Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Reclassification”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 739 records · Page 41Linked to original sources

Margarines and coronary artery disease.

In a previous paper we predicted that health effects of dietary fats in humans would require half a century or more to be understood, instead of the decade or so predicted during 1956 by an Editorial in The Lancet. It would seem that our prediction may have been optimistic since it has now been reported that trans unsaturated fatty acids present in high concentrations in margarines promote hypercholesterolemia in humans. Consequently, there has been a call for the reclassification of dietary fats upon the basis of their hypercholesterolemic properties. Using the latter criterion, therefore, many margarine brands would be classified as coronary artery disease risk foods. The primary adverse metabolic action of trans unsaturated fatty acids is the competitive inhibition of delta-6-desaturase, the hepatic enzyme responsible for the initial metabolic desaturation of the essential fatty acids cis linoleic and cis alpha-linolenic acid. In addition to margarines, many other common foods such as deep-fried foods, many convenience foods and bakery products contain relatively high levels of trans fatty acids. Therefore, since it has become virtually impossible to avoid a consistent, daily dietary intake of trans fatty acids, it would appear that a precautionary, preventative supplementation of the diet with supplements containing the direct metabolic products of delta-6-desaturation of the essential fatty acids, would be prudent. Such supplements are readily available.

Coronary Disease↗

Radiotherapeutic management of primary thyroid lymphoma.

The purpose of this study was to evaluate the radiotherapeutic management of 38 patients, with malignant lymphoma of the thyroid, seen at the Mayo Clinic between 1965 and 1979. There were 8 males and 30 females with ages ranging from 34 to 90 years (mean age of 65 years). A tissue diagnosis was made in all patients and tissue was available for reclassification under the "Working Formulation" in 31 of the 38 patients. Twenty-six patients had intermediate grade histology, four low grade and one indeterminate. Twenty patients were clinical Stage IE, 14 patients Stage IIE, one patient Stage IIIE, one patient Stage IV and two patients were unstaged. All patients were treated with approximately 4000 rad megavoltage irradiation (range 2400-6000 rad) to the neck only (10 patients) or neck and mediastinum (28 patients). Twenty patients received subdiaphragmatic radiotherapy and four patients received adjuvant chemotherapy. Median follow-up was 56 months with minimum follow-up of 30 months. Overall disease-free survival at five years was 59%. Of 14 patients who experienced a recurrence, 10 (71%) failed in two or more sites. The most common site of failure was in para-aortic lymph nodes. One year survival following recurrence was 29%; however, four of six patients receiving salvage therapy survived at least two years. Patients receiving radiation treatment to the neck and mediastinum and those with no gross residual disease at the initiation of radiotherapy were less likely to develop a recurrence. Patients receiving a planned break during the course of therapy did not have reduced overall disease-free survival. However, 4 of 20 patients (20%) who received split course therapy failed within the radiation fields compared to 2 of 18 patients (11%) who had no treatment break. Only 1 of 4 patients (25%) receiving adjuvant chemotherapy survived one year. Side effects of radiotherapy were minimal. We believe the radiotherapeutic management of clinical Stage IE and IIE primary thyroid lymphoma should include treatment of the neck, axillae and mediastinum to a dose of approximately 4000 rad using a continuous course technique. Additionally, gross total removal of the disease surgically may be beneficial.

Adult↗

Day-to-day variability of voltage measurements used in electrocardiographic criteria for left ventricular hypertrophy.

Although electrocardiographic (ECG) voltage can be used to estimate left ventricular mass, day-to-day variability of voltage combinations used for this purpose must be established before ECG changes are taken as evidence of progression or regression of hypertrophy. Accordingly, serial ECGs (mean 8 days apart), derived from 10 s samples digitized at 250 Hz, were examined in 78 patients with no intercurrent change in clinical status. The coefficient of variation was calculated as 1 SD of the difference between paired voltage measurements, divided by the average mean value. Coefficient of variation for single leads was 22.3% for SV1, 27.0% for RV5 or RV6, 27.1% for RaVL and 34.7% for SV3. Coefficient of variation was lower for voltage combinations than for individual lead measurements: 18.5% for Sokolow-Lyon voltage (SV1 + RV5 or RV6), 22.3% for Gubner-Ungerleider voltage (R1 + S3) and 24.8% for Cornell voltage (RaVL + SV3). Serial reclassification due to variation above and below standard criteria for left ventricular hypertrophy occurred in only 3% of patients for Sokolow-Lyon voltage and 4% of patients for Cornell voltage in this group. Minute to minute reproducibility of voltage was assessed with electrodes in place in a separate group of 26 patients, and the coefficient of variation was 2.6% for Sokolow-Lyon voltage, 5.9% for Gubner-Ungerleider voltage and 2.9% for Cornell voltage. These data indicate that serial variability of computer-measured ECG voltage combinations is high, due primarily to changes in lead placement and body position, but less than the variability of computer-measured voltage in individual leads.

Adult↗

Managed delay for coronary artery bypass graft surgery: the experience at one Canadian center.

OBJECTIVES: This study sought to assess the impact of delaying coronary artery bypass surgery at one Canadian academic tertiary referral center. BACKGROUND: Universal access to medical services in Canada comes at the expense of waiting lists whose impact has been incompletely assessed. METHODS: A prospective, observational study of all residents of Nova Scotia and Prince Edward Island accepted for bypass surgery between 1 April 1992 and 31 October 1992 was undertaken to determine 1) whether triage guidelines were being followed; and 2) the incidence of cardiac death, nonfatal myocardial infarction and worsening symptoms associated with delayed operation. The analysis had 90% power to detect a mortality rate of > or = 3% (alpha 0.05). RESULTS: Of 423 patients referred, 35% were triaged as urgent, 9.7% as semiurgent A, 39% as semiurgent B and 16.3% as elective, with no age or gender bias identified. Operation occurred at < or = 1 week in 25%, < or = 1 month in 47%, and >6 months in 1.4%. There were no nonfatal myocardial infarctions, but five cardiac deaths occurred (1.2%). Of 275 patients not initially classified as urgent, 12.4% required reclassification to higher priorities because of worsening symptoms; none had perioperative myocardial infarction or died. One in four patients queued longer than target waiting times. Only 4% of patients considered prioritization on the basis of medical need unfair, but 64% experienced at least moderate anxiety. CONCLUSION: This triage system equitably stratified patients to a queue. Deaths were rare and could not be attributed to the triage process. Patients with worsening clinical status were safely accommodated with earlier waiting times, but concerns remain regarding excessive waiting times and patient anxiety.

Aged↗

Increase in tuberculin skin test converters among health care workers after a change from Tubersol to Aplisol.

BACKGROUND: Comparability of the 2 commercially available tuberculin skin testing (TST) preparations, Aplisol (Parkdale Pharmaceuticals, Inc, Rochester, MI) and Tubersol (Aventis Pasteur, Inc, Swiftwater, PA), remains uncertain, particularly in groups that undergo repeated testing, such as health care workers. METHODS: Data from the annual tuberculosis screening program for health care workers at the Kennedy Krieger Institute in Baltimore, Maryland, were analyzed. Conversion rates during 1997-2003 in workers screened with Tubersol (n = 8897 screenings) were compared with 1203 workers who underwent screening with Aplisol in 2004. Repeat testing with Tubersol was examined in those who converted in 2004 with Aplisol. RESULTS: Annual TST conversion rates ranged from 0.3% to 0.9% between 1997 and 2003 using Tubersol. After switching to Aplisol in 2004, the TST conversion rate significantly increased to 2% (P < .001). Among 24 health care workers who were converters with Aplisol in 2004, only 6 of 23 (26%) were converters on repeat testing with Tubersol (1 declined retesting). None of the apparent converters (n = 24) had radiographic evidence of Mycobacterium tuberculosis infection, and there was no epidemiologic evidence of transmission. Reclassification based on Tubersol testing in 2004 resulted in conversion rates comparable with previous years. CONCLUSION: We conclude that the change from Tubersol to Aplisol resulted in falsely elevated conversion rates. Our results support the guidelines from the Centers for Disease Control and Prevention recommendations that 1 product should be used consistently in populations undergoing periodic testing.

Adult↗

Impact of season of food frequency questionnaire administration on dietary reporting.

PURPOSE: Foods consumed near the time of food frequency questionnaire (FFQ) administration may prime the memory, such that FFQ responses emphasize recently consumed foods. This study investigates the effect of season of FFQ administration, a proxy for the recent diet, on FFQ responses. METHODS: FFQ data from 74,958 Shanghai Women's Health Study (SWHS) subjects were compared with FFQ data from these subjects by season of FFQ administration (i.e., winter, spring, summer, and fall). All analyses were adjusted for age, BMI, and energy intake. Furthermore, quintile categories derived from all study subjects were compared with categories derived from the distribution of subjects recruited in the same season. RESULTS: Compared with the study group as a whole, subjects completing the FFQ in winter reported higher intakes of meat (2.1%), vegetable (3.9%), fish (3.1%), and soy foods (4.1%), but lower fruit (- 3.9%) intake. Subjects completing the FFQ in summer reported lower than average meat (- 2.0%), vegetable (- 3.2%), fish (- 2.3%), and soy food (- 4.6%) intakes, but greater fruit intake (0.9%). Completion of the FFQ in spring and fall usually led to intermediate differences from the group average, although fruit intake was 5.9% higher among subjects completing the FFQ in the fall. Variations across macronutrients and micronutrients by season of FFQ administration were smaller. If seasonal FFQ reporting is ignored, up to 13% of subjects would be classified to a different diet intake exposure category. However, reclassification was always to an adjacent category. CONCLUSIONS: FFQ responses varied with season of FFQ administration, consistent with theory that current diet intake influences reporting of habitual past diet intake. However, season of FFQ administration did not alter dietary exposure category assignments sufficiently to effect interpretation of most epidemiologic studies.

Adult↗

[Movement disorders in childhood: classification and genetic update].

Abnormal movements are not unusual in childhood. Recent genetic progresses provide a new approach of childhood movement disorders. Several loci have been identified in paroxysmal dyskinesia, or in Gilles de la Tourette syndrome. A gene has been cloned in Hallervorden-Spatz syndrome, and a gene has recently been implicated in benign hereditary chorea. Considerable advances concern the genetic of dystonic syndromes: several chromosomal localizations have been identified, and several genes have been cloned. Genetic advances allow nosographic reclassification of some entities and offer new molecular tools for a more appropriate diagnosis. The increasing wealth of genetic knowledge will provide further insight in the understanding of abnormal movement disorders in childhood.

Child↗

Pineal parenchymal tumours: I. Pineocytoma: a tumour responsive to platinum-based chemotherapy.

Pineocytoma and pineoblastoma are now recognised as a spectrum of the same disease. Three cases of pineocytoma (grade I-II) are presented, in which platinum-based chemotherapy was used with some success, either as part of primary therapy or at the time of relapse. With the recent reclassification of pineal parenchymal tumours into a grade I-IV continuum, the place of chemotherapy, previously only well-established in pineoblastoma, is discussed.

Adult↗

Molecular evidence for species-level distinctions in clouded leopards.

Among the 37 living species of Felidae, the clouded leopard (Neofelis nebulosa) is generally classified as a monotypic genus basal to the Panthera lineage of great cats. This secretive, mid-sized (16-23 kg) carnivore, now severely endangered, is traditionally subdivided into four southeast Asian subspecies (Figure 1A). We used molecular genetic methods to re-evaluate subspecies partitions and to quantify patterns of population genetic variation among 109 clouded leopards of known geographic origin (Figure 1A, Tables S1 ans S2 in the Supplemental Data available online). We found strong phylogeographic monophyly and large genetic distances between N. n. nebulosa (mainland) and N. n. diardi (Borneo; n = 3 individuals) with mtDNA (771 bp), nuclear DNA (3100 bp), and 51 microsatellite loci. Thirty-six fixed mitochondrial and nuclear nucleotide differences and 20 microsatellite loci with nonoverlapping allele-size ranges distinguished N. n. nebulosa from N. n. diardi. Along with fixed subspecies-specific chromosomal differences, this degree of differentiation is equivalent to, or greater than, comparable measures among five recognized Panthera species (lion, tiger, leopard, jaguar, and snow leopard). These distinctions increase the urgency of clouded leopard conservation efforts, and if affirmed by morphological analysis and wider sampling of N. n. diardi in Borneo and Sumatra, would support reclassification of N. n. diardi as a new species (Neofelis diardi).

Animals↗

Characteristics of community-acquired and health care-associated Staphylococcus aureus bacteremia in patients treated at the emergency department of a teaching hospital.

The changing epidemiology of Staphylococcus aureus bacteremia has been noted worldwide. This enhanced awareness appears to be closely associated with the evolution of health care systems. To further delineate this change and to clarify the prevalence of true community-acquired methicillin-resistant S. aureus (MRSA), reclassification for community-onset bacteremia was proposed. Exposure to health care system, such as nursing home residence, regular outpatient invasive interventions, and prior hospitalization within 1 year, was identified among the community-onset S. aureus bacteremia patients. During the 1-year study period, 102 episodes of S. aureus bacteremia from the emergency department patients of a teaching hospital were prospectively enrolled. Nine of the episodes were hospital-acquired, 56 episodes were associated with health care system exposure, and the remaining 37 episodes were classified as true community-acquired bacteremia. The characteristics of patients, primary site of infection, antimicrobial susceptibilities of S. aureus isolates, adequacy of initial antimicrobial therapy, and percentage of metastatic infections differed significantly between health care-associated and true community-acquired S. aureus bacteremias. Prevalence of MRSA infection in true community-acquired bacteremia was low in contrast to bacteremia with health care-associated exposure (2.7% versus 42.9%, P < 0.01). In conclusion, clinical characteristics and risk of contracting methicillin-resistant S. aureus bacteremia among community patients with and without exposure to health care system are distinct. Precise classification of patients is mandatory for the surveillance of antimicrobial resistance and selection of rationale empirical antibiotics.

Adult↗

Routine methods misidentify Serratia spp.: Limitations of MALDI-TOF MS revealed by whole-genome sequencing.

Accurate species-level identification within the genus Serratia remains challenging due to extensive phenotypic overlap and high genomic relatedness among closely related and recently described taxa. This study presents an evaluation of routine and genome-based identification approaches applied to clinical Serratia isolates, integrating phenotypic assays, MALDI-TOF MS (Bruker Daltonics), 16S rRNA gene sequencing, and Whole-Genome Sequencing (WGS). A total of 103 isolates collected from a teaching hospital were analyzed. WGS was performed on a subset of isolates. Conventional biochemical methods classified all isolates as Serratia marcescens, whereas MALDI-TOF MS identified 60.1% as S. marcescens, 11.6% as S. ureilytica, and 28.1% just at the genus level. Peak analysis from MALDI-TOF MS revealed specific peaks associated with S. marcescens and S. ureilytica, but limited discriminatory power. WGS of six isolates initially identified as S. ureilytica by MALDI-TOF MS revealed reclassification as Serratia sarumanii (n = 5) and Serratia montpellierensis (n = 1), supported by Average Nucleotide Identity (ANI), Average Amino Acid Identity (AAI), and Digital DNA-DNA Hybridization (dDDH) thresholds. In contrast, 16S rRNA analysis showed limited species-level resolution. Phylogenomic and SNP-based analyses confirmed these classifications with strong support. Overall, this study underscores the critical role of high-resolution genomic approaches for precise species identification and highlights the need for continuous expansion and curation of MALDI-TOF MS reference databases to support reliable clinical diagnostics and epidemiological surveillance of emerging Serratia species.

Spectrometry, Mass, Matrix-Assisted Laser Desorpti↗

Short-term benefit of smoking cessation in patients with coronary heart disease: estimates based on self-reported smoking data and serum cotinine measurements.

AIMS: To assess the short-term impact of smoking and smoking cessation measured by self-report and by serum cotinine on the risk of secondary cardiovascular disease events (CVD events). METHODS AND RESULTS: Cohort study among participants of an in-patient 3-week rehabilitation programme following an acute coronary syndrome or coronary artery revascularization. Smoking status at baseline was assessed by self-report (beginning of the rehabilitation programme, rehab) and serum cotinine (end of rehab). Active follow-up was conducted one year later. Subsequent CVD events were observed in 139 of the 967 patients. Both self-reported smoking status (odds ratio (OR) compared to continued smokers: recent quitters 0.96, former smokers 0.83, never smokers 0.54, p for trend 0.04) and serum cotinine (OR 0.59 (95% confidence interval (CI) 0.36-0.97) for cotinine-negative compared to cotinine-positive subjects) were associated with the occurrence of a secondary CVD event. After reclassification of all cotinine-positive subjects to continued smokers and cotinine-negative self-reported smokers to recent quitters, this association became even stronger. The OR now reached 0.71 (95% CI interval 0.38-1.33) for recent quitters, 0.64 (0.36-1.11) for former smokers and 0.44 (0.24-0.81) for never smokers (p-value for trend=0.009). CONCLUSION: The benefits of non-smoking and smoking cessation in cardiac patients are beyond controversy and might even be larger than suggested by previous studies which exclusively relied on self-reported smoking status.

Adult↗

Current soft-tissue sarcoma classifications.

In order to analyse the impact of modern sarcoma classification criteria, pathological material from 281 extremity soft-tissue sarcomas (STS) was reviewed. The cases were originally diagnosed between 1972 and 1994, and the most frequent diagnoses then were malignant fibrous histiocytoma (MFH) (26%), liposarcoma (21%), fibrosarcoma (11%), and leiomyosarcoma (10%). After reclassification, the proportions had changed significantly, with the largest group now being leiomyosarcomas (20%), liposarcomas (17%), synovial sarcomas (14%), and sarcomas "not otherwise specified" (NOS) (11%). The original diagnosis was changed in 57% of the cases; in particular, the number of fibrosarcomas was reduced from 32 to 6, and MFHs from 72 to 2, with 22 renamed as myxofibrosarcomas; 20 (7%) were found not to be sarcomas. The main reasons for these results are the recent advances in immunohistochemistry (IHC) together with changes in nomenclature. The findings have obvious implications, in particular for retrospective research.

Fibrosarcoma↗

Small cell lung cancer in Norway. Should more patients have been offered surgical therapy?

OBJECTIVE: The final outcome of patients with small cell lung cancer (SCLC) is poor with an overall 5-year survival rate of less than 10%. Therefore, the question of surgery in patients with a technically-operable solitary tumor has been raised. The purpose of this study was to identify the proportion of patients with operable SCLC and to assess the prognosis of different treatment strategies. For patients who were operated, we compared the resection specimens from patients with more than 5-year survival with those with shorter survival to see whether the specimens belonged to different subclasses of SCLC. METHODS: In Norway all clinical and pathologic departments submit reports on cancer patients to the Cancer Registry. The Registry also has a law-regulated authority to collect supplemental information regarding diagnosis, treatment and outcome for all cancer patients from the hospitals in charge. All reports on patients diagnosed as having SCLC in limited disease or unknown stage during the time interval 1993-1999 were reviewed. Patients with a T2-tumor, in whom a pneumonectomy would have to be performed, were classified as potentially operable. Five-year relative survival was calculated for patients diagnosed in 1993-1997. RESULTS: During the actual period 2442 individuals with SCLC were identified. The majority was treated with conventional chemotherapy or concurrent chemoradiotherapy while 38 underwent surgical therapy. Following reclassification of 697 patients reported to have limited disease or unknown stage 180 were judged to be in stage I. In addition to the 38 resected patients 14 were considered fit for surgery technically and medically while 97 were found to be potentially operable treatment modalities apart from surgery yielded a 5-year survival rate <7%. For stage I (N=96) the rate was 11.3% in conventionally treated patients compared to 44.9% for those who underwent surgical resection. By pathological review of surgical specimens a diagnosis of SCLC was confirmed in all patients treated by surgery in the groups with long and short survival. CONCLUSION: This investigation demonstrates that patients with SCLC having a peripherally located tumor should be referred to surgery, as long time survival is far better than for conventionally treated patients.

Aged↗

Can whole genome analysis refine the taxonomy of the genus Rhodococcus?

The current systematics of the genus Rhodococcus is unclear, partly because many members were originally included before the application of a polyphasic taxonomic approach, central to which is the acquisition of 16S rRNA sequence data. This has resulted in the reclassification and description of many new species. Hence, the literature is replete with new species names that have not been brought together in an organized and easily interpreted form. This taxonomic confusion has been compounded by assigning many xenobiotic degrading isolates with phylogenetic positions but without formal taxonomic descriptions. In order to provide a framework for a taxonomic approach based on multiple genetic loci, a survey was undertaken of the known genome characteristics of members of the genus Rhodococcus including: (i) genetics of cell envelope biosynthesis; (ii) virulence genes; (iii) gene clusters involved in metabolic degradation and industrially relevant pathways; (iv) genetic analysis tools; (v) rapid identification of bacteria including rhodococci with specific gene RFLPs; (vi) genomic organization of rrn operons. Genes encoding virulence factors have been characterized for Rhodococcus equi and Rhodococcus fascians. Based on peptide signature comparisons deduced from gene sequences for cytochrome P-450, mono- and dioxygenases, alkane degradation, nitrile metabolism, proteasomes and desulfurization, phylogenetic relationships can be deduced for Rhodococcus erythropolis, Rhodococcus globerulus, Rhodococcus ruber and a number of undesignated Rhodococcus spp. that may distinguish the genus Rhodococcus into two further genera. The linear genome topologies that exist in some Rhodococcus species may alter a previously proposed model for the analysis of genomic fingerprinting techniques used in bacterial systematics.

Actinobacteria↗

Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.

PURPOSE: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype. METHODS: We collected patients with duplications encompassing ARID1A and ARID1B duplications. RESULTS: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 10.3 Mb (2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay, and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation reanalysis, resulting in the reclassification of 2 ARID1A and 2 ARID1B duplications as pathogenic. CONCLUSION: Our findings reveal that ARID1B duplications manifest a clinical phenotype, and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole-gene duplication rather than haploinsufficiency.

Humans↗

Pathogenicity assessment of genetic variants identified in patients with severe hypertriglyceridemia: Novel cases of familial chylomicronemia syndrome from the Dyslipidemia Registry of the Spanish Atherosclerosis Society.

PURPOSE: Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases. METHODS: 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients. RESULTS: Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in LMF1 remained as VUS. Additionally, 1 variant in LPL and 2 in GPIHBP1 were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations. CONCLUSION: The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.

Humans↗

RNU4ATAC-opathy: Clinical, molecular, and transcriptomic insights from a large cohort.

PURPOSE: We aim to better define the genotype and phenotype spectrum of RNU4ATAC-opathy, demonstrate the utility of RNA sequencing (RNA-seq) for variant classification, and highlight the challenges in detecting variants in this noncoding gene. METHODS: Sixty individuals with molecularly confirmed RNU4ATAC-opathy were recruited from multiple clinical and research centers internationally. RNA-seq was available for 7 affected individuals. RESULTS: We report the clinical and molecular findings of 60 individuals, including 42 not previously described, and 33 distinct RNU4ATAC variants, 13 of which are novel. Core features in this cohort-present in most individuals assessed and varying in severity-include microcephaly, short stature, skeletal anomalies, developmental delay, cerebral anomalies, skin conditions, and immune deficiency. Additional findings, such as diabetes, holoprosencephaly, and the absence of various core features in some individuals, highlight the broad phenotypic spectrum. All individuals who underwent RNA-seq showed a consistent pattern of minor intron retention. In 6 individuals, RNA-seq enabled the reclassification of variants of uncertain significance as likely pathogenic. Although RNU4ATAC variants are generally covered by clinical exomes, they are often overlooked in analysis because of their noncoding nature. CONCLUSION: This study highlights the variability of phenotypes and genotypes associated with RNU4ATAC-opathy. Laboratories should ensure RNU4ATAC and other noncoding genes are appropriately assessed by their analysis pipelines.

Lowry-Wood syndrome↗