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PubMed2026

Whole-exome characterization of host genetic variation in HIV-associated genes across the high-prevalence Mizo population, Northeast India.

BACKGROUND: The Mizoram state of Northeast India has one of the highest HIV prevalence rates in Asia, yet the host genetic factors influencing HIV susceptibility in this Tibeto-Burman population remain uncharacterised. METHODS: We performed whole-exome sequencing using Illumina NovaSeq 6000, mean coverage 100X on 76 HIV-negative Mizo individuals. Variants were called using GATK HaplotypeCaller v4.3 against GRCh38p14, annotated with ANNOVAR, and filtered using hard-quality thresholds (QD ≥ 2, SOR ≤ 3, MQ ≥ 40, DP ≥ 10, GQ ≥ 20). The allele frequencies were compared against gnomAD v2.1.1 population databases. Hardy-Weinberg equilibrium was assessed using the Wigginton exact test with Bonferroni correction. RESULTS: Post-quality filtering resulted in 12,011 sample-variants across 2,821 unique positions from 36 HIV-associated loci (33 protein-coding genes, 2 chemokine ligands, and 3 lncRNA targets). Of these, 784 observations (51 unique positions) were high-impact nonsynonymous or loss-of-function variants. ADAR rs2229857 (p.K384R, NM_015840) was the most frequently observed variant (Mizo carrier frequency = 0.895; 95% CI: 0.806-0.946). CXCR1 rs16858808 (p.R335C) showed the greatest population enrichment (Mizo carrier frequency = 0.197; 95% CI: 0.123-0.300; 7.65-fold carrier-frequency enrichment versus gnomAD South Asian; CADD = 15.60). Sixteen of 20 tested variants deviated from Hardy-Weinberg equilibrium after Bonferroni correction (p < 0.0025), predominantly showing excess homozygosity consistent with the endogamous Mizo population. The protective variant CCR5-Δ32 was absent in all the 76 individuals tested. CONCLUSION: This first whole-exome characterization of HIV host genes in the Mizo population identifies CXCR1 rs16858808 as the most population-enriched functional variant and reveals a pervasive endogamy signature. These findings provide a population-specific genetic framework for future HIV susceptibility studies and ART pharmacogenomics research.

Humans↗

PubMed1988

[Squamous cell carcinoma with a sarcomatoid variant of the vagina].

A case of squamous cell carcinoma with a sarcomatoid variant, usually called a spindle cell carcinoma, located in the vagina of a postmenopausal woman is reported. Although a cytologic examination of a smear of the scraped tumor showed the coexistence of sarcomatous spindle and keratinizing carcinomatous cells, the first bioptic specimen consisted only of sarcomatous tissue. Further histologic, immunohistochemical and ultrastructural examinations succeeded in making a definite diagnosis of a squamous cell carcinoma with a sarcomatoid variant. We would like to emphasize that combined cytologic and histologic examinations led us to make a correct diagnosis after discussing the differential diagnosis.

Aged↗

PubMed1995

[Variant gap phenomenon in A-V conduction].

In 361 consecutive patients 4 with variant gap phenomenon (VGP) underwent intracardiac electrophysiological studies. The premature atrial response initially delayed in His-Purkinje system (HPS) which had a long relative refractory period (RRP), and H-V interval was prolonged. However, as atrial responses were more premature, the atrioventricular node (AVN) showed RRP and slowed down the conduction, that made HPS get rid of RRP before the response arriving. Thus the conduction resumed, and H-V interval became normal. It was different from the classic gap phenomenon. We call it variant gap phenomenon.

Adult↗

PubMed1998

Deep dermatofibrosarcoma protuberans: a subcutaneous variant.

AIMS: Dermatofibrosarcoma protuberans (DFSP) is a distinctive cutaneous spindle cell neoplasm that invariably infiltrates the subcutaneous tissue. Other reports have suggested that exceptional cases of DFSP may be confined to the subcutaneous tissue and lack dermal involvement. We wish to confirm this observation by describing cases of a rare variant of DFSP confined to the subcutaneous tissue, and analyse possible histogenetic implications. METHODS AND RESULTS: Three cases of DFSP located in the subcutaneous tissue are reported. Multiple step sections demonstrated the lack of dermal involvement in two of them, whereas the third case infiltrated the dermis at the junction with the subcutis minimally in one of five blocks. Immunohistochemical studies using a battery of monoclonal antibodies were performed. All the tumours stained strongly for vimentin and CD34. CONCLUSIONS: Because of the lack of dermal involvement in two cases and only minimal dermal involvement in one case, we called this variant deep DFSP. Except for deep setting of the tumour, deep DFSP is indistinguishable from typical DFSP clinically, histologically and immunohistochemically. The existence of deep DFSP provides evidence that specific structures of the skin may be not involved in this tumour's histogenesis.

Adult↗

PubMed1995

Mechanisms of the origin of a G-positive band within the secondary constriction region of human chromosome 9.

We report on a so-called rare variant where a G-positive band was sandwiched within the secondary constriction (qh) region of chromosome 9 and is apparently different from previous cases when characterized by the fluorescence in situ hybridization technique. The major differences included duplication of beta-satellite and satellite III DNA sequences and bands 9q13-->q21.1, without duplication or inversion of the alphoid sequences. Based on the reported cases, at least four types of variations can be accounted for. A variety of mechanisms have been proposed to describe the origin of a G-positive band within the 9qh region, which appears to be similar when studied by routine cytogenetic techniques but differs by molecular methods. It is hypothesized that the clinical consequences depend upon the size of the G-positive band(s) duplicated, and a genetic inactivation mechanism might have some sort of influence during the so-called heterochromatinization process. It appears that heterochromatin, once thought to be composed of junk DNA, may have some role after all in suppression of gene(s) and/or spreading of inactivation, if genes are embedded within the heterochromatic region. Apparently, the mixture of different types of DNA creating patches of genetic debris have become a fundamental hidden treasure, where genetically active chromatin could be inactivated without dire consequences. The variable nature of heterochromatin has resulted in cytogenetic heteromorphisms of a number of human chromosomes. Their characterization by molecular techniques is becoming imperative, because fetal wastage have occurred in many situations where variant chromosomes were wrongly identified as chromosomal abnormalities.

Chromosome Banding↗

PubMed1976

A new genetic variant of galactose-1-phosphate uridyl transferase.

The enzyme galactose-1-phosphate uridyl transferase (E.C.2.7.7.12), which has an important function in the metabolism of galactose, exists in multiple molecular forms. The different phenotypes are genetically determined. They can be distinguished according to their electrophoretic mobility. The enzymatic activity of the different gene products varies within certain limits. A new phenotype of the enzyme has been detected in the red cells of a healthy individual. The electrophoretic migration of this phenotype is slower compared to the wild type and its enzymatic activity is lower, but still sufficient as not to cause galactosemia. An extensive family study revealed that the rare gene is inherited according to mendelian law. Independently the same gene product has been detected in two other, nonrelated individuals out of a total of 1668 samples tested. The gene frequency can therefore be estimated to 0.0009 in the Swiss population. We suggest that the new type be called Berne variant of galactose-1-phosphate uridyl transferase.

Adult↗

PubMed1981

[Albopapuloid epidermolysis bullosa (Pasini's disease)].

The aim for this communication is one case of the dystrophic Epidermolysis bullosa in its variant just called as "albopapuloid". The patient a male of 25 years, suffers from the disease since the age of 2. His mother and one brother show the same disease. The clinical manifestations began as bulloe on the superior and inferior limbs. The bullae heal with atrophic scars and the eruption is constantly relapsing after subsiding. Besides the bullous eruption there are other lesions persistently coming out as whitish elevations which are elongate as to form numerous streaks on the surface of the skin. Such lesions started at the age of 5 and do not come from the bullae but they are quite independent, and constitute the essential characteristic for the albopapuloid clinical variant. Small miliary epidermal cysts are seen over the scars. Dystrophic changes of the nails with absence of many of them and the toes show the lst phalanges partially absorbed. On histological examination the bullae are subepidermal and contain a fibrin-leukocytic exudate. The albopapuloid lesions reveal keratosis, epithelial atrophy, diffuse and condensed fibrosis in the corium and around the hair follicles.

Adult↗

PubMed1981

A congenital abnormality in the arrangement of muscle bundles in a segment of the distal ileum, producing obstruction: a variant of the so-called "giant Meckel's diverticulum".

This 4-year-old male child was diagnosed at birth as having several minor congenital anomalies. X-rays taken during the first year of his life showed a single, massively dilated loop of bowel in the upper abdomen, not appreciated at the time. In 1980 he was admitted to Jackson Memorial Hospital with the diagnosis of small bowel obstruction. An upper gastrointestinal series showed one tremendously dilated loop of distal ileum. At laparotomy, the patient was found to have extreme segmental dilatation of one loop of distal ileum which ended abruptly; there was no evident external cause for obstruction. The resected loop contained in excess of 200 cc of watery brown liquid. The mucosal folds and underlying smooth muscle bundles, in the dilated portion only, were not arranged circumferentially but rather in a distinctive finger-print-like pattern with trifurcations, whorls, and intricate interdigitations which had probably produced contractions of a circus type rather than normal peristaltic waves. We have been able to find only three reports in the literature in which, as was the case here, the so-called "giant Meckel's diverticulum" presented as a single tremendously dilated segment of ileum, sharply demarcated at its distal end. In none of them is there any description of the orientation of muscle bundles. We believe that the abnormal arrangement of smooth muscle in the muscular coat in this specimen, and perhaps in the others, probably represents the underlying cause for the extreme localized dilatation.

Child, Preschool↗

PubMed1993

Methods for epidemiologic analyses of multiple exposures: a review and comparative study of maximum-likelihood, preliminary-testing, and empirical-Bayes regression.

Many epidemiologic investigations are designed to study the effects of multiple exposures. Most of these studies are analysed either by fitting a risk-regression model with all exposures forced in the model, or by using a preliminary-testing algorithm, such as stepwise regression, to produce a smaller model. Research indicates that hierarchical modelling methods can outperform these conventional approaches. I here review these methods and compare two hierarchical methods, empirical-Bayes regression and a variant I call 'semi-Bayes' regression, to full-model maximum likelihood and to model reduction by preliminary testing. I then present a simulation study of logistic-regression analysis of weak exposure effects to illustrate the type of accuracy gains one may expect from hierarchical methods. Finally, I compare the performance of the methods in a problem of predicting neonatal mortality rates. Based on the literature to date, I suggest that hierarchical methods should become part of the standard approaches to multiple-exposure studies.

Bayes Theorem↗

PubMed1985

Transferrin variants in Tuscany (Italy). Evidence for two "new" Tf alleles.

Polyacrylamide gel isoelectric focusing (PAGIF) with carrier ampholytes was used for the determination of Tf phenotypes in a sample of 965 unrelated healthy blood donors from Tuscany (Italy). Thirteen rare variants in a heterozygote state were found (four Tf D, seven Tf B, and two rare Tf C subtypes). Among them two apparently new variants, tentatively called Tf C15 and Tf B4, were identified. The rare Tf B0 mutant was also observed.

Alleles↗

PubMed1986

DNA-flow fluorescence--cytometry of ependymomas. Report on ten surgically removed tumours.

The distribution of DNA is estimated from flow cytometric histograms in surgical specimens of ten ependymomas of different location and varying anaplasia. In three cerebral tumours grade I--II, including one ependymoma of the 4th ventricle, only limited elevation of the 4 C maxima was a prominent feature, corresponding to the microscopical frequency of typical mitoses. Four grade-III ependymomas showed aneuploid or polyploid histograms with stem lines. One frontal tumour was classified as "transitional" because of more numerous mitoses and abnormally elevated S and G2 + M phases, which increased in tissue culture. A correlation between the degree of anaplasia with the DNA pattern was difficult to pursue in two spinal ependymomas obviously lacking microscopical mitoses: Both--one a so-called tanycytic variant of grade I--II, and the other probably a metastasis from a cerebellar tumour--had a clear polyploid DNA histogram with a strikingly increased proliferation index, similar to the more malignant tumours of grade III. Also flow DNA measurements probably allow the decoding of heterogenous mixtures of tumour cells which are not always benign in ependymomas of lower grades of anaplasia microscopically.

Adolescent↗

PubMed1988

Alveolar soft part sarcoma. An immunohistochemical, cytologic and electron-microscopic study and a quantitative DNA analysis.

The type, differentiation and histogenesis of the tumor cells of alveolar soft part sarcoma (ASPS) have been analyzed in a series of ten cases by a light-microscopic, ultrastructural, immunohistochemical and cytologic investigation and quantitative DNA analysis. Four tumors deviated from ordinary ASPS: three were wholly or partly of the so-called pleomorphic variant of ASPS and a fourth tumor showed calcifications of the psammoma body type. The ultrastructural findings and immunohistochemical demonstration of desmin supported the hypothesis of a rhabdomyomatous differentiation and gave no support to epithelial (negative immunoreactions for cytokeratins, epithelial membrane antigen, HMFG-1 and -2, tissue polypeptide antigen (TPA] or neuroectodermal (negative for S-100 protein, glial fibrillary acidic protein, neurofilaments) differentiation. The negative immunoreactions for vimentin and myoglobin and the positive reaction for neuron specific enolase (NSE) do not exclude a rhabdomyomatous differentiation since in rhabdomyosarcomas the undifferentiated rhabdomyoblasts generally contain vimentin and the differentiated tumor cells contain myoglobin and rhabdomyosarcoma has previously been reported as being positive for NSE. The production of external lamina material peripherally in the tumor cell nests and around vessels in the vascular septa was demonstrated both ultrastructurally and by immunohistochemistry using antibodies against collagen IV and laminin. The cytologic appearance in smears obtained by fine-needle aspiration from a case of the pleomorphic variant showed some resemblance to that of a carcinoma. The seven tumors with an ordinary cell appearance were found to show a diploid DNA-distribution at a quantitative analysis performed on paraffin sections, while the three tumors wholly or partly of the pleomorphic type showed an additional tetraploid peak.

Adolescent↗

PubMed1977

Congenital nonspherocytic hemolytic anemia associated with glucosephosphate isomerase deficiency: variant Paderborn.

The deficient red cell enzyme glucosephosphate isomerase (GPI) was characterized in a patient of German origin who had already been described, with congenital nonspherocytic hemolytic anemia, and in his heterozygous parents. The variant enzyme differs from the known GPI variant enzyme differs from the known GPI variants by the electrophoretic mobility, the thermal stability, and the leukocyte activity. No differences are found between normal GPI and the variant regarding the affinity to fructose-6-phosphate, the pH optimum and the thermal optimum. Since the electrophoretic pattern and the properties of the parenteral GPI are identical the propositus seems to be homozygous for an abnormal allele and not double-heterozygous as some other cases with GPI deficiency are. Recently, immunological studies have shown that the variant differs from other similar variants. According to the birthplace of the patient the variant is called "Paderborn".

Anemia, Hemolytic, Congenital Nonspherocytic↗

PubMed1986

Computed tomography in the differential diagnosis of the enlarged retrorectal space.

The value of computed tomography (CT) in the differentiation of an enlarged retrorectal space was analyzed in 132 cases. Classification of barium enema findings into those with simultaneous mucosal alterations and those without any visible lesions of the rectal mucosa seems to be useful. Computed tomography helps in those cases without mucosal changes to differentiate between retrorectal fibrosis, tumorous masses, and inflammatory diseases of the colon. It also demonstrates the lack of pathologic lesions in equivocal cases of pelvic lipomatosis and so-called "normal variants." If simultaneous mucosal involvement on barium enema--especially in rectal carcinoma or recurrent carcinoma of the rectum--is found, CT may show the perirectal extension of tumorous masses and thus help to clarify local operability.

Abscess↗

PubMed1999

Absence of mutations in ATM, the gene responsible for ataxia telangiectasia in patients with cerebellar ataxia.

Ataxia-telangiectasia (AT) is an autosomal recessive multisystem disorder presenting in childhood with progressive cerebellar ataxia, oculocutaneous telangiectasia, immune deficiency, radiosensitivity, and cancer predisposition. The gene for AT, designated ATM (AT, mutated) encodes a protein with a carboxy-terminal phosphoinositide-3 kinase domain which is involved in cell cycle checkpoints and other responses to genotoxic stress. Most of the patients with the classical AT phenotype are homozygous or compound heterozygous for severe mutations causing truncation or destabilization of the ATM protein. Patients with a milder forms of disease, called AT variants, have been found to be either homozygous for milder mutations or compound heterozygotes for null alleles and mild mutations. In order to define the clinical phenotype of patients homozygous (or compound heterozygotes) for other, milder mutations, we decided to search for ATM mutations in patients with either sporadic or familial idiopathic ataxia. Thirty-four patients with idiopathic cerebellar ataxia, aged 3-77 years, were screened for mutations in the ATM coding region. There were 12 familial cases. None of the patients had abnormal immunoglobulin or alpha-fetoprotein levels, and none had mutations in the ATM coding region. In this heterogeneous group of patients with cerebellar ataxia we found no mutations in the ATM gene. We conclude that mutations in the ATM gene are probably not a common cause for cerebellar ataxia other than AT.

Adolescent↗

PubMed1984

5-azacytidine induction of thymidine kinase in a spontaneously enzyme-deficient murine tumor line.

During the course of our studies on murine tumor cell metastases, one of our variant lines (called L61-M) was found to be unable to incorporate [methyl-3H]thymidine into DNA, due to a spontaneous deficiency in thymidine kinase (TK) activity. L61-M cells are unable to proliferate in HAT selection medium and are resistant to bromodeoxyuridine (BrdU). TK activity in L61-M cells is 4.2% of that found in the wild-type parental MDAY-D2 cell line. Treatment of L61-M with 5-azacytidine, a known inducer of DNA hypomethylation, resulted in the expression of TK activity. These observations suggest that the TK deficiency in the L61-M cell line was due in part to an alteration in the methylation pattern of DNA, resulting in the diminished expression of the TK gene. These results demonstrate the ability of 5-azacytidine to induce TK activity in a spontaneously enzyme-deficient murine tumor cell line.

Animals↗

PubMed2026

Protocol for haplotype-resolved structural variant detection via long-read sequencing using cuteHap.

Long-read sequencing technologies have revolutionized human genome exploration at an unparalleled resolution, particularly facilitating the analysis of structural variation (SV) at haplotype resolution. Here, we present a protocol for using cuteHap, a robust framework for haplotype-aware SV detection through phased alignment reads generated by diverse long-read sequencing platforms. We describe procedures for single-nucleotide variant (SNV) calling, read phasing, SV calling, and genotyping. We also establish a benchmarking pipeline to evaluate the detected SV callsets. For complete details on the use and execution of this protocol, please refer to Cao et al.1.

Bioinformatics↗

PubMed1978

The phenotypic variability of diastrophic dysplasia.

To determine the relationship between so-called "diastrophic variant" and diastrophic dysplasia, four patients considered to have the variant condition were studied in detail and compared to 67 patients (including 17 sets of affected sibs) considered to have classical diastrophic dysplasia. Analysis of the combined clinical, radiographic, histologic, and genetic data indicates that there is wide variability in the phenotypic expression of diastrophic dysplasia, even within sibships, and that those individuals previously labeled as having "diastrophic variant" appear to have mild diastrophic dysplasia.

Adult↗