Molecular Genetics & Genomic Medicine最新文献

Background: The factors influencing the phenotypic heterogeneity of patients with β-thalassemia have been receiving much attention in the field of hematology research. Activating the sustained expression of fetal hemoglobin (HbF) has proven to be one of the effective ways to alleviate the clinical symptoms of β-thalassemia. Studies have reported that single nucleotide polymorphisms (SNP) in KLF1, BCL11A, and HBS1L-MYB can increase the expression level of HbF in patients with β-thalassemia and have an impact on the phenotype.

Methods: In this study, SNaPshot and Sanger sequencing were used to detect SNPs of BCL11A, HBS1L-MYB, and KLF1 in patients with different types of β-thalassemia collected in Hainan. Linkage disequilibrium and haplotype analysis were performed on mutant sites.

Results: As a result, 41 mutation types of the above genes were detected (high mutation frequency and wide distribution range), and there was strong linkage disequilibrium at multiple mutation sites, resulting in multiple haplotypes. However, there are no significant differences in the distribution of gene polymorphisms between different types of β-thalassemia, suggesting that the modifications of KLF1, BCL11A, and HBS1L-MYB may have little impact on the β-thalassemia phenotype in this region.

Conclusion: Our study provides data support for assessing the impact of modified genes on the phenotype of patients with β-thalassemia in Hainan, and also promotes the clinical accurate diagnosis and classification evaluation of β-thalassemia.

Background: Recurrent Implantation Failure (RIF) is defined as the inability to establish pregnancy despite high-quality embryo transfer after the application of at least three consecutive in vitro fertilization (IVF)/intracytoplasmic sperm injection-embryo transfer procedures. Chromosomal abnormalities are one of the primary reasons for pregnancy failure, miscarriage, and birth defects in both natural conception and IVF pregnancies. This study was to evaluate the incidence of chromosomal abnormalities in peripheral blood samples from 100 couples who experienced RIF.

Methods: Chromosomal structure analysis was conducted on peripheral blood samples from 100 couples who experienced RIF between 2018 and 2022. Additionally, cytogenetic assessments were conducted on 200 healthy individuals without clinical issues to ensure the accuracy. The GTG-Banding technique was employed in our research.

Results: Out of the 200 individuals who faced RIF, six (3%) exhibited chromosomal abnormalities, comprising five (83.3%) men and one (16.6%) woman. Translocation was the main type of autosomal structural abnormalities; also, we found one inversion and one pstk - (population polymorphism). Conversely, no chromosomal abnormalities were detected in the control group. We found chromosomal abnormalities in 3% of study participants who had experienced RIF.

Conclusion: Chromosomal abnormalities significantly contribute to RIF. Therefore, it is imperative to conduct cytogenetic screening for both partners before initiating any assisted reproductive technology procedures.

Background: Culler-Jones syndrome (CJS) is an autosomal dominant disorder characterized by hypopituitarism, postaxial polydactyly, and craniofacial anomalies, associated with pathogenic GLI2 variants. Genotype-phenotype correlations suggest missense variants may present with isolated pituitary phenotypes.

Methods: We evaluated an 8-year-old boy referred for short stature, failure to thrive, and neurodevelopmental concerns. Clinical assessment, endocrine evaluation, imaging studies, and trio exome sequencing were performed.

Results: The patient exhibited growth hormone deficiency, dolichocephaly, midline diastema, lip and tongue ties, hypotonia, and ADHD. No polydactyly was noted. Trio exome sequencing revealed a de novo heterozygous likely pathogenic GLI2 variant (c.1496G>T; p.Arg499Leu) located within the DNA-binding zinc finger domain.

Conclusion: This case expands the phenotypic spectrum of GLI2-related disorders and reinforces that non-truncating GLI2 variants are often associated with isolated hypopituitarism and subtle craniofacial or neurodevelopmental features. Genomic testing should be considered in similar clinical presentations.

Background: The identification of actionable secondary findings (SFs) through clinical exome sequencing has become increasingly relevant with the integration of genomics into routine healthcare. The frequency and spectrum of these findings vary across populations.

Methods: We analyzed exome sequencing data from 350 unrelated Maltese individuals, comprising 320 pseudonymised controls and 30 participants from the pilot sequencing phase of the national biobank DwarnaBio, to assess the prevalence of pathogenic or likely pathogenic (P/LP) variants in the ACMG SF v3.2 gene list. All samples underwent uniform sequencing, rigorous quality control, and variant interpretation according to ACMG/AMP guidelines.

Results: Actionable P/LP variants were identified in 12 individuals (3.4%) across autosomal dominant genes, predominantly associated with inherited cardiac conditions and cancer predisposition syndromes. These findings highlight the importance of including underrepresented populations in genomic research and emphasize the need to establish provisions for the return of clinically actionable results to biobank participants, supported by access to genetic counseling.

Conclusion: Our results advocate for the integration of population-specific genomic data into national precision medicine frameworks, particularly for small or isolated populations where tailored approaches to variant curation and clinical translation are required. This study provides the first baseline estimate of actionable SFs in the Maltese population and offers insights for advancing precision medicine frameworks.

Objectives: To investigate the abnormal development of cerebral cortical sulci and gyri in fetuses with Overgrowth Syndrome and/or Cerebral Malformations Due to mTOR Pathway Gene Abnormalities (OCMMPG), focusing on prenatal imaging correlates of mTOR dysregulation.

Methods: Retrospective analysis of three OCMMPG cases diagnosed via whole-exome sequencing (WES). Sulco-gyral morphology was assessed using 2D cross-sectional imaging and 3D inversion Crystalvue/Realisticvue (3D-ICRV) rendering.

Results: Polymicrogyria (PMG) was identified in all cases via 2D and 3D-ICRV imaging. The third fetus exhibited a malformed Sylvian fissure and hypoplastic parieto-occipital sulcus (POS). 3D-ICRV revealed cortical thickening and microgyral fusion, aligning with PMG criteria.

Conclusions: The integration of 2D imaging and 3D-ICRV technology enables comprehensive prenatal assessment of sulco-gyral development. Our findings highlight the utility of this approach in detecting mTOR-related cortical dysplasias, particularly in cases with atypical Sylvian fissure or POS hypoplasia.

Background: Houge-Janssens syndrome type 2 (HJS2, OMIM 616362) is a rare neurodevelopmental disorder caused by pathogenic variants in PPP2R1A, typically characterized postnatally by hypotonia, developmental delay, intellectual disability, and distinctive craniofacial features.

Methods: We describe a 28-year-old pregnant woman referred for increased nuchal translucency (4.4 mm) and high risk on first trimester screening. Noninvasive prenatal testing showed no common aneuploidies. At 23 weeks of gestation, fetal ultrasound revealed ventriculomegaly and suspected partial agenesis of the corpus callosum. Genetic testing included karyotyping, chromosomal microarray analysis (CMA), and trio-based whole exome sequencing (WES).

Results: Karyotype and CMA were normal. WES identified a de novo heterozygous missense variant in PPP2R1A, NM_014225.6: c.548G>A (p.R183Q), classified as pathogenic. Following genetic counseling, the couple elected to terminate the pregnancy. Integrating our findings with 12 previously reported prenatal cases, we conducted a systematic review of fetal phenotypes associated with PPP2R1A variants. The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%).

Conclusion: We present the most comprehensive synthesis to date of prenatal phenotypes associated with PPP2R1A-related neurodevelopmental disorders. These findings provide crucial insights into the prenatal spectrum of HJS2 and highlight key sonographic indicators to support early diagnosis and genetic counseling.

Background: Distal arthrogryposis with impaired proprioception and touch (DAIPT) is a rare autosomal recessive neurological disease characterized by progressive alteration of mechanosensation. DAIPT is caused by loss of function variants in the PIEZO2 gene that encodes an ionic channel involved in mechanotransduction signaling. Our study started from the case of an 11-year-old boy with skeletal and neuromuscular features suggestive of DAIPT.

Methods: Exome sequencing was performed on the trio. The identified variants in PIEZO2 were validated by Sanger sequencing. Functional assays of the variants were performed by minigene assay in HEK-293 cells and on patient-derived cells using NMD inhibitors.

Results: Trio exome sequencing revealed the presence of two novel variants in the PIEZO2 gene: a nonsense variant (c.1924G>T; p.Glu642*) and an intronic variant of uncertain significance (c.2170-15A>G). Functional analysis demonstrated that the intronic variant disrupts splicing, leading to premature stop codon formation and possible mRNA targeting to nonsense-mediated mRNA decay (NMD). Molecular study in patient-derived fibroblasts with specific NMD inhibitors shows that transcripts derived from both alleles are degraded by NMD, thus confirming the effect of the nonsense variant and enabling reclassification of the VUS.

Conclusion: We present the phenotypic and genetic description of a patient with features suggestive of DAIPT carrying novel biallelic variants in PIEZO2, one of which could be reclassified as pathogenic after functional assays. This study also provides a detailed review of all the published patients with DAIPT and expands the phenotypic and genetic understanding of DAIPT, aiding in diagnosis, genetic counseling, and clinical management.

Background: Latest research on ankylosing spondylitis (AS) indicates a link between the B3GNT2, PSMG1 genes and susceptibility to AS among western populations. However, the association of these three genes with AS in eastern populations remains insufficiently explored. It is necessary to replicate these studies in other populations. Consequently, we chose tagSNPs in these three genes in the Chinese Han population to be sequenced.

Purpose: We tried to find the SNP loci that are associated in both eastern and western populations through repeated experiments. Furthermore, our research extended to examining the link between these genes and the severity of AS. This study aimed to evaluate the association between the tagSNPs of B3GNT2 (rs10865331, rs6545925, rs467250), the rs4676410 SNP on GPR35, and the rs4816648 SNP of PSMG1 with AS susceptibility and disease activity in a Chinese Han population.

Method: We collected blood samples from 497 patients with AS and 498 control subjects and sequenced 5 tagSNPs in B3GNT2, 1 tagSNP in GPR35, and 6 tagSNPs in PSMG1.

Result: Within the five selected tagSNPs of B3GNT2, the rs10865331, rs6545925, and rs4672501 tagSNPs are associated with susceptibility to AS. Additionally, the rs4672501 SNP is not only associated with susceptibility to AS, but also with the severity of AS. For the first time, we find that the rs4676410 SNP on the GPR35 gene is associated with susceptibility to AS, but not associated with the severity of AS in the Chinese Han population. We find for the first time that the rs4816648 SNP of the PSMG1 gene is associated with both susceptibility and severity of ankylosing spondylitis.

Conclusion: B3GNT2 and PSMG1 genes are related to both susceptibility and severity of AS. The GPR35 gene is related to susceptibility to AS in the Chinese Han population, which corroborates the findings of research conducted in western populations.

Pediatric cardiomyopathies are rare, heterogeneous, and challenging conditions, often with a genetic etiology. We estimated the yield of genetic testing in a pediatric cohort with cardiomyopathies and evaluated the potential candidacy to current or emerging treatments based on genetic results. Over one-third had a conclusive genetic test, including 25% of potential candidates for emerging precision therapies or developing pharmacological options.