Application of Clinical Genetics最新文献

Objective: To evaluate the system performance of the 20 autosomal short tandem repeats (STR) polymorphic genetic loci in quality control for prenatal diagnosis.

Methods: A genotyping system consisting of 6 STRs on chromosome 13 (chr13), 6 STRs on chromosome 18 (chr18), 8 STRs on chromosome 21 (chr21), and 10 genetic markers on sex chromosomes were used to analyze the genetic profiles of 2333 unrelated adult females from the Han population in East China. The population allele frequencies of the 20 autosomal STRs were obtained using the genotype dataset of the cohort. The established method in forensic genetic fields was used to calculate allele frequencies of the 20 autosomal STRs, observed heterozygosity (H_obs ), expected heterozygosity (H), random match probability (PM), power of non-parental exclusion in duos (PE_duos ), cumulative random match probability (CPM), and cumulative non-parental exclusion rate in duos (CPE_duos ). The possible influence of STR markers on the detection rates of heterozygotes was assessed by employing the binomial distribution approach for every autosomal chromosome.

Results: The average expected heterozygosity for the STRs on chr13, chr18, and chr21 is 0.8097, 0.7478, and 0.7760, respectively. The CPM for the STRs on the three chromosomes is 4.52E-08, 7.34E-07, and 9.30E-10, respectively. The probability of detecting at least one heterozygosity on each chromosome is 0.999952, 0.999742, and 0.999994, respectively. The CPE_duos of the 20 STRs is 0.999982. And the potential linkage effects among the STRs on the autosomal have a negligible impact on the observed heterozygosity.

Conclusion: The 20 autosomal STRs in the 30 plex genotyping system exhibit high polymorphism in the Han population from East China, effective meeting the quality control criteria and providing valuable guidelines in assessing the molecular karyotypes of the chromosomes for prenatal diagnosis.

Background: Transcobalamin II (TC II) deficiency is a rare autosomal recessive disorder that typically manifests in early infancy. Symptoms include failure to thrive, vomiting, weakness, and pancytopenia. If left undiagnosed and untreated, it can be life-threatening. TC II is crucial for transporting cobalamin (vitamin B12), which plays a vital role in homocysteine and methylmalonic acid metabolism. It serves as a cofactor in neurotransmitter synthesis and protein methylation processes.

Methods: In this study, we reviewed the clinical presentation, treatment approaches, and long-term outcomes of four patients with confirmed TC II deficiency. All subjects were born to consanguineous parents and exhibited symptoms between birth and four months of age.

Results: All patients presented with hematological abnormalities, elevated methylmalonic acid (MMA), and increased total homocysteine (tHcy) levels. Whole Exome Sequencing (WES) confirmed TC II deficiency in all cases, revealing diverse mutation spectra, primarily frameshift mutations (leu320Valfs*51, and IIe330Hisfs*9). No clear genotype-phenotype correlations were observed. The majority of patients were treated with intramuscular hydroxocobalamin (OH-Cbl), resulting in clinical and biochemical improvements.

Conclusion: This study underscores the importance of early detection and appropriate management of TC II deficiency to prevent permanent morbidity and potentially fatal outcomes. Regular monitoring of clinical and neurological status, as well as MMA and tHcy levels, is essential to ensure adequate therapy. Intramuscular treatment is the preferred route to prevent neurological deficits and optimal markers normalization.

Background: Conradi-Hünermann-Happle syndrome (CDPX2, OMIM 302960) is an X-linked dominant inherited disorder caused by variants in the EBP gene, which primarily affects the skin, bones, and eyes.

Objective: To describe the clinical manifestations and genetic mutation in a 7-year-old girl presenting with severe scoliosis, hydronephrosis, and other skeletal abnormalities.

Methods: The patient's medical history was collected from birth. Exome sequencing was performed to identify candidate genes, and the detected variant was confirmed by Sanger sequencing.

Results: Exome sequencing revealed a de novo EBP mutation (c.452A>G, p.Gln151Arg) in the patient.

Conclusion: The patient was diagnosed with X-linked chondrodysplasia punctata type 2 (CDPX2). This novel missense mutation expands the mutation spectrum of CDPX2 and underscores the clinical utility of exome sequencing in diagnosing this condition.

Purpose: The hepatic cytochrome P450 2C19 (CYP2C19) superfamily plays a crucial role in converting clopidogrel into its active form. Polymorphisms in CYP2C19 significantly contribute to the interindividual variability observed, often resulting in persistent thromboembolic complications. This study aimed to assess the frequency of the CYP2C19*2 (rs4244285, 681 G>A1) polymorphism among patients with cardiovascular diseases undergoing clopidogrel therapy.

Patients and methods: This cross-sectional study recruited a total of seventy-three (73) patients from the Cardiology Department of the Centre Hospitalier Universitaire Yalgado Ouédraogo (CHU-YO) between January and June 2023. DNA was extracted from blood samples for CYP2C19*2 genotyping using PCR-RFLP.

Results: Genetic analysis revealed frequencies of 65.8% for the wild-type CYP2C19*1/*1, 28.8% for the heterozygous CYP2C19*1/*2, and 2.7% for the homozygous variant CYP2C19*2/*2. The distribution of the genotypic frequencies was consistent with Hardy-Weinberg equilibrium (p> 0.05). The overall frequency of the CYP2C19*2 allele in the study population was 16.4%, with 12.5% observed in females and 19.5% in males.

Conclusion: This study provides valuable insights into the frequency of the CYP2C19*2 polymorphism among cardiovascular patients in Burkina Faso, contributing to the limited data available on CYP2C19 polymorphisms in sub-Saharan Africa. The presence of loss-of-function alleles suggests a potential risk for reduced drug efficacy in a subset of individuals. As one of the pioneering studies in the region, these findings emphasize the importance of further research to understand the clinical implications of CYP2C19 polymorphisms.

The implementation of non-invasive prenatal testing (NIPT) in maternal plasma, based on cell-free DNA (cfDNA) analysis, has progressed over the last two decades and is now integrated into the Spanish National Health System. However, there remains significant heterogeneity in its indications, technical methodologies, and reporting standards, reflecting international variability. This guide, developed by experts from the Spanish Association of Prenatal Diagnosis (AEDP) and the Spanish Association of Human Genetics (AEGH), provides recommendations to standardize NIPT application. It addresses key aspects such as technical and analytical requirements, integration with invasive diagnostic methods, pre- and post-test genetic counseling, and legal considerations. Additionally, the guide discusses the detection of common aneuploidies, the limitations in identifying structural chromosomal abnormalities and rare variants, and the impact of biological and clinical factors on test performance. By establishing a minimum framework based on scientific evidence, this document aims to optimize NIPT implementation in a cost-effective manner, ensuring clinical validity and informed decision-making for both healthcare professionals and pregnant women.

Background: Chromosomal abnormalities and variations are significant contributors to reproductive challenges. This study aims to investigate the types and incidence of structural autosomal anomalies and autosomal variations in a large Vietnamese population undergoing infertility treatment.  .

Material and methods: A retrospective analysis was conducted on 19,191 females and 18,584 males who needed assisted reproductive technology (ART) at the Military Institute of Clinical Embryology and Histology, and Andrology and Fertility Hospital of Hanoi from 2020 to 2023. Karyotyping was conducted using the G-band staining method, and the data were analyzed with STATA 16.0 software.

Results: Males have a higher overall occurrence of structural autosomal anomalies, with a total of 359 cases (1.932%) compared to 306 cases (1.594%) in females, particularly inversions and robertsonian translocations. Chromosome 9 inversions were equally observed in both genders, while robertsonian translocations and reciprocal translocations were more frequent in males (0.183% and 0.468%, respectively) than in females (0.146% and 0.406%, respectively). Deletions and duplications were more prevalent in males, occurring at rates of 0.215% and 0.016%, respectively, versus 0.036% and 0.021% in females. Total autosomal variants were 1478 (7.953%) in males and 1864 (9.7%) in females. Chromosome 9 exhibits the highest occurrence of the q+/qh+ variant, followed by the one of chromosome 1 and chromosome 16. Chromosomes 21 and 22 show notable numbers of ps+ and pstk+ variants.  .

Conclusion: Structural autosomal anomalies and autosomal variations are common in Vietnamese patients undergoing infertility, highlighting the necessity of genetic testing, particularly karyotyping, in the evaluation and management of infertility.   .

Aim: Turner syndrome (TS) is one of the most common genetic diseases in females, with typical physical features and comorbidities. Karyotype-phenotype associations and clinical significance of childhood versus adolescent/adulthood diagnosis are conflicting.

Purpose: Determining the role of certain TS karyotypes and early (<12 years of age) vs late (≥12 years) diagnosis in TS-specific phenotype and comorbidity penetrance.

Patients and methods: Retrospective analysis of baseline characteristics and 45 TS-specific features and comorbidities of 75 TS patients were diagnosed between 2009 and 2019 and followed-up until 2023 in our tertiary care center.

Results: Thirteen different karyotypes were detected: 45,X,inv(10), 45,X,inv(9)(15), 45,X, 46,X,i(Xq), 46,X,del(Xp), 46,XX,del(X)q21, 45,X/46,X,del(X), 45,X/46,X,+mar, 45,X/46,X,rX, 45,X/46,XX, 45,X/46,XY, 45,X/47,XXX, 46,X,i(Xq)/47,XX,i(Xq). The classic karyotype with 45X monosomy showed an increased risk for hypertrichosis (28.6% vs 7.5%, OR 4.93, 95% CI [1.23-19.73]), pterygium colli (34% vs 12%, OR 3.65, 95% CI [1.13-11.75]) and short stature (91% vs 75%, OR 3.56 [0.89-14.17]. Mosaic karyotypes had a smaller risk of pterygium colli (OR 0.28 [0.073-1.092]) and short stature (OR 0.29 [0.086-1.026]. 45X/46XX mosaicism was associated with an increased risk of hypertension (33% vs 6%, OR 7.75 [1.39-43.08]), and the presence of the iso (Xq) chromosome increased the risk of celiac disease (28% vs 3%, OR 13.2 [1.52-114.52]). 44/75 (58.6%) of the cohort were diagnosed at <12 years of age. In the <12-year-old diagnosis group, facial dysmorphism and low hairline, (OR 3.30, [1.26-8.65]), low-set ears (OR 2.51 [0.98-6.46]), and breasts abnormalities (OR 4.71 [1.72-12.83]), short stature (OR 4.09 [1.13-14.82]) and GH therapy (OR 4.93 [1.31-16.01]) occurred more frequently. If diagnosed <12 years, patients had a decreased risk of hepatosplenomegaly (OR 0.10 [0.02-0.50]) and hypertension (OR 0.097 [0.01-0.85]).

Conclusion: TS patients should be handled as a heterogenous group, as they seem to differ in the penetrance of phenotypical features of the disease and the risk of comorbidities depending on karyotype and age at diagnosis.

Alpha 1 Antitrypsin Deficiency (AATD) is a genetic condition that results from mutations in the SERPINA1 gene, which can lead to deficient or dysfunctional Alpha 1 Antitrypsin (AAT) protein production. AATD is linked to chronic obstructive pulmonary disease (COPD) and emphysema. In addition to pulmonary manifestations, AATD has also been associated with vascular pathology due to excessive protease activity, tissue degradation, and vessel stiffening. Early AATD diagnosis is crucial to prevent progressive lung damage and associated pathologies. Here, we present case reports of two patients with AATD from the Temple University Hospital Outpatient Clinic, who exhibited aneurysms of the aorta and splenic artery. AATD should be considered a genetic risk factor for aneurysms and vascular diseases, necessitating cardiovascular monitoring in affected individuals. This report emphasizes both the need for heightened awareness of AATD as a potential etiology of unexplained vascular aneurysms, as well as the need for screening for vascular pathology in patients with AATD-associated COPD and emphysema to facilitate early intervention and improve patient outcomes.

Background: Trimethylaminuria (TMAU) is a rare recessive genetic disorder with limited global prevalence. To date, there have been no official reports of TMAU cases documented in Saudi Arabia.

Purpose: In this study, we developed a liquid chromatography-mass spectrometry (LC-MS) method for the analysis of trimethylamine (TMA) and Trimethylamine N-Oxide (TMAO) in urine and plasma samples for the first reported case of TMAU in Saudi Arabia.

Patients and methods: A 41-year-old Saudi man was diagnosed with TMAU in National Guard Hospital. Blood and urine samples were collected to confirm the diagnosis of TMAU. In this study, we have studied LC-MS, cell culture, flow cytometry, adhesion assay and Sanger sequencing analysis. Additionally, in this study, we have selected 5 healthy controls.

Results: The results have revealed elevated TMA levels were present in both urine and plasma samples, while TMAO levels were significantly lower compared to control group. Further, we utilized plasma sample from the TMAU patient as novel model to investigate the potential effect of low TMAO on monocyte and endothelial cell function in vitro. DNA sequencing analysis identified a c.622G >T (p.Glu208*) which creates a premature stop codon in FMO3 gene.

Conclusion: Our findings revealed differential responses in monocytes and endothelial cells stimulated with plasma from the TMAU patient compared to plasma from non-TMAU patients. These distinct responses may be key modulators of endothelial function and contributes to vascular damage.

Androgen insensitivity syndrome (AIS) is an X-linked genetic disorder caused by mutations in the androgen receptor gene (AR), leading to impaired androgen signaling and resulting in varying degrees of undermasculinization in individuals with a 46,XY karyotype. This study aimed to expand the molecular landscape of AIS by identifying and characterizing pathogenic variants in the AR gene via next-generation sequencing (NGS). Molecular diagnostics revealed eight distinct variants within the AR gene, two of which had not been previously described. These include the following novel variants: c.3G>A, and c.1344_1345insTA. This study broadens the spectrum of known AR gene mutations associated with AIS and highlights the critical role of molecular diagnostics in the accurate classification of variants. These findings will aid in enhancing the clinical management and genetic counseling of individuals affected by AIS.