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PubMed1987

Familial risks of congenital heart defect assessed in a population-based epidemiologic study.

Congenital heart defects (CHD) represent a heterogeneous group of disorders caused by chromosome abnormalities, mendelian disorders, teratogenic exposures, and unknown etiologic mechanisms. A large group of various isolated defects is presumably multifactorial in origin. Previous studies of familial risks for specific anatomic defects obtained from clinical series may include significant biases and obscured pathogenic relationships. In this population-based study we analyzed all cases of CHD in infants and a control birth cohort in the Baltimore-Washington area. The rates of CHD were defined for first-degree relatives of cases with isolated defects, grouped by a pathogenic classification scheme. Precurrence risks were found to vary among the groups, and risks for flow lesions were higher than previously reported. The sibling precurrence risk for hypoplastic left heart syndrome (13.5%) was not significantly different from that expected for an autosomal recessive mechanism; the risks for different types of ventricular septal defects (VSD) varied among mechanistic groups. The results indicate that the additive multifactorial model does not adequately account for the risks in all forms of isolated CHD of unknown etiology.

District of Columbia↗
PubMed2023

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

Male↗
PubMed2026

Dual Aberrant Splicing Caused by an Apparently Missense CHD7 Variant, c.5273A>G (p.Asp1758Gly), in CHARGE Syndrome.

CHARGE syndrome is a rare congenital disorder primarily attributed to heterozygous pathogenic variants of the CHD7 gene. Most pathogenic CHD7 variants are loss-of-function (LoF) variants, whereas the interpretation of missense variants remains challenging in the absence of functional evidence for their pathogenicity. We report a female infant presenting with clinical features characteristic of CHARGE syndrome. Targeted sequencing identified a heterozygous CHD7 variant (NM_017780.4:c.5273A>G), initially annotated as a missense substitution p.Asp1758Gly. This variant has been previously reported and registered with conflicting pathogenicity classifications; however, its transcript-level consequences remain unclear. Long-PCR-based RNA sequencing of total RNA from peripheral blood mononuclear cells revealed two aberrant splicing patterns associated with the variant: a predominant transcript carrying a 28-bp deletion due to cryptic donor splice-site activation, and a minor transcript with partial intron 24 retention. Both transcripts were predicted to result in premature termination codons. These findings demonstrate that c.5273A>G functions as a LoF variant through dual aberrant splicing rather than a simple missense substitution. This case underscores the importance of RNA-level splicing analysis for the accurate interpretation and classification of CHD7 missense variants.

CHD7↗
PubMed1987

Vaginal intraepithelial neoplasia. Report of 14 cases.

From 1978 to 1985 we have found 14 cases of vaginal intraepithelial neoplasia (VAIN) in patients previously hysterectomized. VAIN was detected by an abnormal cytology; diagnostic process included a second cytology, colposcopy, Schiller test, and directed biopsies. VAIN was classified as grade I in 5 patients (35.7%); grade II in 5 patients (35.7%); and grade III in 4 patients (28.6%). Pathogenic classification of VAIN was: VAIN de novo 9 cases (64.3%); VAIN after vaginal irradiation, 3 cases (21.4%); VAIN following incomplete removal of a cervical intraepithelial neoplasia, one case (7.1%); and VAIN as manifestation of a multicentric neoplasia of the lower genital tract, one case (7.1%). The mean time between hysterectomy and VAIN diagnosis was 6.9 years; this time was larger for those women hysterectomized by benign uterine diseases (9.0 years vs. 2.4 years). Our conclusion is that patients who have lost their uterus by malignant or benign diseases should be followed-up with periodic vaginal cytology in order to detect vaginal neoplasia in its pre-invasive stages.

Adult↗
PubMed2024

Estimation of carrier frequencies of autosomal and X-linked recessive genetic conditions based on gnomAD v4.0 data in different ancestries.

PURPOSE: Monogenic rare diseases contribute significantly to infant deaths and pediatric hospitalizations and cause burden to the patients and their families. The American College of Medical Genetics and Genomics recommended in 2021 that carrier screening of autosomal recessive and X-linked conditions with a carrier frequency of ≥1/200 and a severe or moderate phenotype should be offered when planning or during pregnancy. In November 2023 gnomAD v4.0 was released. It contains in total 807,162 individuals, being nearly 5× larger than previous versions, which have been used to estimate gene carrier frequencies (GCF). METHODS: We utilized gnomAD v4.0 (GRCh38) to calculate the GCFs for available genetic ancestry groups for variants having pathogenic or likely pathogenic classification (>80% of submissions) in ClinVar. We calculated GCF separately for exomes and genomes, combined data, and at-risk couple frequencies (ACF) per genetic ancestry group. RESULTS: In total, 324 genes had a GCF ≥1/200 in at least 1 ancestry subgroup. The number of genes with GCF ≥1/200 varied greatly between subgroups. ACFs were more similar, Ashkenazi Jewish having the highest ACF of 6.11%. CONCLUSION: Improved understanding of carrier risks and updated carrier screening content would allow patients to make more informed reproductive decisions.

Humans↗
PubMed1985

Proliferation and hyperplasia of vascular endothelium in human skin.

In a number of diseases of the skin, proliferation of endothelial cells is altered. Replication of endothelial cells has been evaluated by incorporating tritiated thymidine, and compared in inflammatory and neoplastic disorders. An attempt at pathogenic classification is proposed.

Biopsy↗
PubMed1988

Modern biotechnology: a review of current regulatory status and identification of research and regulatory needs.

Modern biotechnology encompasses many technologies. The one that has generated the most public interest is that of genetic engineering. The field has advanced dramatically since the early 1970's, when concern was so high that a moratorium was declared on research using recombinant DNA. Today there are numerous products such as human growth hormone, interferon and monoclonal antibody diagnostic kits on the market. Despite the obvious benefits of these products, there are still concerns over the environmental application of genetically engineered organisms. Many countries have assessed their existing legislation to ascertain its adequacy to regulate such intended releases. Numerous international organizations are becoming involved as well, and optimistically, regulations that are being developed in various countries may be harmonized. These activities have identified several areas where more information is required, including microbial taxonomy and classification, pathogenicity in target and non-target species, environmental behavior and risk assessment processes. Consensus at this time appears to be that our predictive capabilities are still developing and that new organisms should be evaluated on a case-by-case basis.

Biotechnology↗
PubMed2025

Unraveling a novel FBN1 variant in Marfan syndrome with dilated aortic root manifestation.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, with variable incidence rates. A significant portion of cases stems from novel genetic variants, while others inherit it from affected parents. OBJECTIVE: This study focuses on identifying the genetic cause of MFS in a specific family, using whole-exome sequencing (WES). METHODS: A 15-year-old male with confirmed MFS was examined, showing symptoms of palpitations and severe mitral valve regurgitation. WES was performed, followed by confirmation with Sanger sequencing. Variants were assessed for pathogenicity using bioinformatics tools and the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: One potentially novel pathogenic variant was found in exon 14 of the FBN1 gene: c.1676delCinsAAT, p.Ala559GlufsTer21. In silico analysis suggested a deleterious impact on protein structure and function, supporting their pathogenic classification. CONCLUSION: The identification of this novel variant highlights the importance of the FBN1 gene in MFS, especially its cardiovascular manifestations. Early intervention can improve patient outcomes, while ongoing research holds promise for further advancements in treatment for Marfan syndrome.

Humans↗
PubMed2026

Exploring the Melanoma and Pancreatic Cancer Phenotype of a Potential CDKN2A Founder Variant, I49T (c.146T>C; p.Ile49Thr), in Individuals of Predominantly Mexican Ancestry.

PURPOSE: Pathogenic/likely pathogenic variants (P/LPVs) in the CDKN2A gene cause an increased risk of melanoma (MEL) and pancreatic cancer (PANC). The CDKN2A variant I49T (c.146T>C), reported to be recurrent in Hispanics, has conflicting pathogenicity classifications at laboratories, affecting clinical care. Multiple genetics clinics collaborated to explore cancers associated with I49T. METHODS: Institutional clinical databases were queried for the CDKN2A variants, I49T, known P/LPVs, and c.-2G>A (a benign variant [BV]), and history of PANC and MEL was abstracted. A combination of statistical tests was used to investigate cancer history associations. RESULTS: Data on 203 individuals, with qualifying CDKN2A variants detected on multigene testing between 2012 and 2023, were analyzed (I49T, n = 101; known CDKN2A P/LPVs, n = 57; BV, n = 45). Those with I49T were 91% less likely to have MEL than known CDKN2A P/LPVs (odd ratio [OR] = 0.089 [95% CI, 0.031 to 0.025]; P < .001) and were also less likely to have PANC (OR = 0.45 [95% CI, 0.14 to 1.41]; P = .17). However, mean age at PANC diagnosis for I49T was 56.0 years, significantly younger than known CDKN2A P/LPVs (&#x3bc; = 71.0 years; P = .026). CONCLUSION: In the largest I49T study to date to our knowledge, MEL was significantly less frequent compared with known CDKN2A P/LPVs. Although a nonsignificant trend was observed for less PANC in I49T than known P/LPVs, individuals with I49T presented with PANC at a significantly younger age than those with known CDKN2A P/LPVs. The presence of I49T in Hispanics of mostly Mexican ancestry supports that it is a founder variant, relevant to understanding cancer risk in a large proportion of Hispanics in the United States.

Humans↗
PubMed1990

[An anatomicoclinical analysis of the synovial plica syndrome].

The authors describe embryology and anatomy of synovial plica of the knee joint. They propose a clinic and pathogenic classification and after examining the diagnostic problem of plica syndrome, analyze their long-term results after surgical treatment.

Humans↗
PubMed1978

[Perforations of the dura mater during epidural anesthesia. The value of epidurography].

The authors propose a pathogenic classification of perforations of the dura mater occurring during continuous epidural anaesthesia: according to the flow through the communication with the subarochnoid space. Two clinical forms of anaesthesia affecting the cord itself may be distinguished on this basis, one frequent and of immediate onset, diagnosed by the "test dose" and the other rare, of delayed onset, where this safety measure does not suffice. Routine prior epidurography is suggested, in order to ensure the diagnosis of dura mater perforation. In the case of the latter, it show either a more or less typical appearance of radicolography only or, more rarely, a picture which combines opacification of the epidural space with the subarachnoid passage of the contrast medium. This "mixed" appearance, although rare, should be known since it makes it possible to prevent delayed total spinal anaesthesia.

Aged↗
PubMed1980

Newer knowledge in classification, taxonomy and pathogenicity of species in the genus Haemophilus. A critical review.

This critical review deals with our present knowledge on the classification, taxonomy and pathogenicity of the different species of the genus Haemophilus occurring in humans and animals, including the five biotypes of H. influenzae and the 3 biotypes of H. para-influenzae. The first, second, third and fourth stage tests for differentiation of the species are summarized in several tables.

Animals↗
PubMed1982

Current approaches to the classification, characterisation and typing of pathogenic anaerobic bacteria.

Characterisation systems based on the demonstration of soluble antigens and toxins are of much practical value but have clear taxonomic limitations. This is illustrated by reference to our work with some of the pathogenic clostridia. The definition and classification of the anaerobic cocci is a difficult and continuing challenge. Systems for the classification and characterisation of the gram-negative non-sporing anaerobic bacilli are evolving well, though there are still some very difficult areas. A selection of the most helpful tests is indicated. Biotyping systems are compared with serotyping systems; the results of serological approaches to characterisation are encouraging. The further exploration of bacteriocin typing seems to be merited. The challenge of characterisation and classification of anaerobic spirochaetes commonly involved in human infections must now be taken up.

Amino Acids↗
PubMed1975

[Evaluation of the lysozyme and DNAase activity for the identification of pathogenic staphylococci].

The sensitivity of two tests recently proposed for the classification of pathogen staphylococci were evaluated: --production of DNA-ase with the modified method of Lachica et al.; --production of lisozyme. The two above tests were studied with other six tests on 1,000 strains of staphylococci showing a very high specificity. The Authors propose that the DNA-ase production and the lisozyme production, also for their very simple execution, should become routine tests to identify the strains of pathogenic staphylococci.

Deoxyribonucleases↗
PubMed1984

New aspects of staphylococcal infections: emergence of coagulase-negative staphylococci as pathogens.

In contrast to the well-established pathogen Staphylococcus aureus, the coagulase-negative staphylococci, formerly collectively called S. epidermidis, were until recently regarded as harmless commensals. During the last two decades, however, the coagulase-negative staphylococci have clearly emerged as pathogens in patients carrying artificial devices, such as prosthetic heart valves, hip prostheses and cerebrospinal fluid shunts, and in patients with compromised host defenses such as premature neonates and cancer and transplant patients. The present paper reviews current insights on classification, bacteriology, pathogenic potential and virulence factors of coagulase-negative staphylococci. In addition, the role of host defense factors in resistance to staphylococcal infection is summarized as well as the main features of the clinical syndromes in which coagulase-negative staphylococci are involved.

Antibodies, Bacterial↗