Biomedical subjects

Leslie G Biesecker

Publications and source records attributed to Leslie G Biesecker.

5 recordsLinked to original sources

PubMed2026

In Vivo Base Editing Partially Rescues Bone Dysplasia in a Mouse Model of Hutchinson-Gilford Progeria Syndrome.

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most patients harbor a c.1824C>T/p.G608= variant, commonly described as G608G, in exon 11 of LMNA that leads to aberrant splicing and production of the toxic progerin protein. In addition to cardiovascular, dermal, and adipose tissue deterioration, HGPS mouse models also develop progressive bone dysplasia that occurs in patients. Here we characterize the efficacy of in vivo mutation correction with an adenine base editor (ABE) to rescue structural and functional defects in HGPS transgenic murine bone tissue. Treatment of double-copy transgenic osteoblast cultures with a lentiviral-delivered CRISPR-Cas9 ABE achieved nearly 40% gene correction in vitro, resulting in significant reduction of progerin transcripts and protein, in the absence of selective agents. Furthermore, gene correction improved progeroid osteoblasts' capacity to deposit and mineralize extracellular matrix compared to untreated cultures. In vivo, a single intravenous dose of AAV9-delivered ABE corrected the mutation, achieving ~14%, ~22%, ~10% and < 1% correction in bone by six months of age when administered at P3, P14, 1 and 4 months of age, respectively. Partially rescued bone structural and physical parameters were observed in P14-treated mice with concomitant normalization of gene transcriptional programs and intracellular signaling pathways involved in bone remodeling. This work demonstrates in vivo delivery of a locus-specific DNA base editor to bone tissue, delineates the timing of treatment required for maximum efficacy, and suggests that this system might be tailored for application to other monogenic bone disorders.

Animals↗

PubMed2025

Isolated lateralized overgrowth and the need for tumor screening: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

PURPOSE: To provide diagnostic guidance for individuals with lateralized overgrowth (LO) and implement appropriate screening protocols. LO without a syndromic presentation is considered idiopathic isolated lateralized overgrowth (ILO). METHODS: We performed a literature search of LO syndromes and malignancy risk and reviewed existing guidelines and expert input. RESULTS: We integrated 940 unique articles to form recommendations. We defined LO as significantly larger length and/or girth of aspect(s) of one side of the body compared with its contralateral side. It can be associated with somatic overgrowth syndromes. ILO was previously defined based on clinical features and deemed idiopathic by absence of molecular findings. Much of the tumor risk is likely because of specific LO syndromic causes now identified through improved diagnostic technologies; therefore, the tumor risk in idiopathic ILO is likely lower than previously accepted. CONCLUSION: Mosaicism complicates molecular diagnosis for children with LO. However, conditions such as Beckwith-Wiedemann spectrum and PTEN-related hamartoma tumor syndrome necessitate routine tumor screening. Establishing a specific diagnosis via comprehensive molecular testing on affected tissue will guide screening and management. In cases of idiopathic ILO, location of the overgrowth, estimation of tumor risk, regional practice approaches and family concerns all play roles in determining tumor screening.

Child↗

PubMed2025

Implementing secondary findings analysis in a genetic and environmental research study.

PURPOSE: Optimizing return of secondary findings (SFs) in research settings requires an understanding of the complexities and challenges. METHODS: Genome sequence was generated for 4737 participants in a genetic and environmental health study, and 4630 of them consented to SF return. Variants in the American College of Medical Genetics and Genomics v3.0 genes were classified using the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria with ClinGen-approved modifications. RESULTS: Eighty-six variants were eligible for return to 102 participants. Average time to initial recontact attempt was 5.8 years. Recontact attempts reached 95 of 102 individuals. Results were returned to 57 participants. The remainder passively declined (25), actively declined (11), were lost to follow-up (5), were deceased (3), or had prior knowledge of the result (1). Return of results was positively associated with education status (2 × 3 C2, P = .0035). CONCLUSION: The interest in receiving SFs was high at the time of consenting, but a clinically validated result was returned to just over half of the individuals with an SF. Approximately 1 in 3 participants with an SF who had consented to receive them subsequently actively or passively declined receipt of the result. Given the health importance of return of SF, minimizing the time from consent to results return and tailoring outreach to education level may optimize uptake of SF return.

Adult↗

PubMed2025

Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria.

PURPOSE: We previously developed an approach to calibrate computational tools for clinical variant classification, updating recommendations for the reliable use of variant impact predictors to provide evidence strength up to Strong. A new generation of tools using distinctive approaches has since been released, and these methods must be independently calibrated for clinical application. METHODS: Using our local posterior probability-based calibration and our established data set of ClinVar pathogenic and benign variants, we determined the strength of evidence provided by 3 new tools (AlphaMissense, ESM1b, and VARITY) and calibrated scores meeting each evidence strength. RESULTS: All 3 tools reached the Strong level of evidence for variant pathogenicity and Moderate for benignity, although sometimes for few variants. Compared with previously recommended tools, these yielded at best only modest improvements in the trade-offs between evidence strength and false-positive predictions. CONCLUSION: At calibrated thresholds, 3 new computational predictors provided evidence for variant pathogenicity at similar strength to the 4 previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field.

Humans↗

PubMed2025

Patterns of X-linked inheritance: A new approach for the genome era.

PURPOSE: The concepts of X-linked (XL) dominant and recessive inheritance originated long before dosage compensation for X chromosome genes was understood, but now have no scientific basis. However, misunderstanding of the underlying biology persists, prompting our reassessment of XL inheritance. METHODS: We reviewed data on penetrance, expressivity, and X chromosome inactivation (XCI) for 55 XL genes and 57 XL disorders, and examined variations in inheritance based on disease severity, XCI status, cell selection, and other factors. RESULTS: Our analysis demonstrated widely varying penetrance among heterozygous females that was related to severity of the phenotype particularly in males, the degree of cell selection shown by XCI patterns, cell autonomous or non-cell autonomous function of the gene product, and rare cellular interference. CONCLUSION: The conventional classification of XL inheritance into dominant and recessive subtypes is biologically flawed and should be retired. A more nuanced framework for understanding XL disorders is needed that accounts for the underlying biological complexity, and we propose 4 new groups of XL disorders with different patterns that should improve genetic diagnosis and counseling in families with XL disorders.

Humans↗