Molecular Genetics & Genomic Medicine最新文献

Background: Developmental dysplasia of the hip (DDH) is a prevalent congenital musculoskeletal disorder characterized by structural abnormalities of the hip joint. While its etiology involves genetic and environmental factors, specific genetic mechanisms remain poorly understood. Mutations in the COMP gene (COMP; OMIM: 600310), classically associated with skeletal dysplasias such as pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), are rarely linked to isolated DDH.

Methods: A 29-year-old male proband with familial DDH underwent clinical evaluation and radiographic imaging. Whole-exome sequencing (WES) was performed on the proband and his parents, followed by Sanger sequencing to validate variants in affected family members. Pathogenicity was assessed using ACMG guidelines, incorporating population frequency, conservation scores (e.g., REVEL), and clinical correlation.

Results: WES identified a heterozygous missense variant (COMP c.1133A>C, p.D378A) in exon 10, co-segregating with the DDH phenotype across three generations. Radiographic and clinical findings excluded PSACH and MED. Functional predictions (REVEL score: 0.84) and absence in population databases supported its classification as "likely pathogenic." Additional susceptibility genes (e.g., GDF5, OMIM: 601146; TBX4, OMIM: 601719) were detected but did not explain the familial pattern.

Conclusions: The heterozygous COMP c.1133A>C variant may be a highly penetrant pathogenic contributor to familial DDH in this pedigree, suggesting autosomal dominant inheritance. This finding suggests that COMP mutations might extend beyond classical skeletal dysplasias to significantly increase DDH risk, likely interacting with other genetic or environmental factors in line with the multifactorial etiology of DDH.

Background: Developmental and epileptic encephalopathies (DEEs) comprise a diverse range of disorders that can arise from both genetic and non-genetic causes. Genetic DEEs are linked to pathogenic variants in various genes with different molecular functions. The wide clinical and genetic variability found in DEEs poses a considerable challenge for accurate diagnosis even with the use of comprehensive diagnostic approaches such as whole genome sequencing (WGS).

Case presentation: In this study, we describe a girl with a clinical presentation of DEE. Using WGS, we identified several candidate variants in the HNRNPU, NIPBL, and KANSL1 genes with partial overlap with the patient's clinical presentation. Subsequent analysis revealed that only the variant in the HNRNPU gene arose de novo, while the others were inherited from unaffected parents. The variant in HNRNPU was determined to be causative. However, the previously reported pathogenic loss-of-function (LoF) variant in KANSL1, inherited from a healthy mother, complicated the interpretation of the results. A thorough investigation using RNA analysis showed that the variant in the KANSL1 gene is located in a duplicated locus, which does not produce a functional protein, explaining the lack of the variant's contribution to the development of the pathological phenotype.

Conclusions: This case illustrates the importance of integrating WGS with additional analyses to accurately diagnose and understand the molecular basis of the lack of influence of the LoF variant in KANSL1 on the patient's phenotype.

Background: Heterozygous TP63 mutations cause a spectrum of disorders including split-hand/foot malformation 4 (SHFM4) and ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome 3 (EEC3). While some SHFM4 mutations concurrently induce EEC3-like phenotypes (designated SHFM4/EEC3 mutations), their prevalence and distribution-particularly those near the p63 C-terminus-remain poorly characterized.

Method: A multigenerational Chinese family with an isolated form of SHFM was investigated. Genetic analysis included real-time quantitative PCR and Sanger sequencing. Disease mutation databases and literature were systematically reviewed to identify all reported TP63 mutations causing isolated SHFM4 and to classify these mutations by clinical phenotypes.

Results: We identified a novel likely pathogenic variant (NM_003722.5: c.2032G>C, p.E678Q) within a sumoylation motif near the C-terminus of p63. Analysis of 72 families (182 carriers) revealed 28 SHFM4-causing TP63 mutations, comprising 12 dual-phenotype SHFM4/EEC3 mutations and 16 isolated SHFM4-only mutations. Certain clinical traits of SHFM4 mutations and distribution characteristics for SHFM4-only mutations were observed.

Conclusions: This study expands the SHFM4 mutation spectrum, demonstrating significant overlap between SHFM4 mutations and EEC3 mutations. The p.E678Q represents the most reliable SHFM4-only mutation near the protein C-terminus. These findings will improve molecular classification and genetic counseling for TP63-related disorders.

Background: Waardenburg syndrome is a genetic disorder characterized by sensorineural hearing loss and abnormal pigmentation. This study aims to explore the pathogenic variant in a large Waardenburg syndrome family and provide a theoretical basis for prenatal diagnosis of related family members.

Methods: The clinical phenotype of the family members was analyzed. DNA was extracted from collected peripheral blood samples, and then exome sequencing and Sanger sequencing were performed. The pathogenicity of the genetic variant was evaluated by bioinformatics analysis. Amniocentesis was performed on the proband's mother (III13) to collect amniotic fluid samples for prenatal diagnosis.

Results: There were 13 patients in the family. Most of the patients presented with deafness and abnormal pigmentation of hair or eyes, which was consistent with the diagnosis of Waardenburg syndrome type 2. Exome sequencing revealed a heterozygous variant of the SOX10 gene (NM_006941.4: c.386T>C (p.Leu129Pro)) in the proband. Sanger sequencing showed that the variant co-segregated with the disorder in this family. This variant has not been previously reported in relevant databases. The site p.Leu129 was highly conserved among various species and was important for protein structure and function.

Conclusion: In this study, we reported a family with autosomal dominant Waardenburg syndrome type 2 and identified a heterozygous variant of the SOX10 gene by exome sequencing. In addition, prenatal diagnosis and genetic counseling were provided to the family related individual.

Background: Inherited eye disorders are a significant cause of vision loss worldwide. According to the World Health Organization (WHO) estimates approximately 2.2 billion people have some degree of vision loss, but a significant proportion of these are blind since early childhood. Due to poor infrastructure for genetic diagnosis, many affected families remain genetically unexplained in underdeveloped countries, including Pakistan.

Methods: In this study, we utilized homozygosity mapping and exome sequencing to identify the genetic basis of the vision loss in four Kashmiri families that were presented with different types of eye disorders. We also performed quantitative reverse transcriptase-PCR (qRT-PCR) and measured the relative mRNA abundance of ALMS1 in blood cells of patients, carrier parents, and a healthy control.

Results: Genetic analysis identified a novel homozygous 4 base pair frameshift deletion c.5747_5750del; p.(Ala1916Glufs*21) in ALMS1 in a family affected with Alstrom syndrome (AS), and already known variants were identified (CNGA3; c.1315C>T; p.(Arg439Trp) and FYCO1; c.2206C>T; p.(Gln736*) and c.3150 + 1G>T; p.(?)) in the remaining three families. The variant identified in the ALMS1 gene is predicted to activate nonsense mediated mRNA decay (NMD). Comparison of relative mRNA abundance of ALMS1 in patient-specific cells harboring c.5747_5750del negates the NMD activation. The results indicated the absence of NMD in patient-derived cells and therefore support the formation of a truncated ALMS1 protein in the patients with the c.5747_5750del variant.

Conclusions: We expanded the mutation spectrum of ALMS1 but identified known variants in FYCO1 and CNGA3 genes. We also compiled the currently known mutations in these genes to establish genotype-phenotype correlation.

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.