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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↗
PubMed2026

Unraveling the Clinical Spectrum of DNASE1L3 Deficiency: Insights from Case Series and Systematic Literature Review.

BACKGROUND: DNASE1L3 deficiency is a rare monogenic cause of lupus and lupus-like autoimmunity resulting from impaired extracellular DNA clearance and sustained immune activation. Although most reported patients present with early-onset systemic lupus erythematosus (SLE), emerging evidence suggests broader phenotypic variability, including vasculitic and overlap manifestations. Whether these presentations represent distinct clinical entities or a continuum of DNASE1L3-associated immune dysregulation remains unclear. We aimed to define the clinical spectrum of DNASE1L3 deficiency and examine the relationship between recurrent pathogenic variants and disease severity. METHODS: We conducted a combined pediatric case series and systematic literature review. Four children with genetically confirmed biallelic DNASE1L3 variants followed at a tertiary pediatric rheumatology centre were retrospectively analysed for clinical, immunological, genetic, treatment, and outcome data. In parallel, a systematic search of PubMed/MEDLINE, Scopus, and Web of Science identified previously reported patients with confirmed biallelic pathogenic or likely pathogenic DNASE1L3 variants and extractable patient-level clinical data. To facilitate cross-case comparison, we applied an exploratory three-tier descriptive framework reflecting increasing disease severity: vasculitic or organ-limited disease (G1), systemic lupus or overlap phenotypes without irreversible organ damage (G2), and severe systemic organ-damaging disease (G3). The assigned grades were descriptive rather than permanent categories, as some patients may meet the criteria for a higher grade if broader systemic manifestations or irreversible organ damage develop during follow-up. FINDINGS: Fifteen reports provided extractable patient-level data, corresponding to 45 unique previously reported patients after accounting for known or probable overlapping reports. Combined with four patients from our centre, the analysis included 49 genetically confirmed individuals. SLE-dominant disease was the most frequent phenotype (27 [60%] of 45), followed by hypocomplementaemic urticarial vasculitis/HUVS-dominant disease (10 [22.2%]) and overlap phenotypes (8 [17.8%]). Renal involvement was reported in 30 (66.7%) of 45 patients, and disease onset occurred by age 3 years in 20 (44.4%). Persistent hypocomplementemia affecting C3 and C4 was frequently reported across the spectrum. Recurrent DNASE1L3 variants were observed across multiple phenotypic and severity grades. Variants such as p.Asn191Ser and p.Thr97Ilefs*2 occurred in patients spanning organ-limited vasculitic disease, lupus overlap phenotypes, and severe multisystem lupus with major organ involvement. CONCLUSION: DNASE1L3 deficiency was associated with a broad clinical spectrum of immune-mediated disease rather than a single clinicopathological entity. The occurrence of identical pathogenic variants across distinct phenotypic and severity states argues against a simple genotype-phenotype model and suggests that additional modifiers influence disease expression.

Humans↗
PubMed2026

A Novel Splice Variant in the COL1A1 Gene Leads to Exon 46 Skipping and Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a clinical and genetic disorder characterised by bone fragility, growth deficiency and skeletal deformity. Ninety per cent of OI cases are attributable to autosomal dominant variants in the COL1A1 and COL1A2 genes. METHODS: Candidate variants were identified and verified through trio whole-exome sequencing (trio-WES), copy number variation sequencing (CNV-seq) and Sanger sequencing. Minigene splicing assays were performed in HeLa and HEK293T cells with pcDNA3.1 and pcMINI-C vectors to investigate the function of the candidate variants. A systematic review of COL1A1 splicing variants and the corresponding genotype-phenotype spectrum was performed. RESULTS: Trio-WES revealed a novel heterozygous variant in the C-terminal region of the COL1A1 gene: NM_000088.4:c.3423+5G>A. Sanger sequencing confirmed the variant in both the proband (II-2) and her foetus (III-1) who were clinically suspected of having OI. The c.3423+5G>A variant causes complete skipping of Exon 46, as demonstrated by a minigene splicing assay. We retrieved 419 COL1A1 splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers-Danlos syndrome and stratified the remaining 402 variants into three types on the basis of splice site location: (1) Variants at canonical splicing sites (77.8%, 313/402) mostly cause mild phenotypes, whereas a minority may be severe. (2) Intron variants in other locations, such as splice region variants (17.9%, 72/402), usually cause mild clinical phenotypes, and deep intronic splice variants (0.4%, 2/402) that may result in severe phenotypes. (3) Other variants (3.7%, 15/402), such as exon variants or fragment loss, are extremely rare. We also preliminarily discuss the mechanisms underlying phenotypic variability and the characteristics of C-terminal variants. CONCLUSIONS: This intron variant in COL1A1 was classified as likely pathogenic and was confirmed to disrupt COL1A1 expression. The summary analysis results also revealed a correlation among splicing variants, C-terminal region variants and disease, suggesting that variant location provides a useful framework for prognosis prediction.

Female↗
PubMed2025

Methylation patterns of the nasal epigenome of hospitalized SARS-CoV-2 positive patients reveal insights into molecular mechanisms of COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has varied presentations from asymptomatic to death. Efforts to identify factors responsible for differential COVID-19 severity include but are not limited to genome wide association studies (GWAS) and transcriptomic analysis. More recently, variability in host epigenomic profiles have garnered attention, providing links to disease severity. However, whole epigenome analysis of the respiratory tract, the target tissue of SARS-CoV-2, remains ill-defined. RESULTS: We interrogated the nasal methylome to identify pathophysiologic drivers in COVID-19 severity through whole genome bisulfite sequencing (WGBS) of nasal samples from COVID-19 positive individuals with severe and mild presentation of disease. We noted differential DNA methylation in intergenic regions and low methylated regions (LMRs), demonstrating the importance of distal regulatory elements in gene regulation in COVID-19 illness. Additionally, we demonstrated differential methylation of pathways implicated in immune cell recruitment and function, and the inflammatory response. We found significant hypermethylation of the FUT4 promoter implicating impaired neutrophil adhesion in severe disease. We also identified hypermethylation of ELF5 binding sites suggesting downregulation of ELF5 targets in the nasal cavity as a factor in COVID-19 phenotypic variability. CONCLUSIONS: This study demonstrated DNA methylation as a marker of the immune response to SARS-CoV-2 infection, with enhancer-like elements playing significant roles. It is difficult to discern whether this differential methylation is a predisposing factor to severe COVID-19, or if methylation differences occur in response to disease severity. These differences in the nasal methylome may contribute to disease severity, or conversely, the nasal immune system may respond to severe infection through differential immune cell recruitment and immune function, and through differential regulation of the inflammatory response.

Humans↗
PubMed2019

The 22q11 low copy repeats are characterized by unprecedented size and structural variability.

Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.

22q11 Deletion Syndrome↗
PubMed2026

Epigenetic aging and autosomal methylation remodeling in Anderson-Fabry disease.

Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disorder characterized by marked clinical heterogeneity and incompletely understood genotype-phenotype correlations. While X-chromosome inactivation has been extensively investigated, the contribution of autosomal epigenetic mechanisms to phenotypic variability remains poorly defined. Here, we performed an exploratory genome-wide DNA methylation analysis in 32 AFD patients (22 females and 10 males; mean age 51.7 years) recruited within a multicenter regional research project in Calabria (Italy). DNA methylation profiling was conducted using the Infinium MethylationEPIC v2.0 array. The analysis integrated two complementary approaches: differential methylation analysis and evaluation of biological aging through multiple epigenetic clocks, including Horvath, Hannum, PhenoAge, Skin & Blood, GrimAge, and DunedinPACE. Exploratory methylome-wide analysis identified a limited set of CpG loci showing nominal evidence of methylation differences between carriers of pathogenic and non-pathogenic variants; however, none remained statistically significant after correction for multiple testing. Annotation of the top-ranking nominal CpG associations highlighted genes involved in biological processes including vascular regulation, intracellular trafficking, cytoskeletal organization, immune signaling, and lipid metabolism. No significant differences between groups were observed for the conventional epigenetic age-acceleration measures examined. In contrast, carriers of pathogenic variants showed significantly higher DunedinPACE values (p = 0.0328), indicating a faster estimated pace of biological aging. This finding suggests that DunedinPACE may capture aspects of the cumulative systemic burden associated with pathogenic GLA variants, although confirmation in larger independent cohorts is required. Overall, this pilot epigenomic study provides preliminary evidence that autosomal epigenetic remodeling and biological aging acceleration may contribute to phenotypic heterogeneity in AFD.

Anderson-Fabry disease↗
PubMed1978

Epstein-Barr virus infections in the X-linked recessive lymphoproliferative syndrome.

Prospective studies demonstrated variable phenotypic expression of the X-linked recessive lymphoproliferative syndrome (X.L.R.L.S.) in three brothers: (1) hypogammaglobulinaemia and subclinical Epstein-Barr-virus (E.B.V.) infection with antibody response to E.B.V.; (2) E.B.V. infection with defective immune response to E.B.V., fatal infectious mononucleosis (I.M.), and immunoblastic lymphoma; and (3) histiocytic lymphoma. Hypogammaglobulinaemia and measles pneumonitis had preceded infection with E.B.V. The diverse phenotypic expressions probably resulted from the varied immune response to E.B.V. Recombination of X chromosomes was documented by Xg-blood-group studies in a survivor. E.B.V. can induce fatal I.M. and malignant lymphoma in X.L.R.L.S., but an immune response to E.B.V. can be protective.

Adolescent↗
PubMed2026

Retinopathy caused by a primary immune regulatory disorder - the spectrum of AIRE-associated retinopathy: case series and literature review.

BACKGROUND/OBJECTIVE: Retinal involvement in autoimmune polyendocrine syndrome type 1 (APS1), a rare monogenic autoimmune disorder caused by mutations in the AIRE gene, is increasingly recognised but remains poorly defined. Prior reports suggest a variable phenotype, ranging from mild changes to severe vision loss, often presumed untreatable. We explored the range of retinal phenotypes associated with AIRE gene deficiency in a multicentre case series of patients with APS1. METHODS: We performed a retrospective case note review of patients with molecularly confirmed APS1 from tertiary ophthalmic centres. Clinical history, multimodal retinal imaging, electrophysiology, genetic data, and treatment regimens were analysed. Histopathology was available in one case postmortem. RESULTS: Records were reviewed from five unrelated female patients. Median age was 14 years at onset of ocular involvement and 33 years at most recent follow up. Some findings from two cases have been previously reported. Three distinct pathogenic AIRE variants contributing to biallelic genotypes were observed. Retinal findings ranged from structurally and functionally normal to advanced degeneration. One patient demonstrated sharp zonal atrophy on histopathology. Inflammatory features predominated in two cases, both showing durable vision preservation with periocular or systemic immunomodulation. One patient demonstrated four years of disease stabilisation with rituximab. No consistent genotype-phenotype correlation emerged. CONCLUSION: AIRE-associated retinopathy encompasses a diverse spectrum, from clinically silent to profound degeneration. Early, targeted immunomodulation might preserve vision in selected cases. These findings advocate for ophthalmic surveillance in APS1, and support further investigation into predictive biomarkers and possible tailored immunotherapy in this vision-threatening autoimmune disorder.

Humans↗
PubMed2026

Precision Medicine in Transfusion-Dependent and Non-Transfusion-Dependent β-Thalassemia: Toward Personalized Diagnosis and Therapy.

β-thalassemia comprises a clinically heterogeneous group of disorders in which anemia severity, transfusion exposure, iron loading, and organ complications vary widely among individuals. This structured narrative review summarizes practical applications of precision medicine in transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT), with explicit attention to which strategies apply to each clinical category. Literature indexed in PubMed and Scopus from 2000 to 2025 was reviewed using terms related to thalassemia, precision medicine, magnetic resonance imaging (MRI), chelation tailoring, next-generation sequencing (NGS), fetal hemoglobin (HbF) modifiers, luspatercept, mitapivat, hepcidin, gene therapy, gene editing, and artificial intelligence (AI). Evidence was synthesized descriptively because interventions, outcomes, and populations were heterogeneous, and no pooled meta-analysis was performed. In TDT, precision care is centered on individualized transfusion planning, extended red-cell antigen matching, MRI-guided cardiac and hepatic iron monitoring, organ-directed chelation intensification, and selection of disease-modifying or curative approaches. In NTDT, precision care emphasizes accurate phenotype classification, MRI liver iron concentration, because serum ferritin may underestimate iron burden, selective chelation, surveillance for NTDT-specific complications, and individualized use of agents that improve anemia. Personalized chelation should include deferiprone, either alone or in combination, when cardiac iron is increased. Comprehensive molecular diagnosis should include HBB together with HBA1 and HBA2 assessment, while secondary and tertiary modifiers help explain phenotypic variability and complication risk. Hepcidin and growth differentiation factor 15 (GDF-15) are discussed as investigational biomarkers; transferrin saturation is not recommended for routine iron-overload assessment in thalassemia. AI currently has its strongest role in screening and diagnosis, whereas risk-stratification models remain exploratory. Equitable implementation requires standardized TDT/NTDT pathways, regional MRI and genomics access, longitudinal registries, and multidisciplinary interpretation.

Humans↗
PubMed2026

Clinical proteomics in inborn errors of metabolism: from biomarker discovery to implementation.

INTRODUCTION: Inborn errors of metabolism (IEMs) are rare, heterogeneous disorders traditionally diagnosed through genetic testing, enzyme assays, and metabolite measurements. However, these tools often do not fully explain phenotypic variability, organ involvement, disease progression, or treatment response. Clinical proteomics provides a complementary functional layer by capturing changes in protein abundance, proteoforms, post-translational modifications (PTM), and biological pathways, offering insights beyond genotype- and metabolite-based approaches. AREAS COVERED: This review examines the role of high-resolution mass spectrometry and computational proteomics in biomarker discovery and clinical decision-making for IEMs. It focuses on their contribution to diagnosis, variant interpretation, patient stratification, and treatment monitoring. Disease-specific applications are discussed, with the strongest evidence in lysosomal storage disorders, mitochondrial diseases, congenital disorders of glycosylation, and selected neurodegenerative or renal metabolic conditions. The literature search was performed in PubMed, Scopus, Web of Science, and Google Scholar, covering peer-reviewed articles available up to 2026, with emphasis on methodological advances and translational applications in clinical proteomics for IEMs. EXPERT OPINION: Proteomics will not replace established diagnostic tools, but it can help address clinically actionable questions in selected contexts. Translation into clinical practice will require standardized workflows, multicenter validation, clinically anchored endpoints, and integration with other omics approaches.

Humans↗
PubMed2026

CRISPR-Cas9‑based lipid nanocarriers for advanced therapy of urinary bladder cancer.

Bladder cancer (BCa) exhibits significant genetic and phenotypic variability. This variability suggests that various tumor subtypes could be influenced by several biomarkers and signaling pathways, which presents a problem for monotherapy strategies. Despite the initial effectiveness of traditional therapies, BCa's high rates of progression and recurrence, and the eventual development of drug resistance in many patients, continue to be major concerns. Because of the potential to transform the genetic modifications linked to the disease, genome editing using CRISPR/Cas9 has become a transformative tool in medicine with noteworthy potential for BCa therapy. Although the CRISPR/Cas9 technology is incredibly effective at transforming the field of genome editing, its instability and cellular impermeability pose significant challenges to its delivery. To increase efficient delivery of CRISPR/Cas9, nanovectors may be investigated. Significant promise exists for improving the therapeutic potential of CRISPR-Cas9 technology and addressing complex cancer therapy difficulties because of the rapid development of nanotechnology-based delivery systems. Relevant articles were searched in Google Scholar, Scopus, and Web of Science covering studies published between 2007 and 2026. Along with the impact of lipid-based nanoparticles on their safe transport to cancer cells, this review emphasizes the significance of the CRISPR/Cas9 genome editing system in the treatment of BCa.

CRISPR–Cas9↗
PubMed2025

A pathogenic COL7A1 variant highlights semi-dominant inheritance in dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa is a rare subtype of inherited epidermolysis bullosa, caused by variants in the collagen type VII alpha 1 chain (COL7A1) gene (MIM120120). Both autosomal dominant and recessive inheritance has been reported with variable phenotype. We investigated a Pakistani family with dystrophic epidermolysis bullosa via exome sequencing and identified a pathogenic nonsense variant in COL7A1 NM_000094 c.1573 C > T:p.(Arg525*). The inheritance pattern observed was consistent with a semi-dominant model, where heterozygous parents exhibited a mild phenotype, and homozygous children were more severely affected. For dystrophic epidermolysis bullosa, loss-of-function variants are typically associated with the autosomal recessive form, while missense variants are linked to the autosomal dominant form. A review of the literature suggests a semi-dominance pattern for some missense variants, particularly glycine substitutions, but this concept had not been formally recognized. This study highlights the importance of considering semi-dominant inheritance models for dystrophic epidermolysis bullosa and other Mendelian diseases with an autosomal recessive mode of inheritance, as it can significantly impact diagnosis and genetic counseling.

Humans↗
PubMed2026

[Genetic analysis of a male with Multiple morphological abnormalities of sperm flagella combined with sperm head abnormalities due to compound heterozygous variants of DNAH1 gene and a literature review].

OBJECTIVE: To explore the clinical phenotype and genetic etiology of a male with Multiple morphological abnormalities of sperm flagella (MMAF) combined with sperm head abnormalities due to compound heterozygous variants of DNAH1 gene, with an aim to provide guidance for assisted reproductive technology in his family. METHODS: A man with MMAF combined with sperm head abnormalities who visited Women and Children's Hospital of Ningbo University in October 2024 was selected as study subject. Clinical data of the patient's family were retrospectively collected. Peripheral blood samples were collected from the patient and his spouse, and G-banding karyotyping and whole exome sequencing (WES) were carried out. Candidate variants were validated by Sanger sequencing. Conservation of the DNAH1 protein was queried on the UCSC website. The difference between wild type and variant DNAH1 proteins were analyzed using AlphaFold v3.0.1 and PyMOL v2.5.6. The pathogenicity of variant was rated based on the guidelines from American College of Medical Genetics and Genomics (ACMG). Previous literature was searched using keywords "DNAH1 gene" and "multiple morphological abnormalities of the sperm flagella" on CNKI, Wanfang Data Knowledge Service Platform, and PubMed database to identify cases of MMAF attributed to biallelic DNAH1 gene variants. The retrieval period was set from the establishment of the databases to December 31, 2025. The genotypes and clinical phenotypes of patients with biallelic DNAH1 mutations were analyzed. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2023-094). RESULTS: The 30-year-old patient and his 30-year-old wife had infertility for 2 years. Semen analysis revealed no motile sperm and a 99.0% abnormal morphology rate. Typical MMAF was observed with phase-contrast microscopy. Sperm morphology analysis revealed abnormalities of the head, neck, and tail with an approximate ratio of 9:5:1. The patient's karyotype was 46,XY, and his wife's karyotype was 45,X[4]/47,XXX[1]/46,XX[84]. WES and Sanger sequencing revealed that the patient harbored compound heterozygous variants of the DNAH1 gene, namely c.1435_1444+3del and c.12204_12206del (p.Asn4069del), but their origin remained unidentified. UCSC genome browser query results showed that the amino acid residue at position 4 069 of the DNAH1 protein is highly conserved across various species. Protein structure prediction reveals that, in the wild-type DNAH1 protein, the Asparagine at position 4 069 (Asn4069) can form hydrogen bonds with the Leucine on the main chain at position 4 086 (Leu4086) and the Serine on the side chain at position 4 087 (Ser4087). The c.12204_12206del variant, resulting in deletion of Asn4069, disrupts these hydrogen bonds and does not generate any compensatory interactions. Based on the ACMG guidelines, the c.1435_1444+3del variant was predicted to be likely pathogenic (PM2_Supporting+PVS1), and the c.12204_12206del(p.Asn4069del) variant was rated as likely pathogenic (PM2_Supporting+PM4+PM3+PP4). The couple had elected for in vitro fertilization using donor sperm. During this cycle, 12 oocytes were retrieved, 10 oocytes were successfully fertilized, 1 embryo and 6 blastocysts were obtained. Following the first transfer of a frozen-thawed blastocyst, implantation of an empty gestational sac occurred, which led to a miscarriage. After the second transfer of a high-quality blastocyst, the embryo split into twins following implantation, and the spouse had selected fetal reduction. The gestational age was 33+3 weeks on June 1, 2026. Literature review identified three studies reporting biallelic mutations of the DNAH1 gene in association with MMAF combined with sperm head abnormalities. Together with the patient from this study, a total of 20 patients were included in the analysis. The rate of sperm flagellar abnormalities in these patients was above 80.0%, while the rate of sperm head abnormalities has ranged from 12.0% to 100.0%. In four patients, the genetic basis was unknown. In the remaining 16 patients, 35 mutations were detected, with c.8626-1G>A being the most common (22.9%, 8/35). CONCLUSION: This patient showed MMAF with frequent sperm head defects. Compound heterozygous variants of the DNAH1 gene probably underlay these abnormalities, which in turn has led to his primary infertility. This study revealed the phenotypic variability of MMAF and broadened the mutational spectrum of the DNAH1 gene.

Humans↗
PubMed2026

Personalized approach to infertility treatment in a patient with polyendocrine metabolic ovarian syndrome and chronic pancreatitis.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in fertile women, with an estimated prevalence of 10-15%. It is a heterogeneous disease characterized by a complex pathogenesis. Genetic predisposition, neuroendocrine regulation disorders, and environmental influences play a key role. Dysregulation of the hypothalamic-pituitary-ovarian axis occurs with subsequent chronic anovulation, hyperandrogenemia, and metabolic abnormalities. Phenotypic variability reflects different pathophysiological mechanisms - based on genomic association studies, three subtypes of PCOS can be distinguished: reproductive, metabolic, and indeterminate. PCOS is one of the main causes of female infertility and a risk factor for the development of cardiometabolic diseases. Objective: The aim of the article is to summarize current recommendations of the European Society of Human Reproduction and Embryology (ESHRE 2023) regarding the diagnosis and treatment of polyendocrine metabolic ovarian syndrome (PMOS) in patients with fertility disorders and to demonstrate their practical application through a selected clinical case.

Humans↗
PubMed1975

Broad-beta disease (type III hyperlipoproteinemia) in a large kindred. Evidence for a monogenic mechanism.

The inheritance of broad-beta disease (as specified by a type III lipoprotein pattern) has remained an enigma. Previous reports have variously implicated a single gene (autosomal dominant mode), a double dose of a single gene (autosomal recessive), two separate genes (mixed heterozygosity), or multiple genes (polygenic inheritance). The present study of a single, large kindred of 108 members spanning 4 generations provides evidence for an autosomal dominant mode, since at least 1 member of the first generation pair was normal, at least 5 of their 9 children had type III patterns, and at least 2 of these (whose spouses were normal) transmitted this pattern to their offspring. The findings also suggest that in this kindred the common occurrence of hypertriglyceridemia (in a type IV pattern) may represent either a variable phenotypic expression of the gene for broad-beta disease or the coexistence of a second, independent genetic lipid disorder.

Adult↗
PubMed1978

Delayed diagnosis in a case of secondary amenorrhea caused by a long arm isochromosome--X; i(xq).

Secondary amenorrhea was observed in a 27-year-old woman with a structurally abnormal isochromosome--X, i(Xq), in all cells analyzed. The apparent phenotypical variability that may be observed in subjects with functional monosomy for the short arm of X, must be taken into consideration when patients with amenorrhea are clinically investigated. A correct, and early diagnosis of the etiology of the dysgenetic state of the gonads may only be obtained by accurate cytogenetic investigations, i.e., by utilizing various modern banding techniques.

Adult↗
PubMed2026

Genomic Profiling of Anophthalmia/Microphthalmia-Associated CNVs Reveals Complex Genotype-Phenotype Correlations and Incomplete Penetrance.

BACKGROUND: Anophthalmia/microphthalmia (A/M) is a severe congenital ocular malformation characterized by the complete absence or small size of the eye bulb. Interpreting copy number variations (CNVs) in A/M is challenged by variable genotype-phenotype correlations and reduced penetrance. This study investigated the genetic etiology of A/M-associated CNVs. METHODS: Genomic profiling was performed on four unrelated families presenting with ocular anomalies or harboring A/M-susceptible CNVs. Variants were evaluated by integrating American College of Medical Genetics and Genomics (ACMG) guidelines with clinical phenotypes and familial segregation. RESULTS: An inherited 8.13 Mb deletion (8p23.3p23.1) in Patient 1 was excluded due to genotype-phenotype mismatch. Patients 2 and 3 harbored de novo pathogenic deletions involving OTX2 (14q22.3) and SOX2 (3q26.33), causing typical A/M. Case 4 revealed a 14q22.2q23.1 deletion encompassing OTX2 in a fetus and mother without ocular anomalies, consistent with the incomplete penetrance of OTX2-related microphthalmia. Thus, CNV-induced haploinsufficiency causes A/M with high phenotypic variability. CONCLUSION: Accurate CNV interpretation requires robust genotype-phenotype correlation and careful assessment of incomplete penetrance to prevent diagnostic pitfalls and improve genetic counseling.

Female↗