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PubMed2021

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.

IMPORTANCE: Early-onset atrial fibrillation (AF) can be the initial manifestation of a more serious underlying inherited cardiomyopathy or arrhythmia syndrome. OBJECTIVE: To examine the results of genetic testing for early-onset AF. DESIGN, SETTING, AND PARTICIPANTS: This prospective, observational cohort study enrolled participants from an academic medical center who had AF diagnosed before 66 years of age and underwent whole genome sequencing through the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine program. Participants were enrolled from November 23, 1999, to June 2, 2015. Data analysis was performed from October 24, 2020, to March 11, 2021. EXPOSURES: Rare variants identified in a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories. MAIN OUTCOMES AND MEASURES: Sequencing data were analyzed using an automated process followed by manual review by a panel of independent, blinded reviewers. The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders. RESULTS: Among 1293 participants (934 [72.2%] male; median [interquartile range] age at enrollment, 56 [48-61] years; median [interquartile range] age at AF diagnosis, 50 [41-56] years), genetic testing identified 131 participants (10.1%) with a disease-associated variant, 812 (62.8%) with a variant of undetermined significance, 92 (7.1%) as heterozygous carriers for an autosomal recessive disorder, and 258 (20.0%) with no suspicious variant. The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 years (20 of 119 [16.8%; 95% CI, 10.0%-23.6%]) and lowest after the age of 60 years (8 of 112 [7.1%; 95% CI, 2.4%-11.9%]). Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. The most common genes were TTN (n = 38), MYH7 (n = 18), MYH6 (n = 10), LMNA (n = 9), and KCNQ1 (n = 8). CONCLUSIONS AND RELEVANCE: In this cohort study, genetic testing identified a disease-associated variant in 10% of patients with early-onset AF (the percentage was higher if diagnosed before the age of 30 years and lower if diagnosed after the age of 60 years). Most pathogenic/likely pathogenic variants are in genes associated with cardiomyopathy. These results support the use of genetic testing in early-onset AF.

Adult↗
PubMed1996

[Rare variants of cutaneous T-cell lymphomas].

Besides the classical forms of cutaneous T-cell lymphoma (C-CTCL), such as mycosis fungoides and Sézary's syndrome, unique variants may be encountered. The classification of these rare cutaneous T cell lymphomas is problematic and controversial. Newer classifications of lymphoma in general, such as the Revised European-American Lymphoma (REAL) Classification, emphasize well-established clinico-pathological entities. It seems appropriate to attempt to bring greater clarity to the classification of cutaneous T-cell lymphomas using the same principles. In this review, we list and characterize the rare variants of cutaneous T-cell lymphoma, such as (1) clinical, histological and immunological variants of mycosis fungoides; (2) progressive cutaneous T-cell lymphoma (P-CTCL) including transformed classical cutaneous T-cell lymphoma (TC-CTCL) and primary progressive cutaneous T-cell lymphoma (PP-CTCL); (3) angiocentric and angioimmunoblastic cutaneous T-cell lymphomas; (4) large cell anaplastic, CD30+ cutaneous T-cell lymphoma; (5) HTLV-I-associated adult T-cell leukemia/lymphoma (ATLL); (6) cutaneous manifestations of primary extracutaneous T-cell neoplasias; (7) unclassifiable cutaneous T-cell lymphoma.

Antigens, CD↗
PubMed2005

[Plasma cell leukaemia: a rare variant of multiple myeloma. A case report].

Plasma cell leukaemia is a rare variant of multiple myeloma (2-3%), with an aggressive disease with short survival. It is defined as circulating peripheral blood plasma cells exceeding 2.000/ul and 20% of peripheral blood white cells. We present the case of 32-years-old man with left chest-wall pain, hepatomegaly, righ cervical adenopathy, 8800 leukocytes/ul with 33% of lymphocytes and 40% of plasma cell, 10.8 g/dl of proteins and a monoclonal hypergammaglobulinemia. Bone marrow biopsy showed 40-50 % of intramedullary plasma cell. There was a Ig G-kappa paraproteinemia.

Adult↗
PubMed2002

Pigmented spindle cell carcinoid tumour of the thymus with ectopic adrenocorticotropic hormone secretion: report of a rare variant and differential diagnosis of mediastinal spindle cell neoplasms.

AIMS: A variety of histological variants of thymic carcinoid tumour have been described. A rare case of pigmented spindle cell carcinoid tumour of the thymus is documented and compared with the reported cases of thymic pigmented carcinoid tumour in the literature, with a discussion of the differential diagnosis of spindle cell tumours of the mediastinum. METHODS AND RESULTS: A thymic tumour with ectopic adrenocorticotropic hormone (ACTH) secretion was resected from a 24-year-old man suffering from Cushing's syndrome. Histological, immunohistochemical, and ultrastructural studies revealed an ACTH-producing spindle cell carcinoid tumour harbouring pigmented melanocytes. Among four thymic pigmented carcinoid tumours reported before, only one was similar to the present case by being also an ACTH-secreting pigmented spindle cell thymic carcinoid tumour. The clinicopathological features of this tumour distinguish it from a spindle cell thymoma, spindle cell thymic carcinoma, and other mediastinal spindle cell tumours. CONCLUSIONS: This case illustrates an extremely rare variant of thymic carcinoid tumour exhibiting a spindle cell morphology and harbouring pigmented melanocytes. Awareness of this histological variant is important in the differential diagnosis of spindle cell tumours of the mediastinum.

Adrenocorticotropic Hormone↗
PubMed2024

Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project.

INTRODUCTION: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. METHODS: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. RESULTS: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p&#xa0;<&#xa0;5&#xa0;&#xd7;&#xa0;10-8). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p&#xa0;=&#xa0;1.9&#xa0;&#xd7;&#xa0;10-9). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p&#xa0;=&#xa0;7.2&#xa0;&#xd7;&#xa0;10-8). DISCUSSION: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD. HIGHLIGHTS: We determine the association of genetic variants with Alzheimer's disease (AD) using 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data. We identified genetic variants at apolipoprotein E (APOE), BIN1, PSEN1, and LINC00320 associated with AD. We observed rare non-coding variants in the promoter of TOMM40 distinct of APOE.

Humans↗
PubMed1988

[Vascular eccrine giant spiradenoma--a case report with histology and immunohistology of a rare variant of benign sweat gland tumors].

Giant vascular eccrine spiradenoma (GVES) is a rare variant of benign tumors of the sweat glands, which differs from common eccrine spiradenoma in both its size and vascularity. Clinically as well as macroscopically, this intradermal or subcutaneous encapsulated tumor might be mistaken for an angiomatous lesion or thrombosis. Histological examination reveals clearly delimited "cords" showing two types of cells, prominent blood-filled cavities and extensive hemorrhages. According to immunohistochemical findings, the epithelial cells contain cytokeratin, protein S-100 and carcino-embryonal antigen (CEA). Like the endothelial cells of vessels, some of the luminal epithelial cells also bind Ulex europaeus lectin; however, they do not show factor VIII-associated antigen.

Adenoma, Sweat Gland↗
PubMed1993

The distribution and spreading of rare variants in the histone multigene family of Drosophila melanogaster.

We surveyed the distribution of rare variant restriction sites within and among histone gene arrays of Drosophila melanogaster using restriction fragment length polymorphism (RFLP) analysis. Seventy-three naturally occurring arrays were digested with restriction enzymes that had no recognition sites in the published histone sequence. Of the arrays surveyed, 68.5% had at least two nonconsensus restriction sites present as indicated by the presence of a small band or bands on the autoradiographs. These bands were almost always the length of a single repeat in the histone multigene family or a multiple of this length. In arrays with more than one band, intensity of the bands almost always decreased with increasing size. This shows that within these arrays variant restriction sites were predominantly located on adjacent repeats. If these bands are caused by spreading of variant sites, as is most likely, then variants spread along the array as an inverse function of distance. Overall, if a sequence spread it had a 92% probability of ending up in its nearest neighbor. This pattern may result from the noncontiguous nature of the histone family.

Animals↗
PubMed1982

A rare variant of ureteric ectopia: opening in vagina and vesico-uretero-vaginal communication.

A rare variant of ureteric ectopia, i.e. an opening in the vagina and a vesico-uretero-vaginal communication, is herein reported. This type of congenital anomaly, found in 2 females, has not been reported before. One patient had a free, 2-way communication between the bladder and the vagina via the lower segment of the right ectopic ureter. The other was found to have a one-way communication from the vagina to the bladder through the ectopic distal ureter. Surgical intervention was undertaken in both cases. It is suggested that vaginography after distending the bladder with air is important in the detection of this bizarre anomaly.

Adult↗
PubMed1987

Occurrence of a rare variant of superoxide dismutase in Brazil.

During a paternity test performed in Porto Alegre, Brazil, a rare variant of superoxide dismutase, probably SOD A2, was found in a Caucasian child and the putative father. Studies of 1,700 unrelated white individuals from the same and nearby cities had never disclosed such a variant, which was also absent in 2,480 persons of other ethnic groups living in different regions of Brazil. The presence of this rare phenotype in the child and putative father led to the assignment of a very high probability of paternity to the latter.

Brazil↗
PubMed2005

Partial or total anomalous pulmonary venous drainage caused by malposition of septum primum: echocardiographic description of a rare variant of anomalous pulmonary venous drainage.

We describe the echocardiographic findings in 9 patients, a rare variant of partial and total anomalous pulmonary venous drainage directly to the morphologic right atrium, caused by malposition of septum primum. Displacement of septum primum to the morphologic left atrium was present in all 9 cases leading to partial or complete anomalous drainage of pulmonary veins to the morphologic right atrium. However, all pulmonary veins were connecting normally to the morphologic left atrium. The views that best demonstrated the deviation of septum primum were subxiphoid coronal, apical 4-chamber, and parasternal long-axis.

Child, Preschool↗
PubMed2000

Epithelioid blue nevus: a rare variant of blue nevus not always associated with the Carney complex.

Epithelioid blue nevus is a rare variant of blue nevus that has been recently described in patients with Carney complex. Some of the patients with Carney complex have multiple epithelioid blue nevi and a familial history of similar lesions is often recorded. Epithelioid blue nevus consists of an intradermal melanocytic nevus composed of polygonal epithelioid cells laden with melanin. Neoplastic cells show no maturation at the base of the lesion and, in contrast with the usual stromal changes in blue nevi, epithelioid blue nevus exhibits no fibrosis of the dermis. We have studied three cases of epithelioid blue nevus in three patients with no evidence of Carney complex. The lesions were solitary and there was no family history of similar lesions. Therefore, epithelioid blue nevus is a distinctive variant of blue nevus that may also appear as a sporadic lesion and is not always associated with Carney complex.

Adult↗
PubMed2002

The frequency of different plural renal arteries rare variants.

The aim of this work was to evaluate the frequency of different plural renal arteries rare variants in healthy patients and in many different pathological diseases. Abdominal aortography with following selective angiography was performed on 35 randomly selected patients of Medical Department, with the use of radiopaque and with followed radiological parameters: P--75 kV, I--9 mA, T--10 sec. According to the available literature the following classification was introduced: double renal arteries--two vessels originating from the aorta, similar in diameter, blood supply areas, and their branches entering kidney through hilum (observed in 20% of cases), triple renal arteries--three vessels originating from the aorta with different diameter and blood supply areas, and their branches entering kidney through hilum (observed in 3%), upper pole accessory artery--originates from aorta, diameter of which being comparable to segmental arteries, entering kidney through hilum (6%), lower pole accessory artery (40%), upper pole perforating artery--originates from aorta or one of its major branches, diameter of which being comparable to segmental or subsegmental arteries, supplying one segment only, entering kidney outside of hilum (26%), and lower pole perforating artery (3%).

Angiography↗
PubMed1993

Spindle cell (leiomyomatous) rhabdomyosarcoma, a rare variant of embryonal rhabdomyosarcoma.

A rare case of the leiomyomatous variant of embryonal rhabdomyosarcoma is reported. A 13-year-old boy presented with a recurrent painless mass on the ventral side of the right forefoot. Microscopically, the tumor consisted of spindle-shaped and round tumor cells in a fascicular or storiform, focally hemangiopericytoma-like growth pattern. The cytoplasm of the spindle-shaped tumor cells was eosinophilic and fibrillary, in some areas resembling smooth muscle cells. Immunohistologically, all tumor cells were vimentin-positive, most of them also stained with antibodies to desmin and muscle specific actin (MSA). In addition, many tumor cells showed a co-expression of alpha-sarcomeric actin and myoglobin. All tumor cells were negative with alpha-smooth muscle actin. Two years after surgical treatment and chemotherapy the patient is well with no evidence of distant metastases. The clinicopathological features and differential diagnostic problems are discussed.

Adolescent↗
PubMed2004

Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas.

Clear-cut inherited Mendelian traits, such as familial adenomatous polyposis or hereditary nonpolyposis colorectal cancer, account for <4% of colorectal cancers. Another 20% of all colorectal cancers are thought to occur in individuals with a significant inherited multifactorial susceptibility to colorectal cancer that is not obviously familial. Incompletely penetrant, comparatively rare missense variants in the adenomatous polyposis coli gene, which is responsible for familial adenomatous polyposis, have been described in patients with multiple colorectal adenomas. These variants represent a category of variation that has been suggested, quite generally, to account for a substantial fraction of such multifactorial inherited susceptibility. The aim of this study was to explore this rare variant hypothesis for multifactorial inheritance by using multiple colorectal adenomas as the model. Patients with multiple adenomas were screened for germ-line variants in a panel of candidate genes. Germ-line DNA was obtained from 124 patients with between 3 and 100 histologically proven synchronous or metachronous adenomatous polyps. All patients were tested for the adenomatous polyposis coli variants I1307K and E1317Q, and variants were also sought in AXIN1 (axin), CTNNB1 (beta-catenin), and the mismatch repair genes hMLH1 and hMSH2. The control group consisted of 483 random controls. Thirty of 124 (24.9%) patients carried potentially pathogenic germ-line variants as compared with 55 ( approximately 12%) of the controls. This overall difference is highly significant, suggesting that many rare variants collectively contribute to the inherited susceptibility to colorectal adenomas.

Adenoma↗
PubMed2002

A rare variant of single coronary artery and non-obstructive hypertrophic cardiomyopathy.

A single coronary artery (SCA) constitutes a rare congenital anomaly. The reported incidence of SCA ranges from 0.2 1.6% of the population undergoing coronary angiography. The congenital absence of the ostium of the right coronary artery (RCA) with the origin of the RCA as a continuation of the distal circumflex artery is an extremely rare variant of the SCA. Its real incidence is unknown. We report a case of a 38-year-old white female with non-obstructive hypertrophic cardiomyopathy associated with SCA, in which the RCA arises as an extension of the circumflex artery.

Adult↗
PubMed1982

Three new rare variants of alpha 1-antitrypsin.

Three new rare genetic variants of the serum protein alpha 1-antitrypsin (alpha 1-protease inhibitor) have been identified in a Caucasian population. The new alleles in the PI system are PI*EFRA, PT*PCAS, and PI*XALB. When compared with the normal type M by isolectric focusing in polyacrylamide, Efranklin (EFRA) is anodal, and Pcastoria (PCAS) and Xalban (XALB) are cathodal. These variants have been compared with previously described variants by isoelectric focusing and by electrophoresis in agarose and acid starch gels. All three variant alleles appear to be associated with normal amounts of alpha 1-antitrypsin, assayed both by functional and immunological methods.

Adolescent↗
PubMed1976

Estimation of age and rate of increase of rare variants.

The problem considered is that of estimating the age or rate of increase of a variant on the basis of the present number of replicates observed in a population. In place of previous diffusion equation analyses of age probability distributions, the likelihood for the age is studied on the basis of a discrete branching process model. It is shown that variations inherent in the process of gene evolution in natural populations make it impossible to provide a reliable point estimate of the age of a specified variant, although the likelihood analysis provides a confidence interval which may place useful bounds on the period in which a variant originated. The observed distribution of numbers of several variants may also provide useful information. The problems of estimation are discussed with reference to rare variants arising in American Indian populations.

Alleles↗