Application of Clinical Genetics最新文献

Background: 3M syndrome is a rare autosomal recessive genetic disorder characterized by significant intrauterine and postnatal growth restriction. There is limited research on its genetic basis within the Chinese population.

Methods: We performed trio-based whole-exome sequencing to identify the pathogenic gene in the affected child and collected and organized clinical and imaging data. Relevant information was reviewed through a literature search.

Results: In this study, we present a case involving prenatal diagnostic abnormalities and postnatal confirmation of 3M syndrome, including detailed documentation of clinical features and associated genetic variants. Notably, during prenatal ultrasound examination, the fetus exhibited increased nuchal translucency (NT) and delayed limb development. Postnatally, whole-exome sequencing revealed the compound heterozygous mutations in the CUL7 gene: c.3646-2A>G and c.3355+5G>A. The splicing mutation c.3646-2A>G is a novel pathogenic mutation, while the c.3355+5G>A mutation has been previously reported. In-silico analysis predicted strong pathogenicity for both splicing mutations. Through follow-up, we observed that the patient's height and weight are below the first percentile, with abnormal skeletal development and distinctive facial features. Based on literature review of reported cases, these mutations disrupt the normal function of CUL7-OBSL1-CCDC8 complex in the ubiquitin-proteasome pathway, leading to impaired growth regulation.

Discussion: This study identified a novel splicing mutation in the CUL7 gene in a patient with 3M syndrome, expanding the genetic spectrum of this disorder and contributing novel insights for clinical diagnosis and management.

Purpose: X-linked severe combined immunodeficiency (X-SCID) is an inherited immune disorder caused by pathogenic variants in the IL2RG gene, leading to recurrent infections. Identifying these variants and elucidating their pathogenic mechanisms are crucial for precise diagnosis and treatment, prenatal diagnosis, and preimplantation genetic testing (PGT). This study aimed to identify candidate variants in four families with suspected immunodeficiency, assess their pathogenicity, elucidate their pathogenic mechanisms, and provide a basis for precise treatment, prenatal diagnosis, and PGT.

Patients and methods: Four families with suspected immunodeficiency were recruited from the Reproductive and Genetic Hospital of CITIC-Xiangya. Whole exome sequencing (WES) was used to identify the genetic etiology. Functional experiments were performed to assess the pathogenicity of the identified IL2RG variants, and to elucidate their pathogenic mechanisms.

Results: WES identified four IL2RG variants: three hemizygous (c.569G>C:p.R190P, c.515T>C:p.L172P, c.217A>C:p.T73P) and one heterozygous (c.1091C>T:p.T364I) variants. Three of these variants were novel. Initially three variants (p.R190P, p.T73P, and p.T364I) were classified as variants of uncertain significance (VUS) and one (p.L172P) was likely pathogenic (LP) according to ACMG/AMP guidelines. Functional analyses revealed reduced STAT5 phosphorylation and transcriptional activity across all variants, supporting the reclassification of three variants (p.R190P, p.L172P, and p.T73P) as likely pathogenic (LP), and one variant (p.T364I) as VUS with a Bayesian score of 5. Furthermore, IP-MS analysis revealed that the mutant IL2RG resulted in reduced cell-surface expression and abnormal nuclear localization. Therefore, the identified IL2RG variants impair IL-2-induced STAT5 phosphorylation and transcriptional activity to cause X-linked severe combined immunodeficiency in these families.

Conclusion: This study highlights the critical role of functional analysis in clarifying variant pathogenicity and provides a clear example of pathogenicity assessment for IL2RG variants. Integrating genomic and functional data enhance diagnostic precision and informs precise treatment strategies, genetic counseling, prenatal diagnosis, and PGT for X-SCID.

Zellweger syndrome (ZS) is a heterogeneous group of clinical conditions that commonly manifest with neurodevelopmental delay, multiple neurological abnormalities, visual and auditory impairments, and adrenocortical dysfunction. ZS is an autosomal recessive peroxisomal disorder resulting from mutations in one of over 13 identified genes. We report the case of a male child with episodic seizures starting at 18 days of life, followed by neurodevelopmental delay and neuroimaging findings of asymmetric polymicrogyria and cortical abnormalities. His healthy parents were consanguineous, and notably, a brother, who passed away at the age of 5 years-old, had epilepsy and adrenoleukodystrophy. Exome sequencing allowed the identification of a novel stop-loss homozygous variant in the PEX5 gene in the index case. The phenotype associated to this gene, Zellweger syndrome, as well as the inheritance mechanism, is consistent with that observed in both the patient and his brother.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improve the quality of life in individuals with EGFR mutation-positive non-small cell lung cancer (NSCLC). This study evaluates the treatment outcomes of EGFR-mutant NSCLC patients with concurrent gene alterations, aiming to determine their predictive significance concerning responses to EGFR-TKI therapy.

Materials and methods: We conducted a retrospective cohort study using next-generation sequencing (NGS) data from January 2019 to June 2023. Patients were categorized into two groups: those with a single EGFR mutation (Group 1) and those with concurrent EGFR mutations (Group 2).

Results: Among 109 patients with EGFR mutations, 72 showed partial responses (66.1%), one had a complete response (0.9%), and 17 had stable disease (15.6%); 19 experienced progressive disease (17.4%). The overall response rate (ORR) was 67%, and the disease control rate (DCR) was 82.6%. Progression-free survival (PFS) was 15.03 months (95% CI: 13.17-16.89) in the single EGFR mutation group and 11.00 months (95% CI: 9.95-12.05) in the concurrent mutations group (P = 0.001). Among 43 patients with concurrent mutations, those with ALK mutations had the longest PFS (13.43 months), followed by PIK3CA (11.00 months), while MET alterations showed the shortest PFS (4.77 months).

Conclusion: Concurrent gene alterations in EGFR-mutant NSCLC are associated with reduced efficacy of EGFR-TKIs. Patients with KRAS, BRAF, ROS1, or MET mutations have poorer predictive outcomes compared to those without these alterations.

Familial Mediterranean fever (FMF) is an inherited autoinflammatory disorder resulting in recurrent fever, polyserositis, and arthralgias. It is caused by mutations in the MEFV (Mediterranean Fever) gene. We report a Lebanese pediatric patient with typical FMF symptoms and unique triple homozygous variations E148Q-P369S-R408Q in the MEFV gene. This is the second-ever reported case with this specific triple homozygous variation.

Objective: Allo-HSCT is a well-established treatment for several hematological malignancies. Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a significant problem and is associated with a poor prognosis and low overall survival. Chimerism analysis is one of the tools applied in post-transplant monitoring, as an increasing fraction of recipient cells after HSCT has been linked to a higher risk of relapse.

Study design: In this retrospective, single-centre study we have analysed the data of patients treated with allo-HSCT for a range of hematological malignancies in the Department of Paediatric Haematology, Oncology and Transplantology, Medical University of Lublin, Poland, between years 2002-2018.

Results: For all 103 patients 3-years OS was 72.6 (95% CI: 64.3-82.0) and 3-years EFS was 72.0 (95% CI: 63.5-81.6). There were no differences in 3-years OS and EFS in group of patients who achieved FDC <14 and >14 days: 67.9 (95% CI: 57.4-80.3) vs 81.9 (95% CI: 69.7-96.2), p = 0.220 and 66.0 (95% CI: 55.3-78.7) vs 84.1 (95% CI: 72.3-97.9), p = 0.073, respectively. Early FDC achievement was not significantly associated with risk of relapse, p = 0.181. Based on multivariate Cox regression analysis AML/MDS increased risk of relapse 3x compared to ALL, HR = 2.72, CI95 [1.24-5.98], p = 0.013; PB/CB increased the risk nearly 3x compared to cells from BM, HR = 2.52, CI95 [1.12-5.65], p = 0.025.

Conclusion: In presented study, achieving early FDC was not associated with lower risk of relapse and had no impact on overall and event-free survival. However, the study presents a unique data of very early chimerism in a large cohort of paediatric patients with haematological malignancies treated within a single unit. Possible extensions to this study, to include analysing more data from a larger patient cohort, may allow us to determine the exact prognostic value of very early chimerism analysis to establish relevant cutoff values and risk thresholds for intervention.

Background: Diminished ovarian reserve (DOR) remains a significant challenge in IVF, as it is closely associated with poor ovarian response. Beyond well-established predictive of ovarian response, genetic polymorphisms in the FSH receptor (FSHR) gene rs6165 and rs6166 have been reported as potential markers.

Purpose: Evaluating the expression of FSHR rs6165 and rs6166 in DOR patients and their impact on ovarian response to stimulation.

Materials and methods: This prospective cross-sectional included 79 DOR patients (AMH < 1.2 ng/mL and/or AFC < 5) undergoing IVF treatment at the National Hospital of Obstetrics and Gynecology, Vietnam. GnRH antagonist protocol was applied, using alpha follitropin with individualized dosages combined with clomiphene citrate, followed by dual-trigger ovulation induction. FSHR rs6165 and rs6166 were genotyped by Next-Generation Sequencing (NGS) assays, with Sanger sequencing for validation. Ovarian response was assessed based on follicular development and oocyte retrieval.

Results: The overall prevalence of the rs6165 and rs6166 polymorphisms was 10.1% (8/79), with strong linkage disequilibrium observed between the two loci (OR = 490, p < 0.0001). No significant differences in age, AMH, baseline FSH, and AFC were found in all genotypes (AA, AG, GG) of rs6165 and rs6166. In the rs6165 dominant model, patients with G alleles (AG/GG) had lower total oocyte retrieval, FOI and FORT than the AA genotype. In rs6166 codominant, dominant, and recessive models, the GG phenotype retrieved fewer oocytes (p1 = 0.02, p2 = 0.03, p3 = 0.01). FORT was significantly lower in G allele carriers (AG/GG) than AA (p = 0.04).

Conclusion: In the diminished ovarian reserve patients, FSHR rs6165 and rs6166 were associated with ovarian response to stimulation in IVF treatment. Specifically, the presence of G alleles in both rs6165 and rs6166 was correlated with reduced oocyte retrieval, independent of baseline ovarian reserve markers.

Hereditary hemorrhagic telangiectasia (HHT) coexisting with moyamoya disease (MMD) is exceptionally rare. We report the first case of a 45-year-old female harboring two genetic variants implicated in vascular disease: a pathogenic mutation in ACVRL1 (c.1231C>T, p.Arg411Trp) and a novel variant of uncertain significance in RNF213 (c.13685C>T, p.Pro4562Leu). This case is remarkable for the concurrent manifestation of HHT-associated peripheral telangiectasia and MMD-characteristic intracranial arterial stenosis, suggesting a possible synergistic interaction between variants affecting distinct vascular signaling pathways. These findings offer new insights into the genetic mechanisms underlying complex hereditary vascular disorders and emphasize the importance of comprehensive genetic testing in diagnosing atypical vascular phenotypes.

Introduction: Traditional treatments for non-small cell lung cancer (NSCLC), such as chemotherapy, especially platinum-based regimens, often lack efficacy due to the disease's inherent heterogeneity. Precision medicine in NSCLC recognizes each tumor's unique genetic profile. Alterations in the pharmacokinetics and pharmacodynamics of platinum-based therapies significantly influence their clinical outcomes. Previous research has predominantly focused on genetic polymorphisms in genes like Glutathione S-transferase Pi 1 (GSTP1), ATP Binding Cassette subfamily C member 2 (ABCC2), Excision repair cross-complementation group 1 and 2 (ERCC1, and/ ERCC2), which play crucial roles in detoxification, drug transportation, and Nucleotide Excision Repair (NER). However, findings have shown considerable variability.

Methods: The analysis followed the PRISMA and STROPS Guidelines, using specific search terms including NSCLC, Chemotherapy, Polymorphisms, Single Nucleotide Polymorphisms (SNPs), ERCC1, ERCC2, ABCC2, GSTP1, Effectiveness, and Clinical Response. These studies were subjected to full-text screening process.

Results: Initial screening of 370 studies, comprising 275 from PubMed and 95 from EBSCO, identified 53 relevant ones, excluding those such as reviews, non-English studies, and meta-analyses. Among the genetic variants studied (ERCC1 rs11615, ERCC2 rs13181, ABCC2 rs717620, GSTP1 rs1695), GSTP1 rs1695 emerged as particularly promising, with 11 studies indicating a significant association with improved survival outcomes.

Conclusion: The integration of SNP profiling into clinical decision-making processes holds substantial potential for enhancing the personalization of NSCLC treatment strategies, thereby improving patient outcomes.

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.