Molecular Genetics & Genomic Medicine最新文献

Background: LINS1, the human homolog of the Drosophila segment polarity gene, encodes a key regulator of the Wingless/Wnt signaling pathway. While numerous genes have been implicated in intellectual disability (ID), only a limited number have been conclusively associated with autosomal recessive intellectual disability (ARID). Variants in LINS1 have been identified as one such cause.

Methods: In this study, we employed exome sequencing (ES) to investigate the genetic basis of ID in two consanguineous Iranian families. This variant was confirmed by Sanger sequencing, and segregation analysis supported its pathogenicity. Additionally, in silico analyses were conducted to explore the protein-protein interaction network of LINS1 and its functional connections to ID-associated proteins.

Results: We identified a novel homozygous missense variant in LINS1 (c.1354G>C), leading to an alanine-to-proline substitution (p.Ala452Pro) in exon six.

Conclusion: Our findings provide new molecular and clinical insights into the role of LINS1 in ARID, expanding the genetic landscape of ID. This discovery has significant implications for genetic counseling and prenatal diagnosis, aiding in the identification of at-risk couples.

Background: Li Fraumeni syndrome (LFS) is a hereditary multi-cancer syndrome caused by alterations in TP53 (MIM# 151623). Next generation sequencing (NGS) allows for the detection of TP53 variants at lower variant allele frequencies (VAFs). A TP53 variant with a VAF < 50% may represent mosaic LFS, aberrant clonal expansion (ACE), or possible circulating tumor DNA. Differentiation among these conditions is important for optimal patient management.

Methods: Genetic testing was performed using a custom gene panel, with an average read depth of 350× (range 166-553×). DNA extracted from four different tissues (blood, saliva, cultured skin fibroblasts, and colon) was sequenced.

Results: Here, we describe an adult female patient with a history of an adrenocortical neoplasm and osteosarcoma, diagnosed at 2 and 16 years of age, respectively. Testing of peripheral blood identified a pathogenic TP53 variant, c.733G>A, p.(Gly245Ser) (NM_000546.6); however, subsequent in vitro fertilization with preimplantation genetic testing for monogenic disorders (PGT-M) did not identify this TP53 variant in any of nine embryos tested. Testing for possible mosaicism in the proband was performed on four different specimens, revealing variable VAFs of the TP53 variant (saliva: 44%; blood: 31%; cultured skin fibroblasts: 18%; and colon tissue: 9%). These results suggest a post-zygotic event, consistent with mosaic LFS rather than ACE.

Conclusion: This case highlights the complexity of interpreting mosaic variants in the TP53 gene, and we propose a testing algorithm to aid in the delineation of this phenomenon when relaying cancer and reproductive risk information in the context of mosaicism.

Background: Familial premature coronary artery disease (CAD) is often associated with genetic variants. This study investigated potential causal variants in a Chinese pedigree with premature CAD.

Methods: In total, nine family members were included in the study (six CAD patients and three unaffected controls). Whole-exome sequencing (WES) was performed on six family members (including four patients and two unaffected controls), and the candidate variant was further validated by Sanger sequencing in four individuals.

Results: A strong linkage between c.6406C>G (p.Gln2136Glu; NM_005751.5) in AKAP9 (A-KINASE ANCHOR PROTEIN 9; OMIM 604001) and premature CAD was detected in the pedigree. Functional analysis revealed that the c.6406C>G variant in AKAP9 decreased the interaction between AKAP9 and PRKAR2A. This association was first detected in premature CAD patients.

Conclusions: Our findings indicate that c.6406C>G in the AKAP9 gene could be a causal variant for premature CAD in the Chinese population.

Background: DIAPH3 variants are associated with non-syndromic autosomal dominant auditory neuropathy 1 (AUNA1). To the best of our knowledge, there are no reports of DIAPH3 variants causing sensorineural hearing loss. Here, we present a family with late-onset sensorineural hearing loss as an autosomal dominant trait, caused by a novel DIAPH3 variant.

Methods: Audiological examinations were conducted on family members. Whole exome sequencing was performed on the proband to detect candidate genes, and Sanger sequencing was used for other available family members to confirm the causative variation.

Results: The DIAPH3 c.1472A>G variant was identified as a disease-causing mutation in a Chinese family with late-onset hearing loss. Clinically, manifestations were bilateral sensorineural hearing loss (with pure-tone thresholds broadly correlating with speech discrimination scores), abnormal auditory brainstem response (ABR), and absent distortion product otoacoustic emission (DPOAE), without abnormalities in other organs or systems.

Conclusions: We first identified the likely pathogenic variant DIAPH3 c.1472A>G in a Chinese family with non-syndromic genetic hearing loss. This point mutation of the DIAPH3 gene is associated with late-onset bilateral sensorineural hearing loss, distinguishing it from the auditory neuropathy previously reported in other studies. Our findings expand the phenotypic spectrum of DIAPH3-related disorders and underscore the importance of integrating genetic, electrophysiological, and molecular data to refine diagnostic and therapeutic strategies.

Background: Coffin-Siris syndrome (CSS) is a rare, clinically and genetically heterogeneous disorder characterized by coarse facial features, microcephaly, intellectual disability (ID), developmental delay (DD), and hypo/aplastic digital nails and phalanges, typically of the 5th digit. CSS is an autosomal dominant disease resulting from mutations in genes encoding components of BRG1/BRM-associated factor (BAF) chromatin remodeling complexes. More than 300 CSS patients have been reported with variants in genes in the BAF pathway. Recently, patients carrying SMARCC2 variants have been reported to be associated with CSS8. However, as the number of cases increases, many patients do not exhibit the representative clinical symptoms of CSS. Additional case reports and clinical studies will contribute to a redefinition of SMARCC2-related disorders.

Methods: In this research, three patients with SMARCC2-related disorders from China were recruited. Genomic DNA was extracted from the peripheral blood leukocytes of these patients' parents and other family members, and then subjected to whole-exome sequencing as well as Sanger sequencing.

Results: In the present study, two de novo variants (c.1311-3C>G, c.347G>A (p.Arg116His)) and a novel de novo variant (c.346C>T (p.Arg116Cys)) in the SMARCC2 gene were detected in three patients with neurodevelopmental disorders by whole exome sequencing. The clinical presentation of our patients supports a redefinition of SMARCC2-related diseases, which include mild to moderate DD, mild ID, facial dysmorphism, mild speech delay, hypotonia, feeding difficulties, brain abnormalities, attention deficit hyperactivity disorder (ADHD), and autistic behaviors. Furthermore, both the type of variant and its specific location may be contributing factors influencing the clinical outcomes.

Conclusion: Our study expands the genetic spectrum of SMARCC2 variants and detailed genotypic and phenotypic descriptions are important for the diagnosis of SMARCC2-related disease and accurate clinical management.

Background: Kallmann syndrome (KS) is a genetic disorder characterized by impaired reproductive system and olfactory development. This study aimed to identify a novel variant of SEMA3A in a KS patient and explore its potential pathogenic mechanism.

Methods: A gene panel was used to identify potential pathogenic mutations. Wild-type and mutant SEMA3A overexpression plasmids were constructed. Western blotting, RNA sequencing, and cell migration were performed to assess the effects of SEMA3A gene variations on GnRH neuronal migration.

Results: A novel heterozygous mutation in the SEMA3A gene (NM_006080.3: exon 6-9 deletion) was identified in the proband, as well as in his father and sister. The spatial structure of the SEMA3A mutant protein was relatively looser. In vitro experiments revealed that SEMA3A mutation reduced SEMA3A expression and inhibited GnRH neuronal migration. RNAseq analysis revealed that the expression of 76 genes was upregulated and that of 104 genes was downregulated after SEMA3A mutation. The altered gene clusters were enriched mainly in cell migration, male gonad development, motor proteins, and neuron synapses.

Conclusions: In this study, we identified a novel variant of SEMA3A in a KS patient and verified its function. These findings expand the mutation spectrum of the SEMA3A gene and offer a theoretical basis for the clinical diagnosis of KS.

Background: Hereditary breast and ovarian cancer syndrome (HBOC) is the most common cause of hereditary breast and ovarian cancers in Qatar and worldwide, which is caused by pathogenic variants in the BRCA1 and BRCA2 genes. The aim of this retrospective study is to describe a common recurrent pathogenic variant in the BRCA1 gene that was observed in the native Qatari population with unique genotype-phenotype correlations.

Methods: Medical records of Qatari patients (affected and unaffected) with personal and/or family history of breast and ovarian cancers who carry pathogenic/likely pathogenic variants in the BRCA1 gene were reviewed between 2013 and 2020. Epidemiological information and clinical data were reviewed, including age, gender, ethnic background, personal history of cancer, tumour characteristics, and family history. We used frequencies and proportions to describe the data and used Kaplan-Meier curves and log-rank analysis to compare survival rates. For the analysis, we used Stata Corp. 2015. Stata Statistical Software: Release 14, College Station, TX: Stata Corp. LP.

Ethical compliance: Ethical committee approval was obtained from Hamad Medical Corporation IRB committee (MRC-01-20-1086).

Result: Sixty-three Qatari affected patients and unaffected individuals who carry the BRCA1 variant were included in the study. Our result confirms the presence of a common recurrent pathogenic variant c.4787C>A p.(Ser1596Ter) among Qatari patients who belong to 8 consanguineous large families, followed by c.4065_4068del p.Asn1355fs, both in BRCA1. The BRCA1 c.4787C>A variant is highly associated with early onset breast cancer, specifically invasive ductal carcinoma (IDC) triple negative breast cancer (stage I, grade III), rather than ovarian cancer. Additionally, the c.4787C>A variant was found to exhibit high penetrance in families with early-onset breast cancer.

Conclusion: We showed that BRCA1 c.4787C>A pathogenic variant is a highly recurrent variant among Qatari consanguineous families and contributes to the early onset breast cancer in Qatar. Early identification of this variant can aid in improving patients' survival and guide early personalized treatment and prevention.

Background: Pathogenic variants of IBA57 (OMIM ID: 615330) are usually associated with multiple mitochondrial dysfunction syndrome (MMDS) and hereditary spastic paraplegia type 74 (SPG74). Here, we present a novel compound heterozygous IBA57 mutation in a boy with severe global developmental delay, optic atrophy, spastic paraplegia, and focal epileptic seizures.

Methods: The clinical data of a child diagnosed with MMDS were retrospectively collected. Video electroencephalogram (VEEG), cranial magnetic resonance imaging (MRI), and family whole-exome sequencing (WES) were performed. Suspected mutation sites were further confirmed using Sanger sequencing. The activities of mitochondrial respiratory chain complexes I-IV were determined in peripheral blood mononuclear cells. The phylogenetic conservation of the affected residues was assessed by multiple sequence alignment of IBA57 gene orthologs. Furthermore, we conducted a review of the relevant literature.

Results: Whole-exome sequencing identified compound heterozygous variants in the IBA57 gene: c.395_400dup (p.V132_Q133dup) and c.832delC (p.R278Afs*23), inherited from his phenotypically normal father and mother, respectively. Biochemical assays demonstrated selective reduction of complexes I and II activities, with normal complexes III and IV, consistent with impaired 4Fe-4S cluster maturation. Phylogenetic alignment revealed strict conservation of residues V132-Q133 and R278 across vertebrates. These variants had not been previously reported in domestic or international databases. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the former was classified as a variant of uncertain significance (PM4 + PM2), while the latter was classified as likely pathogenic (PVS1 + PM2).

Conclusion: Diseases associated with IBA57 gene variants are autosomal recessive disorders with a broad clinical phenotypic spectrum. Early genetic testing and family screening are beneficial for the diagnosis, treatment, and prognosis of the disease.

Background: Klinefelter Syndrome (KS) and Turner Syndrome (TS) are the two most common sex chromosome aneuploidies (SCAs). This study aims to investigate genotype-phenotype correlations of SCAs including classic, rare variants, and mosaic cases of KS and TS.

Methods: To understand the relationship between genotype and phenotype (i.e., clinical findings) in SCAs, retrospective cytogenetic and clinical data was collected for KS (n = 57) and TS (n = 92) cases from 2013 to 2022. The cohorts of KS and TS were divided into three subcategories (classic, mosaic, variant/other) based on the genotype.

Results: The other supernumerary SCA (sSCA) group within the KS cohort had a significantly higher rate of developmental delay when compared to other KS groups. Although tall stature, pubertal delay, and congenital heart defects were described in the KS classic and other sSCA cohorts, these phenotypes were not seen in KS mosaics. Within the TS variant cohort, phenotype severity (i.e., number of accumulated pathologic clinical findings) was related to the complexity of the structural abnormality of X chromosomes.

Conclusion: Our study highlights that the SCA genotype (classic, mosaic, variant/other) modulates expression of the phenotype. Analysis of larger datasets may provide a deeper understanding leading to enhanced care management and improved patient outcomes.

Introduction: Whole-exome sequencing (WES) is considered an important tool in investigating the etiology of developmental delay/intellectual disability (DD/ID) and epilepsy. Genetic diagnosis with WES has become an important tool in patients with DD/ID and epilepsy.

Methods: In this study, we present the findings of WES conducted between August 2021 and December 2024 on children with DD/ID and epilepsy. We evaluated clinically important variants identified by WES in 65 pediatric patients by retrospective analysis.

Results: Sixty-five patients with DD/ID were included in the study, 34 of whom (52.3%) were male. The most common symptom was epilepsy (45 patients, 69.2%), and the second most common symptom was DD/ID in 39 patients (60%). A total of 19 pathogenic/likely pathogenic variants (31.2%) with confirmation made in the parents and probands, 9 variants were determined to be de novo. In this study, the number of patients diagnosed was determined as 19 (31.2%). We detected a de novo likely pathogenic heterozygous c.142 T>C (p.Cys48Arg) variant in the BCL11A gene in the first reported Turkish patient with BCL11A-related intellectual disability. Other previously unreported de novo variants identified: ASXL3 gene, NM_030632.2 c.3613G>T p.(Glu1205Ter), ANKRD11 gene, NM_001256182.2 c.4750G>T, SHANK3 gene, NM_001372044.2 c.4711_4712del.

Conclusion: The cases we present contribute to the expansion of the spectrum of genetic variants in genetically heterogeneous patient groups such as DD/ID and epilepsy. These previously unreported variants advance our molecular understanding and broaden the clinical spectrum of these rare genetic disorders.