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PubMed2024

Identification of four TTN variants in three families with fetal akinesia deformation sequence.

BACKGROUND: TTN is a complex gene with large genomic size and highly repetitive structure. Pathogenic variants in TTN have been reported to cause a range of skeletal muscle and cardiac disorders. Homozygous or compound heterozygous mutations tend to cause a wide spectrum of phenotypes with congenital or childhood onset. The onset and severity of the features were considered to be correlated with the types and location of the TTN variants. METHODS: Whole-exome sequencing was performed on three unrelated families presenting with fetal akinesia deformation sequence (FADS), mainly characterized by reduced fetal movements and limb contractures. Sanger sequencing was performed to confirm the variants. RT-PCR analysis was performed. RESULTS: TTN c.38,876-2 A > C, a meta transcript-only variant, with a second pathogenic or likely pathogenic variant in trans, was observed in five affected fetuses from the three families. Sanger sequencing showed that all the fetal variants were inherited from the parents. RT-PCR analysis showed two kinds of abnormal splicing, including intron 199 extension and skipping of 8 bases. CONCLUSIONS: Here we report on three unrelated families presenting with FADS caused by four TTN variants. In addition, our study demonstrates that pathogenic meta transcript-only TTN variant can lead to defects which is recognizable prenatally in a recessive manner.

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PubMed2025

Genetic insight into lung neuroendocrine tumors: Notch and Wnt signaling pathways as potential targets.

BACKGROUND: The molecular landscape of lung neuroendocrine neoplasms is still poorly characterized, making it difficult to develop a molecular classification and personalized therapeutic approaches. Significant clinical heterogeneity of these malignancies has been highlighted among poorly differentiated histotypes and within the subgroup of well-differentiated neuroendocrine tumors (NET). Currently, the main prognostic factors of lung NET include stage, histotype, grade, peripheral location, and demographic parameters. To gain deeper insights into the genomic underpinnings of lung NETs, we conducted a pilot investigation to uncover potential genetic mutations and copy number variations (CNVs) implicated in their pathogenesis. METHODS: Formalin-fixed, paraffin-embedded intraoperative tumor biopsies and matched peripheral blood mononuclear cell samples were collected from six consecutive patients with lung NETs. The whole exome sequencing (WES) was performed to profile germline and somatic mutations, identify novel genetic alterations, and detect CNVs. Clinical and pathological data were systematically documented at diagnosis and during follow-up. RESULTS: The WES analysis identified a subset of mutations shared between germline and somatic; some were of particular clinical interest as they were associated with tumor proliferation and potential therapeutic targets such as the genes KDM5C, ATR, COL7A1, NOTCH4, PTPRS, SMO, SPEN, SPTA1, TAF1. These mutations were predominantly linked to chromatin remodeling and were involved in critical oncogenic pathways such as Notch and Wnt signaling. CONCLUSIONS: This pilot study highlights the potential role of NGS analysis on solid biopsy in the assessment of the mutational profile of lung NET. A comparison of germline and somatic mutations is critical to identifying putative tumor driver mutations. In perspective, the enrichment of a subpopulation of cancer cells in the blood, with one or more specific mutations, is information of enormous clinical relevance, either for prognosis or therapeutic decisions. Translational studies on large prospective series are required to establish the role of liquid biopsy in lung NET.

Humans↗

PubMed2025

Exploring the c.406 C > T variant in TNNI3 gene: pathogenic insights into restrictive cardiomyopathy.

BACKGROUND: Restrictive cardiomyopathy (RCM) is a rare cardiac disorder characterized by diastolic dysfunction and myocardial stiffness, frequently associated with genetic variants. We aimed to explore the genetic basis of RCM in a diagnosed patient through comprehensive genetic analysis. METHODS: Whole exome sequencing (WES) was conducted on the proband, followed by Sanger sequencing for variant confirmation and familial segregation analysis. In silico tools and structural protein modeling were employed to assess the functional impact of the identified variant. RESULTS: The c.406 C > T variant, classified as likely pathogenic, results in a truncated TNNI3 protein. Bioinformatics analysis highlighted significant structural disruptions, likely impairing sarcomere function. The patient presented with growth retardation, progressive dyspnea, and echocardiographic findings consistent with RCM. Both parents were heterozygous carriers, supporting an autosomal recessive inheritance pattern. The homozygosity of the novel variant identified in this study is a critical factor in the genotype-phenotype correlation observed in this case. CONCLUSION: This study identified the novel c.406 C > T variant in TNNI3 as a potential pathogenic driver of RCM, emphasizing the critical role of genetic evaluations in early diagnosis and management of inherited cardiomyopathies. Further studies are warranted to explore therapeutic interventions targeting TNNI3-related pathologies.

Humans↗

PubMed2026

A novel variant combination in COASY associates with severe prenatal onset PCH12: expanding the clinical and genetic spectrum.

Pontocerebellar hypoplasia type 12 (PCH12) is an ultra-rare, perinatal lethal, neurodegenerative disorder with microcephaly and arthrogryposis. Previous reports have associated PCH12 with complete loss-of-function variants in COASY identified in 14 fetuses and newborns from eight unrelated families. In contrast, COASY partial loss-of-function variants have been linked to COASY protein-associated neurodegeneration (CoPAN), a subtype of neurodegeneration with brain iron accumulation (NBIA). Emerging evidence suggests that COASY-related disorders may represent a phenotypic continuum between PCH12 and CoPAN. Using exome sequencing, we identified a previously reported missense variant (c.641C>T, p.Ala214Val) as well as a previously unreported rare nonsense variant (c.1015C>T, p.Arg339*) in a compound heterozygous state in the COASY gene in a patient presenting with clinical features consistent with PCH12. The p.Ala214Val variant has only been described in combination with another missense variant (p.Arg499Cys) in two siblings with CoPAN. The presence of p.Ala214Val in trans with the truncating p.Arg339* variant in this patient is associated with a severe perinatal lethal phenotype resembling PCH12. This case broadens the reported genetic and phenotypic spectrum of COASY-associated disorders and highlights the importance of continued genotype-phenotype correlation investigation.

Humans↗

PubMed2025

Genetic analysis of four cases of Poirier Bienvenu neurodevelopmental syndrome associated with CSNK2B variant.

BACKGROUND: CSNK2B deficiency underlies the pathogenesis of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS). In this study, we present four cases of pediatric seizures caused by de novo variants in CSNK2B, with the aim to reinforce the clinical and variant data pertaining to early genetic factors associated with epilepsy. METHODS: Trio whole exome sequencing were used to detect variants in the proband and her family members, and bioinformatics annotation was performed for the variant. Sanger sequencing and CSNK2B cDNA sequencing were employed to ascertain the carrier status of additional family members and evaluate the potential impact of variants on splicing. RESULTS: All four cases presented with epilepsy as the initial manifestation, accompanied by global developmental delay, particularly in language and motor developmental delay. Cases 1, 3 and 4 exhibited full-scale tonic-clonic seizures, while case 2 displayed myoclonic and typical absence seizures. Furthermore, case 2 demonstrated delayed growth and development compared to age-matched peers. No abnormality was detected in the head magnetic resonance imaging (MRI). Genetic analysis revealed novel heterozygous variants in the CSNK2B gene in all four cases, including c.175 + 1G > A, c.73-2A > G, c.291 + 1G > A and c.481delA. In case 2, reverse transcription analysis of CSNK2B mRNA revealed the retention of the 3' end sequence of Intron 2 and deletion of the 5' end sequence of Exon 3. In treatment, four case received a combination of one to three types of antiseizure medication and rehabilitation training individually. Case 1 continued to experience seizures to varying degrees, while cases 2-4 demonstrated effective seizure control. Overall motor and intellectual development improved in all four cases, however, there was slow recovery in language function. CONCLUSION: This study elucidates the molecular etiology of epilepsy in four cases with POBINDS and expands the mutational spectrum of pathogenic variants in the CSNK2B, highlighting their impact on splicing. The highly genetic heterogeneous phenotype of POBINDS relies on the detection of pathogenic variants in CSNK2B. Conventional antiseizure medication effectively control seizures, while rehabilitation treatment can significantly improve intelligence and motor function to varying degrees; however, language recovery tends to be relatively slow.

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PubMed2023

Structural and functional insights into a novel homozygous missense pathogenic variant in CUL7 identified in consanguineous Pakistani family.

3M syndrome is a rare genetic familial disorder characterized by short stature, growth retardation, facial dysmorphism, skeletal abnormalities, fleshy protruding heels, and normal intelligence, caused by mutations in the CUL7, OBSL1 and CCDC8 genes. In the present study, a novel homozygous missense variant of CUL7 (NP_001161842.1, c.4493T > C, p.L1498P) has been identified in a consanguineous Pakistani family by whole exome sequencing. In silico structural evaluation, molecular docking and simulation studies of mutant CUL7 provides substantial evidence about its crucial role in the progression of discussed ailment. The newly discovered variant significantly altered the protein's three dimensional structure, leading to abnormal interaction with binding proteins. This computational and experimental investigation provides useful information to drug developers for the synthesis of novel therapeutics against the discussed ailment.Communicated by Ramaswamy H. Sarma.

Humans↗

PubMed2026

Clinical and molecular characterization of TCF12 variants in an Asian pediatric cohort with craniosynostosis.

BACKGROUND: Craniosynostosis is a genetically heterogeneous craniofacial disorder caused by the premature fusion of one or more cranial sutures. Pathogenic variants in TCF12, encoding a basic helix-loop-helix (bHLH) transcription factor, represent a major cause of autosomal dominant coronal craniosynostosis and are characterized by incomplete penetrance and marked phenotypic variability. However, clinical and molecular data from Asian pediatric populations remain limited. METHODS: Trio-based whole-exome sequencing was performed on ten pediatric patients with cranial deformities and their parents. The identified TCF12 variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and validated by Sanger sequencing. Detailed clinical and radiological data were collected. In addition, a comprehensive literature review was conducted to summarize previously reported TCF12 variants and associated phenotypes. RESULTS: Ten distinct heterozygous TCF12 variants were identified in ten unrelated pediatric patients, all of which were classified as pathogenic or likely pathogenic according to ACMG criteria. Six variants were inherited, and four occurred de novo. Seven patients had imaging-confirmed craniosynostosis, predominantly involving the coronal sutures (five bilateral and one unilateral), while one patient presented with multisuture craniosynostosis (left coronal and sagittal sutures). Three patients showed cranial deformities without radiographic evidence of suture fusion. Phenotypic heterogeneity and incomplete penetrance were observed, including a mildly affected parent. Most pathogenic variants were truncating variants distributed mainly across exons 14-19 and predicted to induce loss of function, either through nonsense-mediated mRNA decay or the production of truncated proteins lacking the entire C-terminal bHLH domain. Structural modeling analysis further indicated that the bHLH-domain-located missense variant p.Arg603Trp alters the local DNA-binding conformation of TCF12 and impairs its binding affinity to the E-box DNA motif. CONCLUSIONS: This study provides additional clinical and molecular data on TCF12-related craniosynostosis in a pediatric cohort from an Asian population. Our findings support haploinsufficiency as the central pathogenic mechanism, primarily driven by truncating variants affecting the C-terminal bHLH domain. The marked clinical heterogeneity, the presence of mild or evolving phenotypes, and incomplete penetrance observed in our cohort underscore the importance of early diagnosis and longitudinal clinical surveillance in affected families.

Humans↗

PubMed2024

THBS1 is a new autosomal recessive non-syndromic hearing impairment gene.

BACKGROUND: Prelingual hearing impairment (HI) is genetically highly heterogenous. Early diagnosis and intervention are essential for psychosocial development. In this study we investigated a consanguineous family from Pakistan with autosomal recessive (AR) non-syndromic sensorineural HI (NSHI). METHODS: A DNA sample from an HI member of a consanguineous Pakistani family segregating ARNSHL underwent exome sequencing. Using Sanger sequencing select variants were validated and tested for segregation using DNA samples from additional family members. We further investigated RNA expression data for the candidate gene in mouse and human inner ear and human inner ear organoids using data obtained from the gene Expression Analysis Resource. RESULTS: We identified thrombospondin 1 (THBS1) as a new NSHI gene. A homozygous frameshift variant [c.1470del: p.(Ile491Serfs*45)] was observed in the three hearing-impaired and in the heterozygous state in three unaffected family members. Unlike for most ARNSHI, hearing-impaired individuals had audiograms with a sloping pattern, showing more pronounced HI in the mid and high frequencies (ranging from moderate to profound) compared to the low frequencies. RNA expression data indicates THBS1 is expressed during human inner ear development. Additionally, THBS1 is expressed in the cochlear epithelium and supporting cells of the mouse inner ear during embryonic and postnatal stages. Previously, THBS1 was demonstrated to affect hearing in knockout mice by influencing the formation and function of afferent synapses in the inner ear. CONCLUSIONS: Our findings highlight THBS1 as a potential novel candidate gene for human HI characterized by a sloping high-frequency audio profile. This discovery enhances our understanding of the genetic etiology of HI and will aid in advancing molecular diagnosis.

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PubMed2026

Successful Live Birth Following Treatment of Persistent Endometrial Dysbiosis and Recurrent Chronic Endometritis: A Case Report.

CASE: To study the cause of recurrent endometritis, which recurred after standard antibiotic therapy, we report the case of a 40-year-old woman with a history of recurrent pregnancy, preterm birth, and CE. The endometritis recurred following a standard antibiotic regimen. OUTCOME: Microbiome analysis via 16S rRNA gene sequencing revealed persistent dysbiosis in both vaginal and endometrial samples despite antibiotic regimens. Whole-exome sequencing (WES) identified rare variants in TRPV3 and CD36, potentially associated with epithelial barrier dysfunction. Following an extended course of antibiotic therapy, the woman gave birth to a healthy baby at GA 32 weeks. CONCLUSIONS: This case highlights the possibility that barrier gene variants may be associated with persistent endometrial dysbiosis and recurrence of CE. An intensive antibiotic regimen may help achieve a viable pregnancy in patients with recurrent CE following standard antibiotic therapy.

antibiotics↗

PubMed2024

The "genetic test request": A genomic stewardship intervention for inpatient exome and genome orders at a tertiary pediatric hospital.

PURPOSE: Exome sequencing (ES) and genome sequencing (GS) are useful tests to diagnose rare diseases in pediatric patients in critical care settings. Genomic test stewardship can increase the appropriate use of these tests leading to improved diagnostics and cost savings. METHODS: A mandatory review of ES and GS orders for admitted patients was implemented in March 2023. Outcomes of the reviews, cost analysis, and subsequent test results through February 2024 were analyzed with descriptive statistics. RESULTS: There were 444 genetic test request orders placed for 412 unique patients. Of these, 81 (18.2%) were redirected and 57 (12.8%) required modification after approval, leading to an overall cost savings of $345,821.00 or $778.88 per order. The combined diagnostic rate was 28.2% in this patient population. CONCLUSION: Stewardship of ES/GS orders for pediatric inpatients is an effective tool to improve the appropriate usage of these genomic tests. Additional collaboration with stakeholders and expansion of genomic stewardship initiatives may shorten the diagnostic odyssey for critically ill pediatric patients and result in cost savings.

Humans↗

PubMed2024

A novel start-loss mutation of the SLC29A3 gene in a consanguineous family with H syndrome: clinical characteristics, in silico analysis and literature review.

BACKGROUND: The SLC29A3 gene, which encodes a nucleoside transporter protein, is primarily located in intracellular membranes. The mutations in this gene can give rise to various clinical manifestations, including H syndrome, dysosteosclerosis, Faisalabad histiocytosis, and pigmented hypertrichosis with insulin-dependent diabetes. The aim of this study is to present two Iranian patients with H syndrome and to describe a novel start-loss mutation in SLC29A3 gene. METHODS: In this study, we employed whole-exome sequencing (WES) as a method to identify genetic variations that contribute to the development of H syndrome in a 16-year-old girl and her 8-year-old brother. These siblings were part of an Iranian family with consanguineous parents. To confirmed the pathogenicity of the identified variant, we utilized in-silico tools and cross-referenced various databases to confirm its novelty. Additionally, we conducted a co-segregation study and verified the presence of the variant in the parents of the affected patients through Sanger sequencing. RESULTS: In our study, we identified a novel start-loss mutation (c.2T > A, p.Met1Lys) in the SLC29A3 gene, which was found in both of two patients. Co-segregation analysis using Sanger sequencing confirmed that this variant was inherited from the parents. To evaluate the potential pathogenicity and novelty of this mutation, we consulted various databases. Additionally, we employed bioinformatics tools to predict the three-dimensional structure of the mutant SLC29A3 protein. These analyses were conducted with the aim of providing valuable insights into the functional implications of the identified mutation on the structure and function of the SLC29A3 protein. CONCLUSION: Our study contributes to the expanding body of evidence supporting the association between mutations in the SLC29A3 gene and H syndrome. The molecular analysis of diseases related to SLC29A3 is crucial in understanding the range of variability and raising awareness of H syndrome, with the ultimate goal of facilitating early diagnosis and appropriate treatment. The discovery of this novel biallelic variant in the probands further underscores the significance of utilizing genetic testing approaches, such as WES, as dependable diagnostic tools for individuals with this particular condition.

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PubMed2025

Discovery of a MET -driven monogenic cause of steatotic liver disease.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease affects about a third of adults worldwide and is projected soon to be the leading cause of liver cirrhosis. It occurs when fat accumulates in hepatocytes and can progress to metabolic dysfunction-associated steatohepatitis, liver cirrhosis, and HCC. Metabolic dysfunction-associated steatotic liver disease pathogenesis is believed to involve a combination of genetic and environmental risk factors. Single nucleotide polymorphisms have been implicated, but non-syndromic monogenic causes are lacking. APPROACH AND RESULTS: We identified a novel genetic variant in a familial case of metabolic dysfunction-associated steatohepatitis and performed deep variant functional analysis, including protein modeling, dynamics, and cell-based assays to assess molecular mechanisms of dysfunction and altered cellular signaling. We analyzed exome sequencing data of 3904 individuals with steatotic liver disease (SLD) to identify additional cases and establish the link between specific gene variants and SLD diagnosis. We discovered and functionally validated the NM_000245.4:c.3505A>T; p.(Ile1169Phe) variant in the MET (mesenchymal-epithelial transition) kinase domain as a monogenic cause of SLD. Subsequently, we detected additional ultra-rare, previously uninterpreted, and likely deleterious variants in MET from screening sequencing data. Among individuals with confirmed SLD based on electronic record review, 1.1% (45/3904) had rare predicted deleterious MET variants. Eight of 45 (17.7%) individuals had predicted deleterious variants in the MET kinase domain confirmed to be functionally like the familial case variant. CONCLUSIONS: We report the first germline nonmalignant rare MET -driven disease, a monogenic form of SLD.

Adult↗

PubMed2026

Identification of a Novel Splice-Site variant in TACR3 (c.888 + 1G > A) Associated with Asthenozoospermia and Hypogonadotropic Hypogonadism in an Iranian Family.

BACKGROUND: TACR3 encodes the receptor for neurokinin B, a key regulator of the hypothalamic-pituitary-gonadal axis. Disruption of this pathway can impair gonadotropin release and male reproductive function. Given the genetic heterogeneity of male infertility, this study aimed to identify novel variants in TACR3 that may underlie asthenozoospermia and related hormonal abnormalities. METHODS: Fifteen infertile men with confirmed asthenozoospermia were enrolled. Whole-exome sequencing (WES) was performed on genomic DNA from peripheral blood, and the candidate variant was validated by Sanger sequencing. Functional predictions were made using PolyPhen-2, SIFT, MutationTaster, and REVEL. TACR3 mRNA expression levels were assessed by real-time PCR in available samples. RESULTS: A novel splice-site variant, TACR3 (NM_001059.3:c.888 + 1G > A), was detected and found to segregate with infertility in one family, appearing homozygously in two infertile brothers and heterozygously in the proband with severe asthenozoospermia. The variant was absent in public and local genomic databases, suggesting its extremely rare frequency. Furthermore, RT-PCR showed a dramatic reduction or complete loss of TACR3 expression in affected individuals, confirming its deleterious effect on splicing and mRNA stability. CONCLUSION: We identified a previously unreported splice-site mutation in TACR3 (c.888 + 1G > A) that likely causes familial infertility by disrupting the neurokinin B/NK3R signaling pathway. While the heterozygous proband exhibited severe asthenozoospermia, the homozygous brothers displayed hormonal profiles typical of hypogonadotropic hypogonadism. These findings extend the mutational landscape of TACR3 and highlight its essential contribution to male reproductive endocrinology.

Humans↗

PubMed2025

Unraveling a novel FBN1 variant in Marfan syndrome with dilated aortic root manifestation.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, with variable incidence rates. A significant portion of cases stems from novel genetic variants, while others inherit it from affected parents. OBJECTIVE: This study focuses on identifying the genetic cause of MFS in a specific family, using whole-exome sequencing (WES). METHODS: A 15-year-old male with confirmed MFS was examined, showing symptoms of palpitations and severe mitral valve regurgitation. WES was performed, followed by confirmation with Sanger sequencing. Variants were assessed for pathogenicity using bioinformatics tools and the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: One potentially novel pathogenic variant was found in exon 14 of the FBN1 gene: c.1676delCinsAAT, p.Ala559GlufsTer21. In silico analysis suggested a deleterious impact on protein structure and function, supporting their pathogenic classification. CONCLUSION: The identification of this novel variant highlights the importance of the FBN1 gene in MFS, especially its cardiovascular manifestations. Early intervention can improve patient outcomes, while ongoing research holds promise for further advancements in treatment for Marfan syndrome.

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PubMed2024

A novel frameshift variant in the TMPRSS3 gene causes nonsyndromic hearing loss in a consanguineous family.

BACKGROUND: Hearing Loss (HL) is the most common sensorineural condition in humans. Mutations in the TMPRSS3 gene (DNFB8/10 locus) have been linked to autosomal recessive non-syndromic hearing loss (ARNSHL). METHODS: Whole-exome sequencing (WES) was utilized to identify disease-causing variants in a proband from Iran with ARNSHL who presented clinically with sensorineural, bilateral, and prelingual HL. The pathogenicity and novelty of the identified variant were assessed using various databases. A co-segregation study was also performed to confirm the presence of the variant in the proband's parents. Additionally, the secondary and tertiary structures of the mutant TMPRSS3 protein were predicted using bioinformatics tools. Furthermore, a global mutational spectrum of TMPRSS3 was created and statistically analyzed. The Iranome database was also used to identify other putative mutations in the TMPRSS3 gene in the Iranian population. RESULTS: We identified a novel homozygous single nucleotide deletion in TMPRSS3 (c.297delA, p.Asp100ThrfsTer52) in the proband. This is the first report of this mutation in a patient with ARNSHL. Sanger sequencing confirmed that this variant co-segregated from the proband's parents. Bioinformatic tools classified this novel variant as likely pathogenic. Additionally, 49.55% of families with TMPRSS3-related HL patients were shown to have consanguinity, consistent with our study. The Iranome database also revealed the c.268G > A variant as a putative novel mutation in TMPRSS3. CONCLUSION: This research expanded the pool of evidence regarding the association between mutations in the TMPRSS3 gene and ARNSHL. The finding confirmed that a single nucleotide deletion caused HL in the proband, suggesting that genetic testing, such as WES, is a robust technique for diagnosing patients with this condition.

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PubMed2026

A novel hemizygous missense variant in the BEND2 gene is associated with nonobstructive azoospermia.

Nonobstructive azoospermia (NOA), the most severe form of male infertility, frequently arises from genetic defects that disrupt spermatogenesis. In this study, a novel hemizygous missense variant (NM_001184767.2 [c.G1069A; p.V357I]) is identified in the X-linked BEN domain-containing 2 ( BEND2 ) gene of a patient with NOA characterized by spermatocyte maturation arrest. Whole-exome sequencing and Sanger validation confirmed that this rare variant is absent in fertile controls and that no pathogenic variants were detected in established NOA genes. Computational analysis predicted potential structural alterations via AlphaFold modeling, leading to the hypothesis that the ability of BEND2 to recognize genomic targets may be compromised. The patient's phenotype phenocopies the meiotic arrest observed in Bend2 -knockout mice. Expression profiling confirmed predominant BEND2 transcription in human and mouse testes, peaking in early spermatocytes and coinciding with meiotic initiation, with reduced transcript levels detected in the proband's peripheral blood compared with those in an obstructive azoospermia control. This study reports a pathogenic BEND2 variant associated with NOA with spermatocyte arrest, highlighting its critical role in human meiosis and expanding the genetic etiology of male infertility.

Adult↗

PubMed2026

The role of SYNE1/2 variants as a potential predisposition factor for the onset of endometriosis.

Endometriosis (EM) is a chronic, inflammatory gynaecological disorder defined by the presence of endometrial-like tissue outside the uterine cavity, most frequently affecting the ovaries, peritoneum, and uterosacral ligaments. Despite its prevalence and the significant impact on life quality, EM is often underdiagnosed, with an average delay of about nine years, particularly affecting adolescents and young women. The complex aetiology involves genetic, environmental, and immune factors, with whole-exome sequencing (WES) emerging as a potential tool for identifying relevant genetic variants. Research indicates that innate immune dysfunction, mechanotransduction, and epithelial-to-mesenchymal transition promote endometrial cell migration and lesion formation, processes regulated by nuclear envelope integrity and cytoskeletal dynamics. The LInker of Nucleoskeleton and Cytoskeleton (LINC) complex, specifically Nesprin-1 and Nesprin-2, encoded by SYNE1 and SYNE2, is crucial for these processes. Genome-wide studies have linked SYNE genes to EM risk, showing downregulation in affected patients, and rare variants in these genes have been identified, though their functional implications are still unclear. To this purpose, WES was performed on 204 EM patients to identify rare (MAF <0.1%), damaging variants in SYNE1/2. Primary endometriotic cells (EMCs) were isolated from ovarian lesions of variant carriers (n=4) and wild-type (WT) non-carrier controls (n=4). Functional characterization included somatic WES, RT-qPCR, Western blot, confocal immunofluorescence, and Transwell migration assays. WES identified 11 rare, likely damaging SYNE1/2 variants in 12 patients. Immunofluorescence revealed a distinct protein mislocalization, WT EMCs displayed physiological Nesprin-2 confinement at the nuclear envelope, whereas variant carriers exhibited a diffuse cytoplasmic distribution polarized along actin stress fibres. We demonstrated that SYNE1/2 mutated EMCs had a markedly higher migratory capacity compared to WT controls. Here, in vitro experiments demonstrated, for the first time, the involvement of Nesprin-2 in endometrial cell migration, supporting a mechanistic link between nuclear-cytoskeletal disruption and the invasive phenotype of endometriotic cells (EMCs). These findings provide new insights into EM pathogenesis and highlight SYNE2 as a promising molecular marker for improved diagnosis and disease management.

Humans↗

PubMed2025

Novel compound heterozygous DOCK6 variants expand the mutational spectrum in prenatal diagnosis of Adams-Oliver syndrome 2.

BACKGROUND: Adams-Oliver syndrome (AOS) is a rare developmental disorder, and the DOCK6 gene is an identified AOS gene. This report highlights the prenatal diagnosis of AOS-2 by ultrasonography and genetic testing. METHODS: A growth-restricted fetus with bilateral ventriculomegaly, paraventricular calcifications, and ventricular septal defect underwent trio-whole-exome sequencing (trio-WES). Functional validation of the splice-altering variant was performed via minigene assays and protein structural modeling. RESULTS: Trio-WES revealed compound heterozygous DOCK6 variants: a paternal frameshift (c.3190_3191del; p. Leu1064Valfs60) and a maternal splice-site variant (c.3241-1G > T). Minigene assays demonstrated that c.3241-1G > T caused intron 26 retention (486 bp), introducing a premature termination codon (p. Val1081Glufs37). Structural modeling confirmed the loss of critical DHR2 domains in both truncated proteins. CONCLUSIONS: This study expands the mutational spectrum of DOCK6 and underscores the importance of combining prenatal imaging with functional genomics for early diagnosis of AOS2.

Adult↗