Charcot-Marie-Tooth disease (CMT) is among the most common inherited disorders of the peripheral nervous system, and it is broadly categorized as demyelinating type 1 or axonal type 2 based on nerve conduction studies. Mutations in discrete genes usually segregate into a single phenotype. However, mutations in connexin 32 (Cx32) can produce both axonal and demyelinating CMT phenotypes. Although over 300 mutations have been described in Cx32, somatic mosaicism has only been reported once previously. We report a 39-year-old man who was referred for electrodiagnostic evaluation due to a history of bilateral carpal tunnel syndrome. His physical examination and electrodiagnostic findings demonstrated a mild sensorimotor axonal peripheral neuropathy. Sequencing of his Cx32 (GJB1) gene identified a guanine-to-adenine (G>A) transition at nucleotide position 95. This transition mutation involved approximately one-third of leukocyte-derived genomic DNA. This is the second reported case of somatic mosaicism, and it highlights the phenotypic diversity among CMTX patients.
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http://dx.doi.org/10.1002/mus.21145 | DOI Listing |
Genome Med
January 2025
Hereditary Cancer Group, Oncobell Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Av. Gran Via 199-203, L'Hospitalet del Llobregat, 08908, Spain.
Background: Germline heterozygous pathogenic variants (PVs) in TP53 cause Li-Fraumeni syndrome (LFS), a condition associated with increased risk of multiple tumor types. As the associated cancer risks were refined over time, clinical criteria also evolved to optimize diagnostic yield. The implementation of multi-gene panel germline testing in different clinical settings has led to the identification of TP53 PV carriers outside the classic LFS-associated cancer phenotypes, leading to a broader cancer phenotypic redefinition and to the renaming of the condition as "heritable TP53-related cancer syndrome" (hTP53rc).
View Article and Find Full Text PDFJ Hum Genet
January 2025
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
In monogenic diseases, double mosaic variants of the same gene have rarely been identified. Here, we report the case of triple mosaic variants in PURA, a gene responsible for a neurodevelopmental syndrome (OMIM# 616158). Whole-exome sequencing identified three somatic PURA variants in our case with a similar neurodevelopmental syndrome: NM_005859.
View Article and Find Full Text PDFAm J Hum Genet
January 2025
Division of Biostatistics, Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA; Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address:
Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program.
View Article and Find Full Text PDFBMJ Open
December 2024
INSERM UMR1231 Génétique des Anomalies du Développement (GAD), Université de Bourgogne, Dijon, France.
Introduction: The megalencephaly capillary malformation polymicrogyria (MCAP syndrome) results from mosaic gain-of-function variants. The main clinical features are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies. Alpelisib (Vijoice) is a recently FDA-approved PI3Kα-specific inhibitor for patients with PIK3CA-related overgrowth spectrum (PROS).
View Article and Find Full Text PDFInt J Mol Sci
December 2024
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, CA 95817, USA.
Fragile X syndrome (FXS) is a genetic condition caused by the inheritance of alleles with >200 CGG repeats in the 5' UTR of the fragile X messenger ribonucleoprotein 1 () gene. These full mutation (FM) alleles are associated with DNA methylation and gene silencing, which result in intellectual disabilities, developmental delays, and social and behavioral issues. Mosaicism for both the size of the CGG repeat tract and the extent of its methylation is commonly observed in individuals with the FM.
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