Genet Med. 2026 Oct 27:102776. doi: 10.1016/j.gim.2026.102776. Online ahead of print. ABSTRACT PURPOSE: While heterozygous de novo missense variants in the microtubule-binding GAR domain of Microtubule-actin cross-linking factor 1 (MACF1) cause Lissencephaly 9 with Complex Brainstem Malformations (LIS9) [MIM 618325], the phenotypic impact of variants outside this domain remains unclear. METHODS: We assembled a cohort of 5 affected individuals from 4 unrelated families with biallelic non-GAR domain MACF1 variants who exhibit partially overlapping yet unique phenotypic traits. A sixth individual with a de novo, heterozygous frameshift variant was additionally identified. Combined with previously reported cases, we analyzed genotype and phenotype data from 22 individuals using Human Phenotype Ontology (HPO)-based unsupervised hierarchical clustering. RESULTS: Clustering revealed two distinct phenotypic signatures, suggesting domain-associated effects. Variants outside the GAR domain associate with broader neurodevelopmental phenotypes and craniofacial and skeletal involvement. Enrichment analysis (p < 0.001) using OMIM HPO sets supported these findings. In contrast to the GAR domain’s strong correlation with LIS9, biallelic non-GAR domain MACF1 variants were linked to distinct developmental anomalies. CONCLUSION: These results expand the phenotypic spectrum of MACF1-related disorders and provide preliminary evidence for domain-associated MACF1 variant effects. While limited by sample size and lack of functional validation, these findings should be considered hypothesis-generating and underscore the utility of HPO-based clustering for systematic phenotype comparison as additional cases emerge. Comprehensive genetic and phenotypic assessments are essential for understanding the role of MACF1 in development, informing diagnosis, and guiding future research on cytoskeletal regulation in neurodevelopment. PMID:42937053 | DOI:10.1016/j.gim.2026.102776

Cancer Res. 2026 Oct 26. doi: 10.1158/0008-5472.CAN-25-5500. Online ahead of print. ABSTRACT Hormone receptor positive (HR+) breast cancer is the most common breast cancer subtype globally and remains a leading cause of cancer-related death in women. Black women diagnosed HR+ breast cancer experience significantly worse outcomes than White women, a disparity that persists even after accounting for factors such as healthcare access and educational attainment. Understanding the biological mechanisms underlying these differences has been limited by the underrepresentation of Black patients in genomic datasets. To address this gap, we generated an HR+ breast cancer transcriptomic dataset enriched for Black patients while controlling for access to healthcare and education level. Tumors from Black women showed enrichment of tumor microenvironment-related signatures, including increased collagen deposition and prognostically unfavorable T-cell landscapes. Data from in vitro and in vivo experimental models showed that race-aligned collagen deposition patterns were driven, at least in part, by tumor cell-intrinsic signaling and promoted metastatic phenotypes associated with poorer outcomes. Further analysis of the patient transcriptomic dataset revealed that unfavorable T-cell signatures previously attributed to race or ancestry were more strongly associated with poverty burden. Across multiple independent datasets, STAT4 emerged as a potential master regulator of this poverty-associated immune phenotype. Collectively, these findings suggest that molecular features of breast tumors are shaped by both biological and structural factors linked to self-identified race and socioeconomic disadvantage. These results demonstrate that integrating social determinants of health with molecular analyses can reveal mechanisms contributing to cancer outcome disparities and provide a foundation for the development of more effective and equitable precision oncology approaches. PMID:42929736 | DOI:10.1158/0008-5472.CAN-25-5500

Genet Med. 2026 Oct 23:102775. doi: 10.1016/j.gim.2026.102775. Online ahead of print. ABSTRACT PURPOSE: Pathogenic variants in CDH2 cause agenesis of the corpus callosum, cardiac, ocular, and genital syndrome (ACOGS). We aimed to define the clinical and molecular landscape of CDH2-related developmental disorders. METHODS: Newly identified and previously reported families were analyzed for genotype-phenotype correlations; variants were assessed using protein modeling and splicing assays. RESULTS: Screening identified 20 new families carrying (likely) pathogenic ((L)P) alleles (n=16) or high-priority variants of uncertain significance (VUS) (n=4), including 12 novel CDH2 alleles. The combined (L)P cohort (37 individuals) showed variable ACOGS core features (mean 3; range 1-5), along with abdominal wall and/or diaphragmatic hernias and nipple, spine or gastrointestinal anomalies, each seen in ∼20% of individuals. Novel ACOGS findings included ambiguous genitalia, female genital malformations and dilated cardiomyopathy. Missense variants, principally within extracellular cadherin domains, accounted for 86% of unique (L)P alleles with clusters in EC1 and EC4-EC5; the remainder produce late protein truncations or in-frame deletions. Disruption of calcium binding was predicted by modeling. Conversely, VUS were primarily nonsense-mediated decay-sensitive or deletions (71%), linked to neurodevelopmental, kidney or other anomalies. CONCLUSION: We expand the ACOGS spectrum and highlight its striking clinical variability. Additionally, we identify a possible milder phenotype associated with CDH2 haploinsufficiency. PMID:42924497 | DOI:10.1016/j.gim.2026.102775

Int J Mol Sci. 2026 Oct 19;27(20):9262. doi: 10.3390/ijms27209262. ABSTRACT Single-gene disorders are a common cause of infant and young children’s mortality in intensive care units. Many of these genetic disorders have available treatments that may slow disease progression and improve patients’ quality of life. However, clinicians often identify the underlying genetic etiology late in the disease course, when available treatments cannot reverse disease progression. Rapid whole-genome sequencing (RWGS) is increasingly used for early diagnosis of patients with rare disorders. It remains unclear which clinical indications are most efficient for providing actionable genetic diagnoses. It is also not well studied how efficient RWGS is in diverse populations where population genomic data is less abundant. We present RWGS results over a three-year period from four medical centers within a large hospital system in the State of New Jersey, which has one of the most diverse populations in the United States. The patients were referred to RWGS testing from the NICU and PICU units for various severe/life-threatening manifestations. All patients were tested at one laboratory center using the same technology for genome sequencing and analysis, as described, to eliminate possible interlaboratory variation in test efficiency. We identified a causative genetic etiology in 19 (36.5%) of the 52 tested individuals. We observed the highest yield of positive diagnoses in patients with unexplained failure to thrive (FTT). The genetic diagnoses were actionable for disease-specific, supportive, or progression-slowing targeted treatments, better-informed genetic counseling, or modifying the level of care for most positive individuals. Our study provides information on the test efficiency of RWGS in diverse populations and compares testing efficiency across leading referral indications. The study may help guide referral decisions for such testing. PMID:42942031 | PMC:PMC13705538 | DOI:10.3390/ijms27209262

Hum Genet. 2026 Oct 9;145(1):84. doi: 10.1007/s00439-026-02881-y. ABSTRACT Congenital disorders of glycosylation (CDG) represent a diverse group of inborn errors of metabolism caused by defective glycosylation processes, usually characterized by multiorgan involvement and overlapping clinical symptoms. This study aimed to decipher the clinical and genetic landscape of CDG in Egypt to enumerate the most common CDG types and unveil potentially new candidate genes. The study included 80 patients from 57 families with molecular findings consistent with CDG. Consanguinity was noted in 90% of the families. The most common clinical features were global developmental delay (98%), dysmorphic facies (86%), hypotonia (85%), movement disorders (48%), and seizures (42%). Vision impairment, hepatic, skeletal, and hematological abnormalities were the most frequently encountered systemic manifestations. Structural brain anomalies were commonly observed in our cohort and included thin corpus callosum, cortical atrophy, white matter abnormalities, cerebellar atrophy, and cerebellar vermis hypoplasia. Biallelic variants were identified in 94% of patients, while 6% had variants in X-linked genes. A total of 53 variants were identified in 29 genes, of which 38 (72%) were novel. The most frequent variants were in SRD5A3 (16%), PMM2 (11%), ALG1 (10%), NGLY1 (7.5%), MGAT2 (6%), and ALG11 (5%). We identified two sibs with a homozygous missense variant in CAMLG, which has been recently described in only one case, supporting its role as a new CDG type. Additionally, we described a case with the recently reported UGGT1-CDG and proposed ALG10 as a potentially new CDG gene. Our study highlights the striking phenotypic and genotypic variability associated with CDG and broadens the spectrum of variants and causative genes. PMID:42853272 | DOI:10.1007/s00439-026-02881-y

Nat Genet. 2026 Sep 24. doi: 10.1038/s41588-026-02745-1. Online ahead of print. ABSTRACT Medulloblastoma is a biologically heterogeneous childhood cerebellar tumor harboring frequent chromatin-modifying gene alterations. How these alterations promote transcriptional programs governing malignancy remains poorly defined. To address this knowledge gap, we evaluated chromatin states across medulloblastoma subgroups by multi-modal integration of histone modifications with mutational, DNA methylation and transcriptomic profiles. A bivalent/poised enhancer (EnhBiv) state was specifically enriched at the promoters of neurodevelopmental genes in Group 3/4 medulloblastoma. Integrative bioinformatics coupled with chromatin occupancy studies identified aberrant KDM2B binding at EnhBiv-enriched promoters. CRISPR-mediated knockout or acute protein degradation of KDM2B selectively suppressed the growth of medulloblastoma models in vitro and in vivo. Mechanistically, KDM2B promotes sequential recruitment of Polycomb repressive complexes (PRC1/PRC2) and EnhBiv chromatin, thereby repressing neuronal differentiation programs. Collectively, we provide foundational insights into an epigenetic basis of medulloblastoma, nominating KDM2B as a selective dependency in high-risk subgroups that warrants consideration as a candidate therapeutic target. PMID:42786297 | DOI:10.1038/s41588-026-02745-1

Genet Med. 2025 Sep 22:101587. doi: 10.1016/j.gim.2025.101587. Online ahead of print. ABSTRACT PURPOSE: Glutamic-oxaloacetic transaminase (GOT), also known as aspartate aminotransferase, catalyzes the reversible transamination of oxaloacetate and glutamate to aspartate and α-ketoglutarate. Two isoforms, cytosolic (GOT1) and mitochondrial (GOT2), are integral to the malate-aspartate shuttle (MAS), a key regulator of intracellular redox homeostasis. Recently, five patients with biallelic variants in GOT2 were described, presenting with developmental and epileptic encephalopathy. METHODS: We report 11 additional patients with homozygous GOT2 variants, along with additional data from 4 previously reported patients. Through genetic, clinical and biochemical analyses, we further characterize the phenotypic spectrum of GOT2 deficiency. RESULTS: Most patients exhibited progressive neurodevelopmental delay, severe to profound intellectual disability, infantile epilepsy, progressive microcephaly, and hypotonia evolving into spasticity with axial hypotonia. Dysmorphic features included narrow foreheads, broad nasal tips, and tall or pointed chins. Neuroimaging revealed two severity groups based on cerebral volume loss and myelination defects. Thinning of the corpus callosum and white matter abnormalities were common. Biochemical profiling identified low aspartate and high glycerol-3-phosphate in dried blood spots as potential screening markers. Patient fibroblast cells showed reduced serine and glycine biosynthesis, rescuable by pyruvate supplementation. CONCLUSION: These findings expand the phenotypic spectrum of GOT2 deficiency, establish it as a cause of DEE, and propose novel biomarkers for diagnosis and treatment. PMID:41001736 | DOI:10.1016/j.gim.2025.101587

Proc Natl Acad Sci U S A. 2026 Sep 22;123(38):e2531269123. doi: 10.1073/pnas.2531269123. Epub 2026 Sep 14. ABSTRACT Medulloblastomas are considered immunologically cold and refractory to immunotherapy. One factor contributing to their low immunogenicity is impaired antigen presentation, which allows tumor cells to evade cytotoxic T cells. Using a syngeneic mouse model of medulloblastoma, we demonstrate that despite low expression of MHC class I on tumor cells, depletion of CD8⁺ T cells accelerates tumor growth, whereas adoptive transfer of tumor-reactive CD8⁺ T cells prolongs survival. These antitumor effects rely on T cell-derived interferon gamma (IFNγ), which induces MHC class I on tumor cells and facilitates tumor cell killing by T cells. Importantly, delivering IFNγ directly into tumors via convection-enhanced delivery enhances CD8⁺ T cell-mediated killing of tumor cells and significantly prolongs survival in tumor-bearing mice. These studies highlight the importance of T cells in controlling brain tumors and the value of IFNγ as an adjuvant for T cell-based immunotherapy. PMID:42735303 | DOI:10.1073/pnas.2531269123

Eur J Hum Genet. 2025 Sep 17. doi: 10.1038/s41431-025-01923-9. Online ahead of print. ABSTRACT PIGC encodes a protein essential for the biosynthesis of glycophosphatidylinositol-anchored proteins (GPI-APs). So far, three families with biallelic PIGC variants have been reported to exhibit developmental delay/intellectual disability and seizures. Our aim was to further elucidate the clinical and biomolecular characteristics of PIGC pathogenic or likely pathogenic variants. We established a cohort of 18 previously unreported probands. Clinical data were collected, and causative variants were identified though genome/exome sequencing. Variants were modelled in silico using AlphaFold2. Flow cytometry was performed to analyze the cell-surface expression of GPI-APs. The probands displayed a severe neurodevelopmental disorder characterized by developmental and cognitive impairment, early-onset and treatment-resistant seizures, and premature death affecting 10 out of 18 individuals (median age of 40 months, ranging from 40 days to 7 years). Additional features included brain imaging abnormalities (14/15), hypotonia (15/18), and skeletal anomalies (5/17). One patient exhibited mildly elevated alkaline phosphatase levels. All harbored biallelic PIGC variants, with 14 out of 18 of those being homozygous variants. Analysis of samples derived from probands and cellular models showed reduced cell surface levels of GPI-APs. This study confirms the association of PIGC biallelic variants with refractory seizures, severe developmental and cognitive impairments, and highlights their association with childhood-onset mortality. Additionally, it shows that dysfunctional PIGC results in defective biosynthesis of GPI-AP. PMID:40962973 | DOI:10.1038/s41431-025-01923-9

EMBO Mol Med. 2026 Sep 8. doi: 10.1038/s44321-026-00497-3. Online ahead of print. ABSTRACT Genome sequencing is the first-line diagnostic method for primary mitochondrial diseases (PMDs), yet its effectiveness is limited by variants of uncertain significance or unresolved genetic findings. We systematically evaluated the clinical performance of fibroblast-based functional testing, comprised of respiratory chain enzyme assays, blue native polyacrylamide gel electrophoresis with in-gel activity staining (BN-PAGE), complex I assembly assay, and targeted protein abundance assessments, in a cohort of 204 genetically confirmed PMD patients, 51 healthy controls, and 53 patients with differential diagnoses. Individually, enzyme assays, BN-PAGE, and complex I assembly assay showed sensitivities of 46%, 40%, and 49%, with specificities of 93%, 98%, and 99%, respectively. Combined, the assays achieved an overall sensitivity of 76%, a specificity 93%, a positive predictive value 96%, and a negative predictive value of 67%. Sensitivity was highest for isolated respiratory chain deficiencies, nuclear DNA-encoded mitochondrial translation defects, cofactor deficiencies, and mitochondrial aminoacyl-tRNA synthetase disorders, whereas mitochondrial DNA variants and maintenance defects remained challenging. Secondary mitochondrial dysfunction was rare. The strong clinical utility of comprehensive fibroblast functional testing improves PMD diagnosis when used complementary to genomic sequencing. PMID:42711551 | DOI:10.1038/s44321-026-00497-3