2% (18.5, 28.7; I2: 58%) for ES, with 1.7-times odds of diagnosis (95% CI: 0.94, 2.92; p=0.13). In 1st-line testing, diagnostic yield trended higher for GS vs. ES across clinical subgroups. The pooled clinical utility among patients with positive diagnoses was 58.7% (47.3, 69.2%; I 2: 81%) for GS and 54.5% (40.7, 67.6%; I 2: 87%) for ES.

Conclusion: GS appears to have higher diagnostic yield than ES, with similar clinical utility per positive diagnosis.

Introduction: Single Large-Scale mtDNA Deletions (SLSMD) result in Single Large Scale Deletion Syndromes (SLSMDS). SLSMDS presentations have classically been recognized to encompass at least three distinct clinical phenotypes, Pearson Syndrome (PS), Kearns-Sayre Syndrome (KSS), and Chronic Progressive Ophthalmoplegia (CPEO).

Methods: Facilitated review of electronic medical records, manual charts, and REDCap research databases was performed to complete a retrospective natural history study of 30 SLSMDS participants in a single health system seen between 2002 and 2020. Characteristics evaluated included genetic and clinical laboratory test values, growth parameters, signs and symptoms, demographics, and patient reported outcome measures of fatigue, quality of life, and overall function.

Results: Detailed cohort characterization highlighted that a recurrent deleted region involving MT-ND5 (HGNC:7641) occurs in 96% of SLSMD subjects regardless of clinical phenotype, which tended to evolve over time. Higher blood heteroplasmy correlated with earlier age of onset. GDF-15 was elevated in all SLSMD subjects. A PS history yielded negative survival prognosis. Furthermore, increased fatigue and decreased quality of life were reported in SLSMD subjects with advancing age.

Conclusion: Retrospective natural history study of SLSMDS subjects demonstrated the evolution of classically considered PS, KSS, and CPEO clinical presentations within affected individuals, which may inform future clinical trial development.

Purpose: This systematic review aims to identify factors that influence parents' decisions regarding pediatric diagnostic and predictive genetic testing (DT/PT). Factors are integrated into a conceptual model of decision-making. Implications for genetic counseling, research, and ethics are derived.

Methods: PubMed, PsychInfo, WebofScience and references of related reviews were searched for original publications between 2000 and 2023. Extracted factors were categorized into an existing model.

Results: Of 5843 publications, 56 met inclusion criteria. The included studies differentiate between DT, traditional, and expanded PT and describe factors impacting parental decisions on both to have the child genetically tested and to be informed about additional findings. Factors included: 1. benefits/hopes, 2. worries/concerns, 3. values and beliefs, 4. individual circumstances, and 5. emotional states.

Conclusion: Our work extends an existing empirical decision model of family decisions about genome sequencing to genetic testing in pediatrics in general, adding the categories "individual circumstances" and "emotional states". The factors can be further integrated into the Health Belief Model; the importance of emotional states is reflected in dual-process theories, such as Fuzzy Trace Theory. Research is required on emotional states, differences between DT and PT, parents' decisions about result disclosure, and dyadic variables as decision-making predictors.

Background and objectives: While several studies have evaluated neonatal intensive care unit (NICU) parents' perspective on the utility of genetic testing in a research context and concluded positive appraisal, some data point to more varied perceptions.

Methods: We conducted semi-structured interviews to elicit NICU parents' beliefs about the ways in which clinical (non-research) genetic testing could be both helpful and harmful.

Results: We interviewed 43 parents of 36 neonates who had been recommended, and either accepted or declined, clinical genetic testing. Parents described five types of problems they believed genetic information may address, what we term "problem-solving contexts:" treatment, coping, parenting, prognostic, and existential contexts. Most parents considered multiple problem-solving contexts in assessing benefit, frequently resulting in ambivalence.

Conclusions: Parents in the NICU appear to be more ambivalent about the utility of genetic information than is reflected in most recent studies. This discrepancy is likely related to both our sample population, clinical rather than research, and our methodology, which encouraged parents to discuss contexts beyond the medical. Our findings suggest that informed pre-test consent discussions and post-test counseling should engage parents in discussing multiple problem-solving contexts. Researchers should also find ways to incorporate these multiple contexts, and diverse perspectives within each context, into utility measures.

Purpose: The ClinGen Hearing Loss Gene Curation Expert Panel (GCEP) was assembled in 2016 and has since curated 174 gene-disease relationships (GDRs) using ClinGen's semi-quantitative framework. ClinGen mandates timely recuration of all GDRs classified as Disputed, Limited, Moderate, and Strong, every 2-3 years.

Methods: Thirty-five GDRs met the criteria for recuration within two years of original curation. Previous evidence was reevaluated using the latest curation guidelines and a comprehensive literature review was performed for new evidence. The recurations were approved by the GCEP and published to the ClinGen website (www.clinicalgenome.org).

Results: Eight out of 35 (22%) GDRs changed classification. Two Moderate and five Strong GDRs upgraded to Definitive due to new case evidence. One Strong was subsumed under another Definitive GDR, after evaluation of lumping/splitting of disease entities. Twenty-seven out of 35 remained unchanged with little to no new evidence reported.

Conclusion: Genes classified as Moderate and Strong are likely to build evidence and change in classification over time, whereas Limited are unlikely to gain evidence. These findings also highlight the critical role of recuration in ensuring that genetic tests and research studies incorporate the most up-to-date evidence into their efforts.

Purpose: DICER1 tumor predisposition syndrome (DTPS) is a hereditary condition affecting children and young adults. Identification of DICER1 carriers is key for prevention and actionability in families. However, DTPS diagnosis is hindered by its incomplete penetrance and broad phenotypic spectrum.

Methods: We performed an analysis of DICER1 sequencing data from 92 children and 6108 adults with a suspected cancer predisposition syndrome. Clinical and DICER1 somatic data from selected carriers and public datasets were studied.

Results: The prevalence of germline DICER1 PVs was 1:30 in children and 1:3054 in adults. No adult referral phenotype was a known DTPS-associated tumor, although 3/5 carriers developed thyroid alterations. We provide functional evidence supporting the pathogenicity of a novel in-frame deletion. A 56-year-old woman with an ovarian carcinoma and a toxic diffuse thyroid hyperplasia was found to have a postzygotic hotspot missense.

Conclusions: The prevalence of DICER1 PVs in cancer predisposition populations was 5-6 times that reported in the general population. Pediatric-onset DTPS is well characterized, whereas adult carriers mainly present with thyroid abnormalities in the absence of DICER1-related family history, thus requiring accurate criteria for its identification when in constellation with other tumor types. Postzygotic hotspot missenses may exist without the expected severe phenotype.