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PubMed1991

Congenital myopathies.

About forty different congenital myopathies (CM) are defined by clinical and morphological criteria. Classical types like central core disease, centronuclear myopathy, and nemaline/rod myopathy are now well established and recognized as neuromuscular conditions. Clinical subtypes as infantile, juvenile, and adult forms have been recognized in several CM. Not infrequently, different disease-specific morphological features may occur in muscle tissue of the same patient combined. Other CM are marked by aggregates of desmin filaments indicating the importance of recent immunohistochemical techniques. Modern myopathological techniques enabled nosological separation of CM, immunohistochemistry, actually, may usher in a new period of research in and understanding of CM. However, application of molecular genetic and molecular biological methods to CM may clarify still unsolved aspects of gene localisation for which the hereditary nature of many CM is particularly conducive, aspects of heterogeneity versus homogeneity of certain CM or clinical variants, of prenatal diagnosis of CM, of pathogenetic and nosological significance of muscle fiber proteins in CM, and of a new nosological classification of CM.

Child↗

PubMed2026

Emerging genes implicated in human congenital heart disease: a 2023-2025 scoping review.

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly and a leading cause of infant morbidity and mortality. The rapid expansion of genomic technologies has accelerated the discovery of rare genetic variants implicated in CHD pathogenesis. However, most individuals with CHD still lack an identifiable molecular etiology. The purpose of this scoping review is to systematically characterize genes reported in the recent literature as candidate CHD-associated genes and contextualize these findings within the stages of cardiac morphogenesis. METHODS: PubMed was searched using predefined terms related to CHD and genetic variants, supplemented by a prospectively maintained internal database. We included human studies published between January 2023 and December 2025 that identified pathogenic, likely pathogenic, or uncertain monogenic variants in at least one patient with CHD. Animal-only studies, chromosomal abnormalities, copy number variants, multigenic associations, transcriptomic/proteomic analyses, reviews, and maternal-only genetic studies were excluded. Gene-disease validity classifications were assigned using the Clinical Genome Resource (ClinGen) CHD Gene Curation Expert Panel framework. RESULTS: Of 2,834 screened articles, 391 studies met inclusion criteria, identifying 912 unique genes reported as candidate CHD-associated genes. Frequently reported genes included PTPN11, NOTCH1, GATA4, JAG1, MYH6, GATA6, and LZTR1. Identified genes spanned all major stages of cardiogenesis, including developmental priming, cardiac progenitor specification, left-right axis formation, neural crest migration, outflow tract development, septation, and postnatal structural remodeling. Studies increasingly implicated ciliary dysfunction, transcriptional regulation, ribosomal biology, and multigenic inheritance in CHD pathogenesis. Emerging methodologies included stem cell-derived cardiac models, machine learning-based gene prioritization, and epigenetic analyses. CONCLUSIONS: Recent literature substantially expands the catalog of candidate genes that may be associated with CHD and highlights the biologic complexity underlying cardiac morphogenesis. Integration of genomic, developmental, and functional approaches will be essential to improve mechanistic understanding, refine genetic counseling, and support future precision medicine strategies for CHD.

Cardiac development↗

PubMed2001

Transmissible spongiform encephalopathies in Australia.

The Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) commenced surveillance in September 1993 as part of the Commonwealth's response to 4 cases of pituitary hormone (gonadotrophin)-associated Creutzfeldt-Jakob disease (CJD). With the passage of time, the Registry has become responsible for ascertaining all human transmissible spongiform encephalopathies (TSE; also known as prion diseases) within Australia since 1970. Included in the spectrum of diseases monitored are classical (sporadic, genetic, and health care acquired) CJD, and variant CJD (vCJD), first reported in 1996 in the United Kingdom. Variant CJD has not yet been diagnosed in Australia. Final classification of persons with suspected human prion disease is based upon all available clinical, investigational and pathological information. Ascertainment methods are diverse and include prompted, half-yearly personal communications from neurologists and neuropathologists, death certificate searches, and morbidity separation coding searches of major hospital, and State and Territory databases. More recently, referral for diagnostic CSF 14-3-3 protein testing (performed by the ANCJDR) has considerably increased prospective notifications of suspect cases. As at September 2001 there were 460 cases on the register; 237 definite cases, 168 probable and 55 incomplete cases awaiting final classification.

Animals↗

PubMed2000

Atypical hairy cell leukemia.

The morphologic differential diagnosis of mature B-cell neoplasms with cytoplasmic projections includes splenic lymphoma with villous lymphocytes and hairy cell leukemia. Although the classification of hairy cell leukemia is not universally recognized, 3 variants have been described, namely, classic, variant, and Japanese variant, each of which has different clinical and immunophenotypic features. Classic hairy cell leukemia is virtually always CD11c(+), CD25(+), and CD103(+). Variant and Japanese variant hairy cell leukemias are usually CD11c(+), always CD25(-), and occasionally CD103(+). Each variant is characteristically CD10(-). We present a case of hairy cell leukemia with a unique immunoprofile in that the cells were CD10(+), CD25(+), and CD103(-), and we review the criteria helpful in differentiating "hairy" B-cell neoplasms. This case emphasizes the variability of hairy cell leukemia and the need to correlate all clinical and pathologic data in reaching a diagnosis.

Aged↗

PubMed2000

Intracranial pressure processing with artificial neural networks: classification of signal properties.

Intracranial pressure (ICP) is commonly used by neurosurgeons as a source of valuable information about the current condition of the neurosurgical patient. Nevertheless, despite years of effort, extracting clinically valuable information from the ICP signal is still problematical. Approaches, using current values of ICP, may fail to disclose imminent risk, because unpredictable factors can rapidly change the properties of the signal. An alternative approach is to determine some global characteristics of the signal within a longer time interval and such statistical analyses have been proposed by several authors. A further, rarely considered, problem is assessment of the results obtained from the point of view of their practical utility and/or such classification of the obtained properties of the signal that they correspond to certain clinical states of the patient. While this might be a typical task for discriminant analysis, we approached the analysis using an alternative methodology, that of computational intelligence, implemented in artificial neural networks (ANN). We tested two variants of the ANN algorithms for classification and discrimination of global properties of the ICP signal. In a "dynamic pattern classification" the network was presented with several sections of ICP records together with information from the expert-neurosurgeon, classifying 4 risk groups. In this mode no data pre-processing was carried out, in contrast to our second approach, in which the signal had been pre-processed using published statistical analyses and only these intermediate coefficients were fed into the ANN classifier. The results obtained with both classification methods at their current stage of training were similar and approximated to a 70% rate of judgements consistent with the expert scoring. Nevertheless, the method based on the assessment of global parameters from the ICP record looks more promising, because it leaves the possibility for modification of the set of parameters analysed. The new parameters may include information extracted not only from the ICP signal, but also from other diagnostic modalities, like colour coded Doppler ultrasonography. The ultimate goal of this work is to build up a pseudo-intelligent computer expert system, which would be able to reason from a reduced set of input information, available from a standard monitoring modality, because it had been taught salient links between these data and higher-order data, upon which expert scoring was based.

Cerebral Hemorrhage↗

PubMed2003

The skeletal muscle channelopathies: distinct entities and overlapping syndromes.

PURPOSE OF REVIEW: This review outlines recent advances in clinical, genetic and molecular aspects of skeletal muscle channelopathies. RECENT FINDINGS: A new molecular genetic classification of skeletal muscle channelopathies has now emerged. This genetic classification complements previous clinical classifications. It is evident that there is considerable phenotypic diversity associated with dysfunction of a given muscle ion channel. Treatment response is likely to be related to genotype. DNA-based diagnosis is now achievable in most patients. SUMMARY: Ion channel dysfunction is now known to be the basis for familial variants of common neurological diseases such as migraine and epilepsy. Such discoveries were made possible through earlier work on the skeletal muscle channelopathies which remain the best understood example of all channelopathies. Classification of muscle channelopathies initially relied upon their specific clinical and neurophysiological features. This classification remains useful, but recent advances have led to a new system of classification based on the underlying molecular genetic defect. Recent advances have highlighted the broad phenotypic spectrum of muscle channelopathies and remarkable genetic heterogeneity is now recognized. DNA-based diagnosis is now available and should be achieved in all patients. Accurate genetic diagnosis is of major importance for accurate prognosis, for genetic counselling and has implications for therapeutics.

Animals↗

PubMed1982

Immunodeficiency and syndromes: a nosographic approach.

Immunodeficiency disorders can be classified on clinical grounds into two broad groups according to whether all features are the result of the immune defect (immunodeficiency syndromes) or whether many, even prominent, features cannot be explained by the immune defect (syndromes with immunodeficiency). X-linked agammaglobulinemia and X-linked chronic granulomatous disease are paradigmatic examples of immunodeficiency syndromes. Despite some overlap (for instance extra-immune symptoms, although minor, are present in several variants of severe combined immunodeficiency and chronic granulomatous disease) immunodeficiency syndromes and syndromes with immunodeficiency are easily distinguishable. Together with the pathogenetic classification of the WHO, the present approach to a clinical classification amplifies the operational concept of immunodeficiency also from a therapeutic point of view.

Acrodermatitis↗

PubMed2001

Charcot-Marie-Tooth disease (CMT): distinctive phenotypic and genotypic features in CMT type 2.

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), includes two main subtypes of CMT1/HMSN I (demyelinating), and CMT2/HMSN II (axonal). Further heterogeneity has been demonstrated by genetic molecular studies, with at least four responsible genes for CMT1. As for CMT2, a mutation in the neurofilament-light (NF-L) gene has been identified in a single family, and other CMT2 loci have been mapped. We propose a clinical classification of the CMT2 phenotypes, and review the features of the identified CMT2 genotypes. The following main subtypes of CMT2 are considered in the phenotype classification: classical CMT2, the variants of CMT2 showing atypical features that may represent either variance in the classical CMT2 phenotype or separate entities; CMT2 plus, i.e. complex forms with involvement of additional neural structures. The recognized CMT2 genotypes include: CMT2A (mapped to chromosome 1p35-36); CMT2B (3q13-22); CMT2C (with vocal cord paresis); CMT2D (7p14); CMT2E, related to a mutation in the NF-L gene on chromosome 8p21; proximal CMT2, or HMSN P (3q13.1); CMT2 with MPZ mutations; autosomal recessive CMT2 (1q21.2-q21.3); agenesis of the corpus callosum with sensorimotor neuronopathy (15q13-q15); CMT2 X-linked with deafness and mental retardation (Xq24-q26). The identified genotypes may correspond to previously described clinical subtypes of CMT2. In particular, classical CMT2 presents in association with NF-L gene mutation, in the only CMT2 family with known gene mutation, and in CMT2A patients. However, the features of classical CMT2 have been paradoxically reported also in families with MPZ mutation, and conversely several CMT2 families are not linked to the known CMT2 loci. Further cloning of the CMT2 genes will ultimately shed light on the pathogenic mechanism(s) implicated in the process of axonal degeneration, shared by the different CMT2 genotypes.

Charcot-Marie-Tooth Disease↗

PubMed2026

Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.

Gene-based therapies are being developed for retinal diseases, including RS1-related X-linked retinoschisis. Therefore it is essential to determine which variants are pathogenic and which are benign when enrolling patients. The Clinical Genome Resource (ClinGen) X-Linked Inherited Retinal Diseases (XLRD) Variant Curation Expert Panel (VCEP) brings together clinician scientists, molecular biologists, and geneticists to apply their expertise and review the clinical, genetic, population, and functional evidence for variants. American College of Medical Genetics (ACMG) guidelines have been modified for RS1 to develop a highly systematic and conservative framework for evaluating variants. The curation process involves applying 28 different codes, each with 4 strength levels (very strong, strong, moderate, supporting) across different domains of phenotype, population data, computational assessment, functional impact, and segregation. With RS1-specific rules, a total of 54 pilot variants were tested. These included 47 variants in ClinVar. Of these 21 variants were re-classified: 2 likely pathogenic variants and one likely benign were changed to variants of uncertain significance and 4 previously unclassified variants were changed to pathogenic, likely pathogenic and likely benign. Other changes resolved conflicts or multiple classifications.

Humans↗

PubMed2006

[Cutaneous lupus erythematosus. Part 1: clinical manifestations and classification].

Cutaneous lupus erythematosus (CLE) is a heterogenous disorder with a wide range of skin manifestations. Therefore, it has been difficult to develop a unifying concept for classifying CLE from the dermatologic perspective in the past. In 2004, the classification system was updated and includes now acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE), and intermittent CLE (ICLE). Additional rarely described variants are not listed as separate entities but are included in the classical forms. Diagnosis of the different subtypes of CLE is made by considering genetic, clinical, histopathologic, and immunoserologic findings, with a systematic analysis of individual criteria. In the past years, the etiology and pathogenesis of CLE has been subject of intensive research and it has been shown by several groups that exogenous factors, such as ultraviolet light and drugs, can induce CLE. The first part of this review will enable the reader to identify the various clinical manifestations of CLE and to employ characteristic criteria to assess differential diagnostic considerations.

Biopsy↗

PubMed1995

New variant of type II von Willebrand's disease with structural abnormality of plasma von Willebrand factor in a patient with very mild bleeding history.

A new variant of von Willebrand's disease has been discovered in 2 members of a Macedonian family of 6. The proband, an 8-year-old boy, showed a prolonged bleeding episode on 1 occasion. Ristocetin-induced platelet aggregation and bleeding time were normal. In plasma, ristocetin cofactor activity (RCo) and von Willebrand factor (vWf) antigen were reduced to the same clearly low level. The determination of vWf antigen of platelets resulted in borderline values, while RCo was clearly reduced. Low- and intermediate-resolution agarose gel electrophoresis showed absence of the largest multimers in plasma vWf, and slight reduction in platelet vWf. High-resolution gels revealed abnormal multimeric structure only in plasma vWf. The smaller multimers could be resolved in a broad central band flanked by 4 fainter satellite bands; however, satellite bands close to the central band were more intense, and more distant ones were fainter, compared to normal plasma. The central band of the fastest-moving multimer was markedly intensified, and the mobility of the whole quintuplet was slightly reduced. Heredity seems to be autosomal-dominant. No mutation was found in exon 28 of the vWf gene. Because there was only 1 mild bleeding episode in the family, this structural variation seems to have only little clinical consequence. We conclude that this vWf abnormality is different from those observed in other type II variants previously described. Based on the revised classification by the International Society on Thrombosis and Haemostasis, we proposed designation type 2A-Bern for this new subtype.

Base Sequence↗

PubMed1997

The gene for the ataxia-telangiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21.

Nijmegen breakage syndrome (NBS; Seemanová II syndrome) and Berlin breakage syndrome (BBS), also known as ataxia-telangiectasia variants, are two clinically indistinguishable autosomal recessive familial cancer syndromes that share with ataxia-telangiectasia similar cellular, immunological, and chromosomal but not clinical findings. Classification in NBS and BBS was based on complementation of their hypersensitivity to ionizing radiation in cell-fusion experiments. Recent investigations have questioned the former classification into two different disease entities, suggesting that NBS/BBS is caused by mutations in a single radiosensitivity gene. We now have performed a whole-genome screen in 14 NBS/BBS families and have localized the gene for NBS/BBS to a 1-cM interval on chromosome 8q21, between markers D8S271 and D8S270, with a peak LOD score of 6.86 at D8S1811. This marker also shows strong allelic association to both Slavic NBS and German BBS patients, suggesting the existence of one major mutation of Slavic origin. Since the same allele is seen in both former complementation groups, genetic homogeneity of NBS/BBS can be considered as proved.

Alleles↗

PubMed1998

Hereditary dysphasic disinhibition dementia: a frontotemporal dementia linked to 17q21-22.

OBJECTIVE: The clinical and pathologic features of hereditary dysphasic disinhibition dementia (HDDD) are described to determine whether it is a variant of known dementias. BACKGROUND: Several dementing disorders have clinical and pathologic similarities with AD, Pick's disease, and the "nonspecific" dementias. A detailed description of clinical and pathologic presentation will aid classification, but ultimately the discovery of causative gene(s) will define these disorders. METHODS: The authors performed a clinical assessment: gross and microscopic pathologic evaluation of brain tissue, genetic linkage studies, and sequence analyses. RESULTS: HDDD is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease. Salient clinical features are global dementia with disproportionate dysphasia and "frontotemporal" symptoms. A linkage between HDDD and 17q21-22 was shown, with a maximum lod score of 3.68 at zero recombination. CONCLUSIONS: Several dementias have been linked to the same region and have been termed frontotemporal dementia with parkinsonism linked to chromosome 17. These disorders may represent phenotypic variants arising from mutations within a common gene.

Adult↗

PubMed2004

Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entity.

The majority of thyroid tumors are classified as papillary (papillary thyroid carcinomas; PTCs) or follicular neoplasms (follicular thyroid adenomas and carcinomas; FTA/FTC) based on nuclear features and the cellular growth pattern. However, classification of the follicular variant of papillary thyroid carcinoma (FVPTC) remains an issue of debate. These tumors contain a predominantly follicular growth pattern but display nuclear features and overall clinical behavior consistent with PTC. In this study, we used comparative genomic hybridization (CGH) to compare the global chromosomal aberrations in FVPTC to the PTC of classical variant (classical PTC) and FTA/FTC. In addition, we assessed the presence of peroxisome proliferator-activated receptor-gamma (PPARG) alteration, a genetic event specific to FTA/FTC, using Southern blot and immunohistochemistry analyses. In sharp contrast to the findings in classical PTC (4% of cases), CGH analysis demonstrated that both FVPTC (59% of cases) and FTA/FTC (36% of cases) were commonly characterized by aneuploidy (P = 0.0002). Moreover, the pattern of chromosomal aberrations (gains at chromosome arms 2q, 4q, 5q, 6q, 8q, and 13q and deletions at 1p, 9q, 16q, 17q, 19q, and 22q) in the follicular variant of PTC closely resembled that of FTA/FTC. Aberrations in PPARG were uniquely detected in FVPTC and FTA/FTC. Our findings suggest a stronger relationship between the FVPTC and FTA/FTC than previously appreciated and support further consideration of the current classification of thyroid neoplasms.

Adult↗

PubMed2026

Development and evaluation of an ARTIC-based amplicon sequencing assay for whole-genome characterization of respiratory syncytial virus.

Respiratory syncytial virus (RSV), a ~15.2 kb negative-sense RNA virus, causes acute respiratory infections in infants and older adults. Its two subtypes, RSV-A and RSV-B, evolve rapidly, making ongoing monitoring of circulating strains essential. The Georgia Public Health Laboratory (GPHL) developed and evaluated an amplicon-based whole-genome sequencing (WGS) assay for RSV surveillance. A total of 214 de-identified remnant clinical specimens (102 RSV-A and 112 RSV-B) with RT-PCR Cq values <31 were included. RSV genomes were amplified using ARTIC-style and custom primer sets, with the ARTIC set showing superior performance. Libraries were prepared using a modified Illumina COVIDSeq protocol, sequenced on NextSeq 1000/2000 instruments, and analyzed using the GPHL-RSV-PIPE bioinformatics pipeline. Among genomes meeting validation criteria, sequencing depth was slightly higher for RSV-A (median 53,433×; mean 51,076×) than RSV-B (median 49,699×; mean 46,945×), whereas genomic coverage was slightly lower for RSV-A (median 97.5%; mean 96.6%) than RSV-B (median 98.3%; mean 97.6%). Predominant lineages were A.D.3.1 and A.D.5.2 for RSV-A and B.D.E.1 for RSV-B. For RSV-A, the assay showed 92.8% accuracy, 96.2% sensitivity, 87.2% specificity, 92.6% positive predictive value, and 93.2% negative predictive value. Intra- and inter-run precision assessed using 16 and 53-57 genomes, respectively, showed nearly 100% consensus genome identity with 0-5 nucleotide differences. Specificity testing of 31 non-RSV specimens produced no false-positive detections. Limits of detection were 4.4 TCID50/mL for RSV-A and 18.6 TCID50/mL for RSV-B. These results demonstrate that the ARTIC-based RSV WGS assay enables near real-time surveillance and strengthens data-driven public health responses to future outbreaks.IMPORTANCERSV, with two major subtypes, RSV-A and RSV-B, causes acute respiratory infections that can be severe in infants under 6 months and older adults. Current RSV surveillance at the GPHL relies on the Thermo Fisher TaqMan Gene Expression Capillary assay, which detects and subtypes RSV but lacks resolution for lineage classification and identification of emerging variants. To address this critical gap, GPHL developed and evaluated an amplicon-based WGS assay using 214 de-identified RSV clinical specimens. Genomes were amplified using ARTIC-style and custom-primer sets, with ARTIC primers showing superior performance. The assay demonstrated strong sequencing depth, genomic coverage, specificity, repeatability, reproducibility, and low limits of detection. RSV lineages were accurately determined based on genetic variation. These results establish that the ARTIC-based WGS assay enables near real-time genomic surveillance, supporting monitoring of circulating RSV strains and informing data-driven public health responses.

bioinformatics pipeline↗

PubMed1991

Clinical symptoms and DNA repair characteristics of xeroderma pigmentosum patients from Germany.

Sixty-one xeroderma pigmentosum (XP) patients living in the Federal Republic of Germany were investigated. Clinical symptoms were correlated with DNA repair parameters measured in fibroblasts grown from skin biopsies. Classification according to the international complementation groups revealed that of the 61 patients 3 belonged to group A, 26 to group C, 16 to group D, 3 to group E, and 2 to group F; 11 were of the XP variant type. A striking clinical aspect was the frequency of histogenetically different skin tumors varying from one XP complementation group to the other: squamous and basal cell carcinomas predominated in XP group C; lentigo maligna melanomas were most frequent in group D; basal cell carcinomas occurred preferentially in group E and XP variants. Three DNA repair parameters were determined for 46 fibroblast strains: colony-forming ability (D0); DNA repair synthesis (G0); and DNA-incising capacity (E0). Dose-response experiments with up to 13 dose levels were performed throughout to achieve sufficient experimental accuracy. DNA-damaging treatments included UV light, the "UV-like" carcinogen N-acetoxy-2-acetylaminofluorene, and the alkylating carcinogens methyl methanesulfonate and N-methyl-N-nitrosourea. Comparison of clinical signs and repair data was made on the basis of D0, G0, and E0 values of both individual cell strains and weighted means of XP complementation groups. Despite considerable clinical and biochemical heterogeneity within complementation groups distinctive features emerged. In general, D0, G0, and E0 values of all XP strains investigated, including XP variants, were found to be reduced upon treatment with UV light or N-acetoxy-2-acetylaminofluorene. After treatment with UV light or N-acetoxy-2-acetylaminofluorene, cell strains in which DNA-incising capacity was reduced also showed a similar reduction in both colony-forming ability and DNA repair synthesis. Consequently, the weighted mean D0, G0, and E0 values of XP complementation groups and XP variants correlated with each other. Furthermore, the onset of both early dermatological symptoms of XP and tumor growth correlated with the extent of DNA repair defects. Of 45 XP fibroblast strains checked for colony-forming ability after treatment with methyl methanesulfonate only 3 cell strains from group D were found to be more sensitive than normal controls, suggesting that overall repair in XP strains was equal to that in controls. Weighted means of DNA repair synthesis of XP complementation groups, however, showed reductions hinting at impaired excision of distinct alkylated bases.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetoxyacetylaminofluorene↗

PubMed2025

Clinical and genetic variant re-analysis among pediatric probands undergoing genetic testing for arrhythmia syndromes.

BACKGROUND: Despite increases in genetic testing, longitudinal data regarding changes in diagnostic yield and variant reclassification for inherited arrhythmia syndromes are limited. OBJECTIVE: Determine longitudinal changes in diagnostic yield and variant classification. METHODS: Single-center retrospective study of probands <18 years undergoing genetic testing for suspected inherited cardiac conditions associated with arrhythmias, 2007 to 2018. Variants were classified as diagnostic (pathogenic/likely pathogenic), non-diagnostic (benign/likely benign [B/LB]), or variants of uncertain significance (VUS). Variant reclassification was performed in October 2023 using VarSome and American College of Medical Genetics criteria. We evaluated results by era (early 2007-2013 vs. later 2014-2018, coinciding with Sanger and next-generation sequencing, respectively) and by likelihood of disease based on clinical evaluation. RESULTS: Of 306 probands, initial testing was 23.2% diagnostic, 55.6% non-diagnostic (33.7% no variant, 21.9% B/LB), and 21.2% VUS. When comparing eras, diagnostic yield decreased (34.1%-15.3%), VUS increased (9.3%-29.9%), and non-diagnostic remained similar (55% to 57%). Variants for 22.7% (46/203) of probands with ≥1 variant changed: 9.9% of diagnostic variants (7/71) downgraded to VUS or non-diagnostic, and 60.0% of VUS changed (23.1% upgraded, 36.9% downgraded). B/LB variants did not change. Probands with higher disease likelihood had 6-times the odds of diagnostic results compared to lower disease likelihood, regardless of era (odds ratio 6.3, 95% confidence interval 3.2-12.4, P < .0001). CONCLUSION: Variant reclassification led to changes in 23% of probands, both downgrading and upgrading status, even among probands initially thought to be pathogenic. When comparing later to earlier eras, VUS variants increased while diagnostic yield decreased. Findings support the need for variant re-interpretation and periodic reclassification over time.

Humans↗

PubMed1989

Genetic and phenotypic heterogeneity in disorders of peroxisome biogenesis--a complementation study involving cell lines from 19 patients.

Disorders of peroxisomal biogenesis include the Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum syndrome, and hyperpipecolic acidemia. These names were assigned before the recognition of the peroxisomal defect and the distinction between phenotypes is uncertain. Recent studies have identified at least four complementation groups, and indicate the presence of at least that number of distinct genotypes. The purpose of the present study was to examine the relationship between genotype and phenotype. We studied cultured skin fibroblasts from 19 patients in whom deficiency of peroxisomes had been established. Complementation analysis was performed with the criterion of complementation being the restoration of the capacity to synthesize plasmalogens when fibroblasts from two patients were fused. Six complementation groups were identified, and consisted of one 13 member group, one two member group, and four groups comprising single cases. The phenotype of each group was examined with respect to age of survival, clinical manifestations, and biochemical alterations. The 13 member group included patients with all of the four currently designated phenotypic entities, while the most common phenotype (Zellweger syndrome) was distributed among five of the six groups. We conclude that the currently used clinical categories do not represent distinct genotypes. Apparently different genes code for a similar phenotype and one defective gene may lead to variant phenotypes. Definitive classification and understanding of these disorders await definition of the specific biochemical defect in each of the genotypes.

Adrenoleukodystrophy↗