SEARCH · PubMed Health

Results for “genetic test utilization”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2025

The Clinician-reported Genetic Testing Utility InDEx for Neonatal Intensive Care (C-GUIDE NICU): Quantifying genome-wide sequencing utility in the NICU.

PURPOSE: Use of genomic sequencing (GS) in neonatal intensive care units (NICUs) has increased with improved diagnostic yield. However, uncertainty persists regarding when and for whom GS is most useful. Because a standardized approach to assessing utility is lacking, we developed a novel version of the Clinician-reported Genetic testing Utility InDEx (C-GUIDE) to quantify the utility of GS in NICUs. METHODS: Informed by a scoping review, we developed a draft C-GUIDE NICU tool to quantify utility, which underwent iterative revisions through feedback from clinician interviews and questionnaires on item relevance, comprehensibility, and comprehensiveness. We finalized the expert-informed C-GUIDE NICU using an international Delphi consensus process. RESULTS: Scoping review (n = 25 articles) and interviews (n = 21) revealed key themes of utility. Guided by qualitative feedback and item scoring, C-GUIDE was iteratively reduced to include 21, 18, and 14 items. The Delphi consensus process with 22 experts achieved item consensus and stability, yielding a final 10-item tool. CONCLUSION: Using a rigorous process, we developed a consensus-based standardized method for capturing the clinical utility of GS in NICUs. C-GUIDE NICU can be used by clinicians, researchers, and payers to assess GS value to patient care and will be available for licensed use following reliability and validity testing.

Humans↗

PubMed2025

BRCA genetic testing utilization and expenditures among privately insured adults in the United States, 2013 to 2022.

PURPOSE: Recent clinical guidelines have broadened the criteria for BRCA counseling and testing for women and men, including indications based on family history, personal history, and current diagnosis of breast, ovarian, pancreatic, and prostate cancer. METHODS: Using claims data from 2013 to 2022, we identified BRCA testing using procedure codes to evaluate annual utilization, median expenditures per enrollee, and the percentage of 0 out-of-pocket expenditures by sex among enrollees aged 18 to 64 years who were continuously enrolled within calendar years. We examined BRCA utilization by metropolitan status and indications. RESULTS: Annual BRCA testing utilization among women (and men) increased 10.2% (44.5%) per year during 2014 to 2015 and 1.7% (10.0%) per year during 2016 to 2019, decreased 34.4% (44.8%) in 2020, and rebounded 8.5% (22.3%) per year during 2021 to 2022, remaining below prepandemic levels in 2022. Median expenditures for comprehensive BRCA testing per enrollee decreased by 68% from 2013 to 2022, most of whom had 0 out-of-pocket expenditures. Most BRCA testing was done based on family health history of breast, ovarian, or prostate cancer and among women aged 18 to 50 years. CONCLUSION: Health care providers who are knowledgeable about evolving indications for germline BRCA testing can help ensure that eligible individuals have access to germline BRCA testing as preventive service.

Humans↗

PubMed2025

Genetics first approach: Expanding the utility of genetic testing by nongeneticist physicians.

PURPOSE: The increasing demand for genetic testing and a global shortage of geneticists has significantly strained health care systems worldwide. This highlighted the need for new strategies aiming to increase testing accessibility, reduce wait times, and enhance patient care quality. METHODS: We implemented a 4-step program, "Genetics First," to empower nongeneticist physicians (NGPs) to play an active role in the process of genetic consultation and testing. The steps included (1) establishing criteria to identify suitable clinical domains, (2) selecting clinical indications within the domain through expert panel review, (3) designing tailored education and workflows for NGPs across indications, and (4) monitoring test outcomes and providing further support for complex cases. Test outcomes were compared between NGPs and clinical geneticists. RESULTS: Endocrinology was selected as the first domain, with 114 endocrinologists who completed the program. During the study, 260 gene panels were performed for monogenic diabetes, with NGPs initiating 68% of tests, leading to a 107% increase in referrals. The diagnostic yield was 30%, with no significant difference between NGP- and clinical geneticist-initiated tests. CONCLUSION: This study demonstrates the feasibility and impact of involving NGPs in genetic testing, offering a paradigm shift that could expand access to genetic testing and improve patients' care and clinical outcomes.

Humans↗

PubMed2024

A novel start-loss mutation of the SLC29A3 gene in a consanguineous family with H syndrome: clinical characteristics, in silico analysis and literature review.

BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene. METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing. RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein. CONCLUSION: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.

Humans↗

PubMed2025

Precision diagnostic and therapeutic interventions in rare genetic neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs) include a broad spectrum of phenotypes spanning from intellectual disability (ID) to developmental delay (DD) and autism spectrum disorder (ASD). As neurodevelopmental phenotypes are a common presenting feature of an underlying genetic condition, professional medical organizations recommend genetic testing for all individuals with a NDD. When testing is pursued, identified genetic differences can lead to personalized clinical management with early diagnosis supporting the development of surveillance and intervention for co-occurring adverse health outcomes. Despite this, barriers to testing have prevented individuals from receiving a genetics referral and testing. Current therapeutic modalities including small molecule drugs, gene therapies, and antisense oligonucleotide therapies have emerged and shown promise in preclinical trials with therapeutic drugs gaining FDA approval. However, translational challenges are extensive, especially for identifying biomarkers of drug effects in the CNS. In this review, we discuss diagnostic approaches and clinical utility of genetic testing for rare genetic neurodevelopmental disorders, emerging development of individualized therapies, and progress for current therapeutics in addition to challenges with clinical translation and delivery. We will highlight opportunities for early diagnosis and treatment that are steadily gaining ground in favor of optimizing long-term health outcomes and improving quality of life for neurodiverse individuals. IMPACT: The path from genomics to therapeutics for neurodevelopmental disorders continues to present multiple opportunities and challenges. While emerging genome-wide sequencing and gene editing technologies deliver increased diagnostic yields and alternatives to life-long small molecule therapies, clinical translation has been challenging due to inherent cost and genetic heterogeneity. Limited access to genetic testing despite practice guidelines remains a barrier towards precision therapeutics for rare neurodevelopmental disorders, while pre-clinical investigations face obstacles when translating to human subjects. This review will summarize the impact of existing successes in diagnosis and therapeutics for neurodevelopmental disorders while highlighting ongoing challenges and areas of future opportunities.

Humans↗

PubMed2026

Genetic Testing Unveils a Novel Thrombospondin-1 Domain Containing Protein 1 Gene Variant as the Cause of Chronic Edema in a 79-Year-Old Woman.

Edema requires management tailored to its underlying etiology; however, in some cases the cause remains elusive. We describe a 79-year-old woman with lifelong unexplained peripheral edema. Comprehensive evaluation excluded common etiologies such as heart failure, renal dysfunction, and venous thrombosis. Whole-genome sequencing identified a novel homozygous splice-site variant (NM_018676.4:c.58+2T>G) in the thrombospondin-1 domain-containing protein 1 (THSD1) gene, which has previously been associated with non-immune hydrops fetalis (NIHF). This report describes, to our knowledge, the first elderly patient with chronic peripheral edema harboring a likely pathogenic THSD1 variant, suggesting that THSD1-related disease may, in rare instances, persist beyond the perinatal period and present into late adulthood. Although causality cannot be established definitively from a single case, the findings highlight the potential utility of genetic testing in adults with chronic unexplained edema.

chronic edema↗

PubMed2025

Ten years of exome sequencing and reanalysis among racial, ethnic, and ancestral groups: The importance of equitable reanalysis access.

PURPOSE: Race, ethnicity, and ancestry (REA) affect the diagnostic utility of genetic testing. In addition to barriers to accessing genetics services, some non-European REA groups experience decreased diagnostic results and increased uncertain results. Exome sequencing (ES) is a unique genetic test because data can be reanalyzed with new information and variants may be reclassified after the original result. METHODS: We performed a retrospective review of 10,416 clinical ES cases originally analyzed by Ambry Genetics between 2011 and 2021 with reanalysis events through 2023. The relationship between assigned REA group, ES result, reanalysis and reclassification rates, and reanalysis initiators were analyzed with logistic regression. RESULTS: Reanalyses increased the total diagnostic yield from 21.4% to 25.5%. There were no significant differences in reclassification rate among REA groups. However, the African American and Black group (P = 2.8E-07), the Hispanic and Latino group (P = .0022), and the Asian group (P = .033) were significantly less likely to receive provider-initiated reanalysis compared with the White group. CONCLUSION: Although reclassification rates were not found to be associated with REA group, not all REA groups had the same access to ES reanalysis. Laboratory-initiated proactive reanalysis can help reduce disparities in ES diagnostic utility by reducing barriers to accessing reanalysis.

Female↗

PubMed2026

Potential contributors to variable penetrance of NOTCH3 p.Arg1231Cys Variant.

Missense mutations in NOTCH3, especially cysteine-altering pathogenic variants, are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. The NOTCH3 p.Arg1231Cys variant, located in EGFr domain 31, is classified as low-risk under the three-tiered EGFr domain risk stratification system. We report two cases of p.Arg1231Cys heterozygosity presenting with early-onset dementia, strokes, and extensive leukoencephalopathy. These cases highlight the potential contributing factors to increasing penetrance of p.Arg1231Cys variant, and the need for functional evaluation to improve the clinical utility of genetic testing in hereditary small vessel disease.

Humans↗

PubMed2026

A novel truncating FBN1 variant in a family with Marfan syndrome.

Marfan syndrome is caused by pathogenic variants in FBN1. We identified a novel heterozygous frameshift variant in FBN1 (NM_000138.5: c.6784_6787del, NP_000129.3:p.(Gln2262TrpfsTer28)) in an adult male with severe cardiovascular manifestations. The variant was absent from population databases and fulfilled PVS1 and PM2 criteria. This finding expands the mutational and phenotypic spectrum of FBN1 and highlights the clinical utility of genetic testing in family-based clinical management of Marfan syndrome.

Journal Article↗

PubMed2025

Characterizing trends in clinical genetic testing: A single-center analysis of EHR data from 1.8 million patients over two decades.

A lack of structural data in electronic health records (EHRs) makes assessing the impact of genetic testing on clinical practice challenging. We extracted clinical genetic tests from the EHRs of more than 1.8 million patients seen at Vanderbilt University Medical Center from 2002 to 2022. With these data, we quantified the use of clinical genetic testing in healthcare and described how testing patterns and results changed over time. We assessed trends in types of genetic tests, tracked usage across medical specialties, and introduced a new measure, the genetically attributable fraction (GAF), to quantify the proportion of observed phenotypes attributable to a genetic diagnosis over time. We identified 104,392 tests and 19,032 molecularly confirmed diagnoses. The proportion of patients with genetic testing in their EHRs increased from 1.0% in 2002 to 6.1% in 2022, and testing became more comprehensive with the growing use of multi-gene panels. The number of unique diseases diagnosed with genetic testing increased from 51 in 2002 to 509 in 2022, and there was a rise in the number of variants of uncertain significance. The phenome-wide GAF for 6,505,620 diagnoses made in 2022 was 0.46%, and the GAF was greater than 5% for 74 phenotypes, including pancreatic insufficiency (67%), chorea (64%), atrial septal defect (24%), microcephaly (17%), paraganglioma (17%), and ovarian cancer (6.8%). Our study provides a comprehensive quantification of the increasing role of genetic testing at a major academic medical institution and demonstrates its growing utility in explaining the observed medical phenome.

Humans↗

PubMed2024

Assessment the carrier frequency of monogenic diseases in populations requiring assisted reproductive technology.

PURPOSE: The objective of this study is to assess the carrier frequency and pathogenic variation of monogenetic diseases in a population of 114 subjects in Han Chinese from Hebei province who are undergoing assisted reproductive technology through the utilization of Expanded Carrier Screening (ECS). METHODS: The study utilized a panel consisting of 155 severe monogenic recessive genetic diseases for ECS. Next-generation sequencing technology was employed to identify specific variants associated with ECS in a cohort of 114 subjects from 97 couples, comprising 97 females and 17 male spouses. RESULTS: A total of 114 individuals received ECS. The carrier rate of pathogenic genes in the enrolled population was 44.74% (51/114). Among the 97 females, the carrier rate of pathogenic genes was higher in those without assisted reproduction indicators than in those with assisted reproduction indicators (59.09% vs. 41.33%). However, the carrier rate of pathogenic genes in males without assisted reproductive technology was slightly lower than that with assisted reproductive technology (40% vs. 41.67%). Among both female and male participants, the carrier rate of pathogenic genes between individuals without indicators of assisted reproduction and those with such indicators was 55.55% vs. 41.38%. In 51 carriers, 72.55% (37/51) carried one genetic variant, 25.49% (13/51) carried two genetic variants, and 1.96% (1/51) carried three genetic variants. A total of 38 pathogenic genes were detected in this study, and GJB2 and MMACHC were most common. The carrier rates of the two genes were both 5.26% (6/114). A total of 55 variations were detected, and c.235delC was most frequently found. The carrier rate was 3.51% (4/114). The incidence of couples carrying the same pathogenic genes was 1.03% (1/97). CONCLUSIONS: The findings elucidate the carrier rate of pathogenic genes among 155 severe monogenic recessive genetic diseases and underscore the significance of ECS as a preventive measure against congenital anomalies. When both partners carry the same genetic mutation for a monogenic disease, preventive strategies can be taken in offspring through preimplantation genetic testing (PGT), prenatal genetic testing, or the utilization of donor gametes. ECS is instrumental in assessing reproductive risk, guiding fertility-related decisions, and reducing the prevalence of monogenic recessive genetic disorders in subsequent generations.

Humans↗

PubMed2024

Cost-effectiveness of population-wide genomic screening for Lynch Syndrome and polygenic risk scores to inform colorectal cancer screening.

PURPOSE: Genomic screening to identify individuals with Lynch Syndrome (LS) and those with a high polygenic risk score (PRS) promises to personalize colorectal cancer (CRC) screening. Understanding its clinical and economic impact is needed to inform screening guidelines and reimbursement policies. METHODS: We developed a Markov model to simulate individuals over a lifetime. We compared LS+PRS genomic screening with standard of care (SOC) for a cohort of US adults at age 30. The Markov model included health states of no CRC, CRC stages (A-D), and death. We estimated incidence, mortality, and discounted economic outcomes of the population under different interventions. RESULTS: Screening 1000 individuals for LS+PRS resulted in 1.36 fewer CRC cases and 0.65 fewer deaths compared with SOC. The incremental cost-effectiveness ratio was $124,415 per quality-adjusted life year; screening had a 69% probability of being cost-effective using a willingness-to-pay threshold of $150,000/quality-adjusted life year . Setting the PRS threshold at the 90th percentile of the LS+PRS screening program to define individuals at high risk was most likely to be cost-effective compared with 95th, 85th, and 80th percentiles. CONCLUSION: Population-level LS+PRS screening is marginally cost-effective, and a threshold of 90th percentile is more likely to be cost-effective than other thresholds.

Humans↗

PubMed2025

The impact of genetic counselor involvement in genetic and genomic test order review: A scoping review.

PURPOSE: The increasing complexity of genetic technologies paired with more genetic tests being ordered by nongenetic health care providers, has resulted in an increase in the number of inappropriately ordered tests. Genetic counselors (GCs) are ideally suited to assess the appropriateness of a genetic test. METHODS: We performed a scoping review of GC involvement in utilization management initiatives in order to describe the impact of having GCs involved in this process. Five databases (MEDLINE, EMBASE, CINHAL, EBM reviews, and Web of Science Core Collection) and gray literature were searched. We considered literature published in English since 2010. RESULTS: A total of 51 studies were included. The most commonly evaluated outcomes included cancellation rate, economic efficiencies, impact on medical management, diagnostic rate, and time or triage efficiencies. Several studies also described GC impact on nongenetic health care providers. CONCLUSION: Employment of GCs in the laboratory has been implemented widely as a solution to test misordering. These studies describe ways in which GCs can be integrated into testing workflows to reduce the number of inappropriate tests and have wider impacts on nongenetic health care providers' ordering practices and the patient experience.

Humans↗

PubMed2026

Real-world clinical utility of exome sequencing in pediatric drug-resistant epilepsy: Experience from a tertiary center in Thailand.

BACKGROUND: Genomic testing has increasingly contributed to the diagnosis and management of pediatric drug-resistant epilepsy (DRE), particularly in patients with suspected genetic etiologies. This study evaluated the diagnostic yield and real- world clinical utility of whole-exome sequencing (WES) in children with DRE. METHODS: Children with DRE and seizure onset before 15 years of age were enrolled between January 2020 and December 2023. Clinical data, including demographics, seizure characteristics, developmental history, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and prior investigations, were reviewed. WES was performed in all probands and, when available, their parents. Variants were interpreted according to standard guidelines. Clinical utility and 1-year seizure and developmental outcomes were assessed from follow-up records. RESULTS: Fifty-six patients (23 males, 33 females) were included. The median age at seizure onset was 1 year (interquartile range [IQR] 0.3-4 years), and 96.4% had developmental comorbidities. Pathogenic or likely pathogenic variants were identified in 39% (22/56), with the highest diagnostic yield in children with seizure onset before 3 years of age. Channelopathies accounted for most genetically solved cases (68%), predominantly involving sodium channel genes. Genetic diagnoses provided clinical utility in 73% (16/22) of solved cases by guiding treatment and precision management. At 1-year follow-up, genetically solved patients showed more favorable seizure and developmental outcomes than those with genetically unsolved patients. CONCLUSION: WES achieved a 39% diagnostic yield and substantial clinical utility in pediatric DRE, particularly in early-onset and channelopathy-related disorders. These findings support early molecular diagnosis to facilitate genotype-informed management in appropriately selected children. However, the more favorable developmental and seizure outcomes observed in genetically solved patients should be interpreted with caution, as they may have been influenced by multiple factors beyond genetic diagnosis. In resource-limited settings, careful clinical phenotyping remains essential for treatment decisions and for prioritizing children for genomic testing.

Clinical utility↗

PubMed2025

Clinical Actionability of Genetic Findings in Cerebral Palsy: A Systematic Review and Meta-Analysis.

IMPORTANCE: Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated. OBJECTIVE: To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies. DATA SOURCES: Published pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n = 1345) or research (n = 496) cohorts of CP were analyzed. A systematic literature review for evidence of effective therapies for specific genetic etiologies was performed. STUDY SELECTION: Nonstandard interventions that led to a detectable improvement in a defined outcome in individuals with variants in the gene of interest were included. DATA EXTRACTION AND SYNTHESIS: Literature was evaluated using PRISMA guidelines. A diverse, expert working group was established, scoring rubrics adapted, and scoring consensus built with a modified Delphi approach. MAIN OUTCOMES AND MEASURES: Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety and practicality of the intervention, and anticipated intervention efficacy on a scale from 0 to 3. RESULTS: Of 1841 patients with CP who underwent exome sequencing, 502 (27%) had pathogenic or likely pathogenic variants related to their phenotype. A total of 243 different genes were identified. In 1841 patients with identified genetic etiologies of CP, 140 (8%) had a genetic etiology classified as actionable, defined as prompting a change in clinical management. Also identified were 58 of 243 genes with pathogenic or likely pathogenic variants with actionable treatment options: 16 targeting the primary disease mechanism, 16 with specific prevention strategies, and 26 with specific symptom management. The level of evidence was also graded according to ClinGen criteria; 45 of 101 interventions (44.6%) had evidence class D or below. The potential interventions have clinical utility with 98 of 101 outcomes (97%) being moderate-high severity if left untreated and 63 of 101 interventions (62%) predicted to be of moderate-high efficacy. Most interventions (72 of 101 [71%]) were considered moderate-high safety and practicality. CONCLUSIONS AND RELEVANCE: The findings indicate that actionable genetic findings occurred in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy, outcome severity, and intervention safety and practicality indicates moderate-high clinical utility of these genetic findings. Genetic sequencing can identify precision medicine interventions that provide clinical benefit to individuals with CP. The relatively limited evidence base underscores the need for additional research.

Humans↗

PubMed2025

A meta-analysis of diagnostic yield and clinical utility of genome and exome sequencing in pediatric rare and undiagnosed genetic diseases.

PURPOSE: To systematically evaluate the diagnostic yield and clinical utility of genome sequencing (GS) and exome sequencing (ES; genome-wide sequencing [GWS]) in pediatric patients with rare and undiagnosed genetic diseases. METHODS: We conducted a meta-analysis of studies published between 2011 and 2023. To address study heterogeneity, comparative analyses included within-cohort studies using random-effects models. RESULTS: We identified 108 studies including 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% (95% CI: 13.1-24.6; I2: 89%) for non-GWS, with 2.4-times odds of diagnosis (95% CI: 1.40-4.04; P < .05). The pooled diagnostic yield among within-cohort studies (N = 3) for GS was 30.6% (95% CI: 18.6-45.9; I2: 79%) vs 23.2% (95% CI: 18.5-28.7; I2: 58%) for ES, with 1.7-times the odds of diagnosis (95% CI: 0.94-2.92; P = .13). In first-line testing, the diagnostic yield tended to be higher for GS than for ES across clinical subgroups. The pooled clinical utility among patients with a positive diagnosis was 58.7% (95% CI: 47.3-69.2; I2: 81%) for GS and 54.5% (95% CI: 40.7-67.6; I2: 87%) for ES. CONCLUSION: GS appears to have a higher diagnostic yield than ES, with similar clinical utility per positive diagnosis.

Child↗

PubMed2026

Comprehensive functional testing in fibroblasts has strong utility to diagnose mitochondrial disease.

Genome sequencing is the first-line diagnostic method for primary mitochondrial diseases (PMDs), yet its effectiveness is limited by variants of uncertain significance or unresolved genetic findings. We systematically evaluated the clinical performance of fibroblast-based functional testing, comprised of respiratory chain enzyme assays, blue native polyacrylamide gel electrophoresis with in-gel activity staining (BN-PAGE), complex I assembly assay, and targeted protein abundance assessments, in a cohort of 204 genetically confirmed PMD patients, 51 healthy controls, and 53 patients with differential diagnoses. Individually, enzyme assays, BN-PAGE, and complex I assembly assay showed sensitivities of 46%, 40%, and 49%, with specificities of 93%, 98%, and 99%, respectively. Combined, the assays achieved an overall sensitivity of 76%, a specificity 93%, a positive predictive value 96%, and a negative predictive value of 67%. Sensitivity was highest for isolated respiratory chain deficiencies, nuclear DNA-encoded mitochondrial translation defects, cofactor deficiencies, and mitochondrial aminoacyl-tRNA synthetase disorders, whereas mitochondrial DNA variants and maintenance defects remained challenging. Secondary mitochondrial dysfunction was rare. The strong clinical utility of comprehensive fibroblast functional testing improves PMD diagnosis when used complementary to genomic sequencing.

Journal Article↗

PubMed1976

Mutations affecting catabolite repression of the L-arabinose regulon in Escherichia coli B/r.

Expression of the L-arabinose regulon in Escherichia coli B/r requires, among other things, cyclic adenosine-3', 5'-monophosphate (cAMP) and the cAMP receptor protein (CRP). Mutants deficient in adenyl cyclase (cya-), the enzyme which synthesizes cAMP, or CRP (crp-) are unable to utilize a variety of carbohydrates, including L-arabinose. Ara+ revertants of a cya-crp- strain were isolated on 0.2% minimal L-arabinose plates, conditions which require the entire ara regulon to be activated in the absence of cAMP and CRP. Evidence from genetic and physiological studies is consistent with placing these mutations in the araC regulatory gene. Deletion mapping with one mutant localized the site within either araO or araC, and complementation tests indicated the mutants acted trans to confer the ability to utilize L-arabinose in a cya-crp- genetic background. Since genetic analysis supports the conclusion, that the mutant sites are in the araC regulatory gene, the mutants were designated araCi, indicating a mutation in the regulatory gene affecting the cAMP-CRP requirement. Physiological analysis of one mutant, araCi1, illustrates the trans-acting nature of the mutation. In a cya-crp- genetic background, araCi1 promoted synthesis of both isomerase, a product of the araBAD operon, and permease, a product of the araE operon. Isomerase and permease levels in araCi1 cya+ crp+ were hyperinducible, and the sensitivity of each to cAMP was altered. Two models are presented that show the possible mutational lesion in the araCi strains.

Adenylyl Cyclases↗