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Results for “phenotype-genotype correlation”

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PubMed1992

Phenotype-genotype correlations in X linked retinitis pigmentosa.

Retinitis pigmentosa (RP) represents a group of clinically heterogeneous retinal degenerations in which all modes of inheritance have been described. We have previously found two different clinical profiles in X linked RP as a function of age and mode of onset. The first clinical form has very early onset with severe myopia. The second form starts later with night blindness with mild myopia or none. At least two genes have been identified in X linked forms, namely RP2 (linked to DXS7, DXS255, and DXS14) and RP3 (linked to DXS84 and OTC) on the short arm of the X chromosome. In order to contribute to phenotype-genotype correlations in X linked RP, we tested the hypothesis that the two clinical profiles could be accounted for by the two different gene loci. The present study provides evidence for linkage of the clinical form with early myopia as the onset symptom with the RP2 gene (pairwise linkage to DXS255: Z = 3.13 at theta = 0), while the clinical form with later night blindness as the onset symptom is linked to the RP3 gene (pairwise linkage to OTC: Z = 4.16 at theta = 0).

Female↗

PubMed2025

Molecular characterization of drug-resistance genes and dynamics of multidrug-resistant Salmonella spp. in waterfowl: a pre- and post-antibiotic ban surveillance in Guangdong, China from 2013 to 2023.

BACKGROUND: Multidrug-Resistant Organism (MDRO) refers to bacteria that are Resistant to three or more types of antibiotics in clinical use. The global health threat posed by multidrug-resistant (MDR) bacterial pathogens and their cross-species transmission necessitates rigorous Surveillance. This urgency is amplified in China where antibiotic growth promoters were widely used in animal husbandry until the 2020 implementation of Announcement No. 194 launched by Ministry of Agriculture and Rural Affairs (Announcement 194), banning non-therapeutic antibiotics in feed. This study conducted a decade long investigation on the correlation between antimicrobial resistance (AMR) phenotypes and genetic determinants in 314 Salmonella isolates collected from waterfowl across Guangdong Province, China, utilizing disk diffusion (Kirby-Bauer method) and PCR-based detection of antibiotic resistance genes (ARGs). The study period covered the antibiotic policy transition in China, specifically encompassing the pre-ban (2013-2019) and post-ban (2020-2023) phases of the nationwide prohibition on growth-promoting antimicrobials in animal feed. METHODS: Antimicrobial Susceptibility profiles against 16 agents were determined via Kirby-Bauer testing, while PCR amplification targeted 20 ARGs. Statistical analyses evaluated phenotype-genotype correlations using Pearson`s chi-square test. RESULTS: Surveillance revealed escalating resistance rates annually. Highest resistance prevalence was observed against β-lactams and amphenicols (92.25%), whereas amikacin exhibited the lowest resistance rate (9.55%). MDR prevalence reached 87.23%, with the AMP-CAZ-GEN-FFC-TET resistance profile predominating (51.6% of isolates). Genetic analysis identified 3 to 16 ARGs per isolate was harboring, with blaTEM demonstrating the highest detection frequency (90.76%). Significant phenotype-genotype correlations (p < 0.05) were observed for 13 genes: blaCTX-M, blaTEM, blaOXA, aacC2, aph(3')-I, aac(3)-IV, aadA1, qnrS, qnrA, clmA, floR, sulII, tetA. Notably, significant declines in resistance to aminoglycosides (e.g., gentamicin from 71.7 to 3.5%) and florfenicol (from 81.1 to 9.6%) were observed after China's 2019 antibiotic ban policy (p < 0.001), underscoring the impact of targeted antimicrobial stewardship in avian husbandry. CONCLUSIONS: Analysis of 314 waterfowl Salmonella strains revealed severe multidrug resistance (MDR) and diverse resistance genes (DRGs), with 13 DRGs linked to resistance. China's antibiotic ban reduced targeted resistance, but MDR persists alarmingly via acquired DRGs and adaptation. Continued enforcement may lower aminoglycoside/phenicol resistance, but β-lactam resistance will likely endure, worsened by transcontinental blaCTX-M spread. Critically, plasmid co-selection threatens to amplify MDR, demanding genomic surveillance. Mitigation requires boosting policy compliance, developing non-antibiotic therapies, mapping mutations, establishing cross-species barriers, and prioritizing One Health interventions to block resistance spread.

China↗

PubMed1991

Molecular analysis of Gaucher disease: screening of patients in the Montreal/Quebec region.

Gaucher disease, the most prevalent lysosomal storage disease, is an autosomal recessive sphingolipidosis resulting from deficient glucocerebrosidase activity. Genomic DNA of the structural gene of glucocerebrosidase from normal individuals and fifteen unrelated patients with the three clinical forms of Gaucher disease from the Montreal/Quebec region were amplified by the polymerase chain reaction technique. Allele-specific oligonucleotide dot blot hybridization and restriction fragment length polymorphism were used to screen for five of the mutations [mutations 120, 370, 415, 444 (Nci), and 463] in exons 5, 9, and 10 of glucocerebrosidase gene. It was noted that all of the patients had at least one of the known mutant alleles. However, 9 patients (9/15 = 60%) had an unknown allele. Mutation 370 in exon 9 was present in the heteroallelic form in eight out of the nine patients with type 1 Gaucher disease, but was present in none of the six patients with type 2 or type 3 Gaucher disease. The Nci mutation in exon 10 was present in the heteroallelic form in three patients with type 1 Gaucher disease and in either the heteroallelic or homoallelic form in all of the six patients with type 2 or type 3 Gaucher disease. The 415/Nci mutations were found in a mildly affected 29-year-old patient with type 1 Gaucher disease, as well as in an infant with the type 2 form. These findings demonstrate the clinical and molecular genetic heterogeneities of Gaucher disease, the presence of unknown Gaucher allele(s) in most (60%) of the patients surveyed, and the occasional inexplicable lack of phenotype-genotype correlation among some patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗

PubMed2026

Dental phenotypes associated with novel PHEX variants in X-linked hypophosphatemia.

OBJECTIVES: X-linked hypophosphatemia (XLH) is a genetic disorder related to bone, mainly due to the mutations in PHEX gene. Previous studies have reported that XLH patients had various tooth phenotypes. It is unclear whether there are any rules about these abnormal tooth phenotypes, especially in those XLH cases with PHEX mutations. The objectives of this study were to find the most representative dental characteristics of XLH and the possible phenotype-genotype correlation. DESIGN: Two unrelated patients with XLH underwent clinical, radiographic, biochemical, and genetic evaluation. Whole-exome sequencing and whole-genome sequencing were used to identify pathogenic variants. The ultrastructure of extracted teeth was analyzed using a stereomicroscope, micro-CT, and scanning electron microscopy. In addition, a PubMed search (up to January 2026) identified 22 articles involving 366 patients for descriptive phenotype comparison. RESULTS: Two novel PHEX variants were identified: a novel complex structural variant (NC_000023.11, g.22035649-22041668delins) and a novel heterozygous splice-site variant (NM_000444.6, c.850-1 G>A). Radiographic examination showed enlarged pulp chambers and irregular pulp morphology. Ultrastructural analysis revealed dentin defects, including globular dentin, irregular interglobular dentin, disrupted dentinal tubules, and exposed collagen fibrils. Literature-based analysis indicated prevalent clinical manifestations (pulp necrosis, tooth loss, periodontitis) and radiographic findings (enlarged pulp chamber, and prominent pulp horn). CONCLUSION: In these two patients, novel PHEX variants were associated with a recurrent dentin-pulp phenotype. Integrated clinical, radiographic, ultrastructural, and literature evidence supports dentin defects as a central component of the dental phenotype in XLH and underscores the importance of early dental assessment.

Humans↗

PubMed1991

Molecular cytometry applied to detection and characterization of disease-linked chromosome aberrations.

Flow karyotyping and FISH with chromosome-specific or disease locus-specific probes are powerful adjuncts to conventional cytogenetic analysis. Flow karyotyping is well suited to quantitative analysis of the DNA content changes that occur during structural rearrangement. FISH with probes for repeated sequences allows ready detection of aneuploidy in interphase cells. FISH with whole-chromosome composite probes to metaphase spreads facilitates detection of subtle structural changes and allows detection of structural aberrations that occur at frequencies as low as 10(-3). FISH with locus-specific probes facilitates diagnosis of specific genetic diseases, may allow phenotype-genotype correlation on a cell by cell basis and will permit sensitive detection of residual disease.

Chromosome Aberrations↗

PubMed2025

Genetic heterogeneity in patients with enlarged vestibular aqueduct and Pendred syndrome.

BACKGROUND: Pathogenic variants in the SLC26A4 gene, encoding for Cl-/HCO3- and I- anion transporter pendrin, are associated with non-syndromic hearing loss with enlarged vestibular aqueduct (NSEVA) and Pendred syndrome (PDS). In the Caucasian population, up to 75% of patients fail to identify a genetic cause through biallelic mutations in the SLC26A4 gene. The CEVA haplotype could therefore play an important role in the diagnostics of NSEVA. The aim of the study was to determine the genetic etiology of hearing loss with EVA or with fully developed PDS in 37 probands and the functional characterization of novel variants identified in the SLC26A4 gene. METHODS: To determine the genetic etiology, Sanger sequencing, WES and KASP genotyping assay were used. Functional characterization of SLC26A4 variants c.140G>A (p.R47Q), c.415G>A (p.G139R), c.441G>A (p.M147I), c.481T>A (p.F161I), c.1589A>C (p.Y530S) and c.2260del (p.D754Ifs*5) involved determination of iodide influx, total and plasma membrane pendrin expression level and subcellular localization of pendrin by confocal imaging. The nanopore sequencing of nasopharyngeal swab samples was performed to confirm the pathogenic effect of potential splice site variant c.415G>A. RESULTS: Biallelic variants in the SLC26A4 gene (M2 genotype) were identified in ten probands and a complete CEVA haplotype was confirmed in three probands harbouring SLC26A4 monoallelic variants (M1 genotype). Fifteen variants in the SLC26A4 gene were identified in total, three of which are novel. The functional characterization of the novel variants and variants which were not yet functionally characterized confirmed the pathogenic potential of five out of six tested variants (p.G139R, p.M147I, p.Y530S, p.D754Ifs*5, and p.F161I). Analysis of nasopharyngeal swab samples confirmed exon 4 skipping due to novel variant SLC26A4:c.415G>A. Probands with biallelic SLC26A4 variants had significantly larger thyroid volume per m2 of body surface area than subjects with monoallelic SLC26A4 variants and the CEVA haplotype. CONCLUSIONS: The genetic aetiology was determined in 13 out of 37 probands (35%), seven manifested with PDS and six with NSEVA. The present study highlights the importance of functional testing to confirm the pathogenicity of SLC26A4 variants and the phenotype-genotype correlation in SLC26A4-related disorders.

Humans↗

PubMedDate not supplied

New perspectives and hope for cure-reflecting recent genetic developments in cystic fibrosis.

The isolation of cystic fibrosis gene at the CF locus assigned to the long arm of chromosome 7 band q31 and definition of its protein product named CFTR (cystic fibrosis transmembrane conductance regulator) permits to understand the basic defect in this inherited disorder known as cystic fibrosis (CF) or mucoviscidosis. A variety of mutations of CF gene was revealed and the most common, a deletion of the 3 nucleotides that encode phenylalanine (Delta F508) with the variable incidence among the different ethnic groups of CF patients was delineated. CF is a variable disease and genetic testing can be useful to explain this variation but to date the phenotype-genotype correlation is not clarified. Polymerase chain reaction (PCR) amplification is used to test CF gene in CF patients and their families but is not sufficiently genetically informative to population screening for carrier detections. Recently identified glycoprotein encoded by CF gene is responsible for the regulation of the membrane chloride channel of epithelial cells and the experiments used retro-virus-mediated gene transfer demonstrated complementation CF defect in vitro. The way for gene therapy in this disease is open. An alternative approach to use the germ line cells to CF gene therapy is prerequisite of the development of the preimplantation preconception genetic CF diagnosis. The researchers managed already to express human CFTR gene in vivo in cotton rats lungs through the viral delivery system. It will be generalized into the airways of CF patients with hope that normal CFTR will reverse the physiological defect in CF cells.

Cystic Fibrosis↗

PubMedDate not supplied

[The correlation between the genotype and the clinical expression of cystic fibrosis].

The authors report a phenotype-genotype correlation in a population of patients from center and south Italy affected by cystic fibrosis (CF). Thirteen (21%) of patients with pancreatic insufficiency (PI) were homozygous for delta F508, seventeen (27%) were delta F508 heterozygous with an associated unknown allele. Two other described mutations (N1303K, G542X) were also found in a heterozygote status and associated with a severe clinical expression of disease.

Adolescent↗

PubMed2025

Characterizing trends in clinical genetic testing: A single-center analysis of EHR data from 1.8 million patients over two decades.

A lack of structural data in electronic health records (EHRs) makes assessing the impact of genetic testing on clinical practice challenging. We extracted clinical genetic tests from the EHRs of more than 1.8 million patients seen at Vanderbilt University Medical Center from 2002 to 2022. With these data, we quantified the use of clinical genetic testing in healthcare and described how testing patterns and results changed over time. We assessed trends in types of genetic tests, tracked usage across medical specialties, and introduced a new measure, the genetically attributable fraction (GAF), to quantify the proportion of observed phenotypes attributable to a genetic diagnosis over time. We identified 104,392 tests and 19,032 molecularly confirmed diagnoses. The proportion of patients with genetic testing in their EHRs increased from 1.0% in 2002 to 6.1% in 2022, and testing became more comprehensive with the growing use of multi-gene panels. The number of unique diseases diagnosed with genetic testing increased from 51 in 2002 to 509 in 2022, and there was a rise in the number of variants of uncertain significance. The phenome-wide GAF for 6,505,620 diagnoses made in 2022 was 0.46%, and the GAF was greater than 5% for 74 phenotypes, including pancreatic insufficiency (67%), chorea (64%), atrial septal defect (24%), microcephaly (17%), paraganglioma (17%), and ovarian cancer (6.8%). Our study provides a comprehensive quantification of the increasing role of genetic testing at a major academic medical institution and demonstrates its growing utility in explaining the observed medical phenome.

Humans↗

PubMed2026

Twenty-Three Years of Surveillance in Chinese Avian Pasteurella multocida Reveals Declining Antimicrobial Resistance but Increasing Therapeutic Challenges.

Pasteurella multocida (Pm) is an important veterinary and zoonotic pathogen that causes significant economic losses in poultry production. However, long-term surveillance studies integrating antimicrobial resistance (AMR), biocide tolerance, and genomic epidemiology of Pm remain scarce. In this study, we investigated the antimicrobial susceptibility, biocide tolerance, and the phenotypic associations of 136 avian Pm isolates collected from six provinces in China between 2002 and 2024. Whole-genome sequencing was performed to characterize population structure, identify antimicrobial resistance genes (ARGs), and assess genotype-phenotype concordance. The A:L1:ST129 lineage remained the predominant clone throughout the 23-year surveillance period, with a high prevalence of AMR-associated traits observed within this lineage. Although resistance to several commonly used antimicrobial classes declined significantly after 2021, florfenicol resistance continued to increase, suggesting an emerging challenge for the clinical management of pasteurellosis. While the isolates generally exhibited low tolerance to the four representative biocides tested, phenotypic correlations were observed between AMR profiles and biocide tolerance patterns. Furthermore, substantial phenotype-genotype discordance was observed, indicating that the presence of ARGs alone may not be sufficient to accurately predict antimicrobial susceptibility. Overall, this study provides a longitudinal assessment of long-term AMR trends, biocide tolerance, and genomic epidemiology of avian Pm in China, offering epidemiological evidence for monitoring AMR trends and improving antimicrobial management strategies in poultry production.

Animals↗