Aug 2026· American Journal of Medical Genetics. Part A· 0 citations· 22 references
Medicine
TL;DR
The father-to-daughter transmission of a novel constitutional TUBB variant, alongside literature review of constitutional and mosaic tubulinopathies, suggest that pathogenic germline TUBB variants can occasionally be inherited.
Abstract
Most pathogenic tubulin variants arise de novo in sporadic patients, causing severe brain malformations and significant neurodevelopmental impairment. The resulting reproductive disadvantage typically prevents these mutations from being transmitted to offspring. While a few variants are inherited from somatic or gonadal mosaic parents, vertical transmission of constitutional variants remains rare, though increasingly documented. Here, we report the father-to-daughter transmission of a novel constitutional TUBB variant [NM_178014.4:c.991C>T; p.(Leu331Phe)]. Both individuals presented with intellectual disability and a malformation of cortical development (MCD). To validate the pathogenicity of this variant, we performed functional and immunofluorescence assays in vitro on patient-derived fibroblast cultures. These experiments supported the involvement of the variant in significantly impairing cell motility, altering cytoskeleton organization, and affecting cellular morphology. Our findings from this family, alongside literature review of constitutional and mosaic tubulinopathies, suggest that pathogenic germline TUBB variants can occasionally be inherited. Transmission is facilitated by the relatively mild clinical anatomoclinical phenotype. When a pathogenic TUBB variant is identified in an index patient, comprehensive parental clinical, neuroradiological, and genetic evaluation is crucial to accurately assess reproductive risk.
It is indicated that reduced protein stability and functional impairment of β-tubulin represent key pathogenic mechanisms underlying this condition, and the experimental evidence further supports the implication of TUBB dysfunctions in haematological abnormalities.
Ilaria Svezia, Riccardo Zocchi, Michela Piccione et al.· Orphanet Journal of Rare Dis...· 0 citations
Chiari 1 malformation (CM1) is the most common congenital malformation of the human hindbrain. Although prior studies have implicated chromatin-remodeling genes in CM1, the de novo genetic architecture and underlying neurodevelopmental mechanisms remain incompletely defined. To investigate the molecular genetics of a novel familial form of CM1 linked with syringomyelia and tethered cord and determine whether rare, damaging de novo variants (DNVs) contribute to sporadic CM1 risk with gene- and pathway-level resolution, we performed whole-exome sequencing in an ultra-rare multigenerational family with CM1 and associated spinal pathology, and in the largest assembled trio-based cohort to date, comprising 1,585 proband-parent trios with sporadic, idiopathic CM1 (2017-2025). The comparison cohort included 1,798 unaffected control siblings. Clinical phenotyping was by systematic medical record review. Structural domain mapping, in silico modeling, and integration with single-cell transcriptomic data from developing human cerebellum was conducted to assess biological plausibility. A heterozygous loss-of-function variant in CHD3 segregated with CM1 and syringomyelia in a multigenerational family. In the trio-based cohort, rare protein-altering DNVs were significantly enriched across multiple chromodomain helicase DNA-binding (CHD) genes, including CHD1, CHD3, CHD4, and CHD8, exceeding gene-specific mutation expectations (protein-damaging variants: P = 1.3 × 10-9; predicted loss-of-function variants: P = 8.6 × 10-5). CHD1 contained two pathogenic DNVs (p.A999D and p.E984K). CHD4 (p.D744N, p.T1813P, and p.I1102T) and CHD8 (p.R1402X, p.R1472X, and p.R2035X) each contained three new DNVs. Variants clustered within conserved ATPase, helicase, and chromodomain regions essential for chromatin remodeling, and these patients frequently had comorbid developmental delay and related neurodevelopmental features. Single-cell transcriptomic analyses demonstrated enrichment in Purkinje cells and inhibitory neurons of midgestational cerebellum, where CHD gene products form a coherent chromatin-regulatory network. Rare, large-effect DNVs that disrupt chromatin-remodeling programs contribute to sporadic CM1, implicating genetically encoded dysregulation of cerebellar development as a central disease mechanism. Exome sequencing may complement surgical evaluation of children with sporadic CM1, particularly when accompanied by neurodevelopmental concerns, informing prognosis and family counseling.
Neel H. Mehta, G. Allington, Evan Dennis et al.· Brain : a journal of neurolo...· 0 citations
TrioMix-UPD, an integrated short- and long-read sequencing framework for UPD detection and classification, is developed and established UPD as an underrecognized contributor to CHD.
Nahyun Kong, Javier Abello, Christopher J. Yoon et al.· Research Square· 0 citations
The phenotypic spectrum of SOX4-related disorders is expanded to include nystagmus for the first time, and one patient presenting with severe hypospadias and cryptorchidism is Documented, providing new evidence to facilitate clinical recognition and genetic counseling.
H. Miao, Ting Zhang, Kexin Fang et al.· Genes· 0 citations
The findings expand the evidence that pathogenic MECP2 variants can produce neurological phenotypes distinct from classic RTT, including mild neurodevelopmental impairment without regression, and predominantly cerebellar or spastic-ataxic manifestations associated with limited cognitive involvement.
Camilla Meossi, Alessandro De Falco, Deianira Rinaldi et al.· Journal of Neurology· 0 citations
Somatic overgrowth and vascular anomalies are often present at birth but may only be clinically recognized later in life. Affected tissues commonly include veins and arteries, skin, adipose tissue, bone, and brain, resulting in a broad phenotypic spectrum encompassing vascular malformations, lipomatous and melanocytic nevus syndromes, skeletal abnormalities, and brain malformations. These conditions are typically caused by postzygotic variants present in a subset of cells due to mosaicism. The developmental timing and cell lineages involved determine the extent and distribution of affected tissues. While germline variants and their clinical consequences are well characterized, the impact of somatic mosaic variants remains less well understood. Because these variants are often absent or present at very low levels in blood, sensitive assays and analysis of affected tissues are required for detection. Advances in high-depth next-generation sequencing have enabled reliable identification of low-level mosaic variants and are central to the genetic diagnosis of these disorders. Numerous causative genes have been described, most notably activating variants in the PI3K-MTOR and RAS-MAPK pathways. Genetic testing provides diagnostic confirmation, informs prognosis and recurrence risk, and in some cases enables targeted therapy, such as alpelisib for PIK3CA-related overgrowth spectrum. However, testing strategies vary across laboratories in gene panel content, sequencing depth, and tissue requirements, leading to inconsistent diagnostic approaches. This review summarizes known causative genes, current testing methodologies, variant interpretation and reporting practices, major genomic alteration classes and recurrent hotspot variants, and highlights key knowledge gaps from clinical and laboratory perspectives.
Avinash V. Dharmadhikari, Candace T. Myers, Katherine A. King et al.· Genetics in Medicine· 0 citations
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