Russ Jeffrey B, Stone Alexa C, Maney Kayli, Morris Lauren C, Wright Caroline F, Hurst Jillian H, Cohen Jennifer L
Department of Pediatrics, Division of Neurology, Duke University, 2301 Erwin Rd, Durham, NC, 27710, USA.
Department of Pediatrics, Pediatric Neurology Residency Program, Duke University, 2301 Erwin Rd, Durham, NC, 27710, USA.
Sci Rep. 2025 Jul 2;15(1):23172. doi: 10.1038/s41598-025-05117-7.
Up to one third of congenital brain malformations and neurodevelopmental disorders are attributable to single-gene pathogenic variants, and yet we have little understanding of the cellular pathophysiology in the nervous system that arises from these variants. To investigate cortical cell type-specific biases in gene expression associated with distinct neurodevelopmental phenotypes, we integrated phenotypic information from two cohorts of subjects with monogenic neurodevelopmental diagnoses with two human cortical single-nucleus RNA-sequencing (snRNAseq) datasets. Phenotype data was gathered from (1) a single-institution cohort of 84 neonates with pathogenic single-gene variants referred to Duke Pediatric Genetics, and (2) a cohort of 4,238 patients with neurodevelopmental disorders and pathogenic single-gene variants enrolled in the Deciphering Developmental Disorders study. Human cortical snRNAseq datasets were obtained from public repositories and included 86 samples from human cortex spanning the 2nd trimester of gestation to adulthood. We identified reproducible cell-specific expression biases for genes in which pathogenic variants are associated with speech/cognitive delay and seizures. Enriched expression of these genes in excitatory neurons or microglia highlights the unique role both cell types play in neurodevelopment. Moreover, this information illuminates distinct cortical cell types that are more likely to be impacted by pathogenic variants and may mediate their symptomatology.
高达三分之一的先天性脑畸形和神经发育障碍可归因于单基因致病变异，然而我们对这些变异在神经系统中引发的细胞病理生理学知之甚少。为了研究与不同神经发育表型相关的基因表达中皮质细胞类型特异性偏差，我们将来自两个单基因神经发育诊断受试者队列的表型信息与两个人类皮质单核RNA测序（snRNAseq）数据集进行了整合。表型数据来自：（1）一个由84名患有致病变异的新生儿组成的单机构队列，这些新生儿被转诊至杜克儿科遗传学部门；（2）一个由4238名患有神经发育障碍和致病变异的患者组成的队列，他们参与了发育障碍解读研究。人类皮质snRNAseq数据集来自公共数据库，包括从妊娠中期到成年期的86个人类皮质样本。我们确定了与言语/认知延迟和癫痫相关的致病变异基因的可重复细胞特异性表达偏差。这些基因在兴奋性神经元或小胶质细胞中的富集表达突出了这两种细胞类型在神经发育中所起的独特作用。此外，这些信息揭示了更可能受到致病变异影响并可能介导其症状的不同皮质细胞类型。
