🎙️ Episode 72: The POC5 Syndrome — A Ciliopathy Linking Retina, Muscles and Metabolism

🧬 In this episode of Base by Base, we explore a multi-institutional study by Vulto-van Silfhout et al. (2025), published in Genetics in Medicine, that uncovers a novel syndromic ciliopathy caused by bi-allelic loss-of-function variants in the POC5 gene. The research describes twelve families with a rare constellation of clinical features—including rod-cone dystrophy, severe insulin-resistant diabetes, partial lipodystrophy, renal impairment, and muscle cramps—all tied to defective POC5 function.

The POC5 protein plays a central role in centriole maturation and cilium assembly. Through comprehensive clinical characterization, RNA analysis, and immunofluorescence studies in patient-derived fibroblasts, the authors demonstrate mislocalization of POC5 and aberrant centriolar structure. While primary ciliogenesis and sonic hedgehog (SHH) signaling appeared preserved, affected individuals exhibited systemic abnormalities that strongly align with ciliopathy phenotypes.

This work not only broadens the phenotypic spectrum associated with POC5 deficiency—beyond previously reported retinitis pigmentosa—but also highlights the underrecognized link between ciliary dysfunction and adipose tissue abnormalities. Particularly striking is the presence of partial lipodystrophy and metabolic dysregulation, features rarely associated with classical ciliopathies, suggesting a distinct role of POC5 in adipocyte development and endocrine homeostasis.

🧠 Conclusion:
The study defines a new multi-organ ciliopathy driven by POC5 loss, linking ciliary biology with retinal integrity, neuromuscular function, and systemic metabolism. This discovery paves the way for improved diagnostic strategies for patients presenting with overlapping ocular, endocrine, and neuromuscular symptoms—and reinforces the relevance of ciliopathy research in metabolic diseases.

📖 Reference:
Vulto-van Silfhout AT, Jazet IM, Yzer S, et al. (2025). Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine and neuromuscular ciliopathy. Genetics in Medicine. https://doi.org/10.1016/j.gim.2025.101513

📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 71: ELFN1 Deficiency Disorder — Mechanistic Basis and Phenotypic Spectrum of a Neurodevelopmental Disorder with Epilepsy

🧬 In this episode of Base by Base, we dive into the recent pre-proof study by Dore et al. (2025) in Genetics in Medicine, which defines a new autosomal recessive neurodevelopmental syndrome caused by biallelic variants in the synaptic adhesion molecule ELFN1. Through detailed clinical phenotyping of fourteen patients, molecular assays in human cells, and in vivo modeling in mice and zebrafish, the authors reveal how loss-of-function ELFN1 variants disrupt cell-surface trafficking, impair synaptic localization of group III metabotropic glutamate receptors, and give rise to developmental delay, epilepsy, and movement abnormalities.

🔍 Study Highlights:
Affected individuals uniformly present with moderate to severe developmental delay and intellectual disability accompanied by a broad range of seizure types and movement disorders; functional characterization shows that pathogenic ELFN1 variants fail to reach the neuronal surface, leading to loss of synaptic ELFN1 function; both Elfn1 knockout mice and zebrafish morphants exhibit hyperactivity, motor deficits, and spontaneous epileptiform brain activity, validating ELFN1 deficiency as the causal mechanism .

🧠 Conclusion:
This work establishes “ELFN1 Deficiency Disorder” as a distinct, rare monogenic condition and provides a mechanistic framework for future studies into its pathophysiology and the development of targeted therapeutic strategies.

📖 Reference:
Dore R., Chang C.-T., Declève A., Brunori G., Ludlam W.G., Huang A., Movahedinia M., Damseh N.S., Anwar I., Vahidi Mehrjardi M.Y., Ny A., Khorrami M., Kheirollahi M., Frederiksen H., Eghbal F., Mirjalili M.R., Dehghani M., Karimiani E.G., Oreshkov S., Alves C., Striano P., Suri M., Martinez-Agosto J., Ansar M., Zahid M., Akram S., Ansar M., Nelson S.F., Undiagnosed Diseases Network, Antonarakis S.E., Houlden H., Copmans D., Martemyanov K.A., Maroofian R. ELFN1 Deficiency: the mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy. Genetics in Medicine (2025). https://doi.org/10.1016/j.gim.2025.101506

📜 Licença:
Este episódio é baseado em um artigo de acesso aberto publicado sob a licença Creative Commons Attribution 4.0 International (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 70: Scalable Screening of Ternary-Code DNA Methylation Dynamics Associated with Human Traits

🧬 In this episode of Base por Base, we delve into a methodological breakthrough reported by Goldberg et al. (2025) in Cell Genomics, where the authors introduce the methylation screening array (MSA) — a next-generation Infinium BeadChip designed for large-scale, high-throughput profiling of DNA cytosine modifications across human populations. By integrating curated trait-associated loci from epigenome-wide association studies with novel cell-type discriminants, the MSA provides a compact yet comprehensive platform to measure ternary-code methylation (5mC, 5hmC, and unmodified cytosine) at base resolution across diverse tissues .

🔍 Highlights of the study:
The authors demonstrate that the MSA enables scalable and quantitative profiling of human epigenomes, overcoming the coverage–cost trade-offs of previous array designs; they construct a base-resolution atlas of matched total modifications (5modC) and 5hmC landscapes across multiple human tissues; they uncover how distinct patterns of 5modC and 5hmC correlate with gene expression to regulate tissue identity; and they reveal underappreciated roles for 5hmC in aging dynamics and the performance of epigenetic clocks .

🧠 Conclusion:
By consolidating extant EWAS discoveries and leveraging advances in whole-genome methylation profiling, the MSA inaugurates a scalable approach for trait-focused methylation screening in large cohorts. This tool promises to dissect cell-type-specific epigenetic mechanisms underlying human traits, improve the annotation of disease-associated loci, and inform genomics-driven strategies for prevention and precision medicine.

📖 Reference:
Goldberg, D. C., Cloud, C., Lee, S. M., Barnes, B., Gruber, S., Kim, E., Pottekat, A., Westphal, M. S., McAuliffe, L., Majounie, E., Kalayil Manian, M., Zhu, Q., Tran, C., Hansen, M., Stojakovic, J., Parker, J. B., Kohli, R. M., Porecha, R., Renke, N., & Zhou, W. (2025). Scalable screening of ternary-code DNA methylation dynamics associated with human traits. Cell Genomics, 5, 100929. https://doi.org/10.1016/j.xgen.2025.100929

📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 69: Synthetic Dosage Lethality of PLK1 — Targetable Vulnerabilities in PLK1-Overexpressing Cancers
🧬 In this episode of Base por Base, we delve into a comprehensive study by Cunningham et al. (2025) in Cell Genomics that harnesses genome-wide synthetic dosage lethality (SDL) screening to uncover novel therapeutic targets in cancers driven by Polo-like kinase 1 (PLK1). By integrating pooled shRNA and CRISPR-Cas9 screens in both in vitro and in vivo patient-derived xenograft models, followed by single-cell Perturb-seq analysis, the authors identify IGF2BP2 as a critical dependency in PLK1-overexpressing tumor cells. Mechanistic investigations reveal that loss of IGF2BP2 not only destabilizes PLK1 mRNA via disrupted m6A-mediated binding but also impairs mitochondrial oxidative phosphorylation, collectively crippling the energy metabolism of malignant cells. Finally, the first small-molecule inhibitors of IGF2BP2 recapitulate these effects, suppressing tumor growth in xenograft and PDX models and offering a dual-mechanism strategy to overcome tumor heterogeneity .

🔍 Highlights of the study:
Synthetic dosage lethality screening pinpoints IGF2BP2 loss as selectively lethal to PLK1-overexpressing cells.
Disruption of IGF2BP2 reduces PLK1 transcript and protein abundance by impairing m6A-dependent mRNA stabilization.
IGF2BP2 deficiency downregulates key oxidative phosphorylation genes, diminishing mitochondrial ATP production.
Pharmacological inhibition of IGF2BP2 mimics genetic knockout, decreasing cellular respiration and inducing apoptosis in PLK1-high models.
Combined genetic and chemical targeting of IGF2BP2 effectively suppresses tumor growth in multiple breast cancer xenograft and PDX systems.

🧠 Conclusion:
This work establishes IGF2BP2 as a synthetic lethal partner of PLK1, offering a two-pronged attack—downregulation of PLK1 and collapse of mitochondrial bioenergetics—to selectively target PLK1-overexpressing cancers. The identification of IGF2BP2 inhibitors lays the groundwork for precision therapies aimed at overcoming intratumoral heterogeneity in PLK1-driven malignancies.

📖 Reference:
Cunningham, C. E., Vizeacoumar, F. S., Zhang, Y., et al. (2025). Identification of targetable vulnerabilities of PLK1-overexpressing cancers by synthetic dosage lethality. Cell Genomics, 5, 100876. https://doi.org/10.1016/j.xgen.2025.100876

📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 68: Indels Empower Antiviral Proteins to Achieve Functional Novelty Beyond Missense Mutations
🧬 In this episode of Base by Base, we dive into pioneering work by Tenthorey et al. (2025) in Cell Genomics that uncovers how insertion and deletion mutations—indels—can unlock evolutionary innovations in the antiviral protein TRIM5α. By applying both deep mutational scanning and a novel deep indel scanning approach to the v1 loop of human TRIM5α, the authors reveal that while no single-nucleotide missense change can confer restriction of the simian immunodeficiency virus SIVsab, a single in-frame duplication of phenylalanine at position 339 instantaneously grants potent antiviral activity against SIVsab and other lentiviruses. This discovery highlights indels as a powerful, yet often overlooked, mechanism for traversing otherwise insurmountable fitness landscapes in host–virus evolutionary arms races.
🔍 Study Highlights: In exhaustive screens, human TRIM5α variants bearing every possible missense change failed to inhibit SIVsab, underscoring the limits of point mutations. Deep indel scanning then identified three in-frame duplication variants that gained SIVsab restriction, with the F339dup alone replicating nine independent rhesus-like mutations in one step. This single amino acid duplication not only enabled defense against SIVsab but also broadened activity to HIV-1 and SIVcpz without impairing existing N-tropic murine leukemia virus restriction, demonstrating a net evolutionary gain. Comparative analysis of primate TRIM5α orthologs confirmed that naturally occurring indels—such as a two-residue insertion in rhesus monkeys and a 20-residue duplication in sabaeus monkeys—directly determine species-specific antiviral specificities.
🧠 Conclusion: By revealing that indel mutations can deliver high-risk, high-reward leaps in protein function inaccessible by missense changes alone, this work reshapes our understanding of antiviral adaptation. Indels emerge not as mere byproducts of genetic drift but as strategic evolutionary tools that enable rapid, robust innovation in host defenses.
📖 Reference: Tenthorey, J. L., del Banco, S., Ramzan, I., Klingenberg, H., Liu, C., Emerman, M., & Malik, H. S. (2025). Indels allow antiviral proteins to evolve functional novelty inaccessible by missense mutations. Cell Genomics, 5, 100818. https://doi.org/10.1016/j.xgen.2025.100818
📜 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 67: Smarter Signals — How Multimodal AI Boosts Genetic Prediction of Heart Disease

🧬 In this episode of Base por Base, we delve into a major advancement in the intersection of artificial intelligence and cardiovascular genomics. A study by Zhou et al. (2025), published in The American Journal of Human Genetics, introduces M-REGLE (Multimodal Representation Learning for Genetic Discovery on Low-dimensional Embeddings), a novel AI framework designed to enhance genome-wide association studies (GWAS) by integrating multiple physiological waveform modalities such as ECG and PPG.

M-REGLE jointly analyzes these complementary health signals using variational autoencoders to generate low-dimensional, uncorrelated embeddings, which are then used to uncover new genetic associations. This multimodal approach allows for more effective representation of biological data than traditional unimodal models, significantly improving the power of GWAS and the accuracy of polygenic risk scores (PRS), especially for conditions like atrial fibrillation.

Compared to unimodal learning, M-REGLE identified 19.3% more loci from 12-lead ECG data and 13.0% more loci from ECG+PPG data. It also achieved superior PRS performance across several datasets, including UK Biobank, Indiana Biobank, EPIC-Norfolk, and the British Women’s Heart and Health Study. Notably, the embeddings generated by M-REGLE remained unsupervised yet were predictive of cardiovascular diseases, suggesting that the model captures meaningful physiological and pathological patterns from raw data alone.

🧠 Conclusion:
M-REGLE exemplifies the transformative potential of combining multimodal physiological data with deep generative models for genetic discovery. By capturing both shared and complementary information across modalities, this AI-driven approach opens new doors to understanding the genetic architecture of cardiovascular diseases and improving clinical prediction tools using data already available from wearable devices.

📖 Reference:
Zhou, Y., Khasentino, J., Yun, T., et al. (2025). Applying multimodal AI to physiological waveforms improves genetic prediction of cardiovascular traits. The American Journal of Human Genetics, 112, 1562–1579. https://doi.org/10.1016/j.ajhg.2025.05.015

📜 License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 66: Mainstreaming Clinical Genetic Testing — A Conceptual Framework

🧬 In this episode of Base por Base, we delve into the consensus-based framework introduced by Mackley et al. (2025) in Genetics in Medicine, which proposes a structured approach to integrate genetic testing into non-geneticist clinical practice to meet growing demand amid a stable genetics workforce .

🔍 Study Highlights:
The authors convened a focus group of thirty-five experts representing twenty clinical genetics services across Canada to define “mainstreaming,” map the diagnostic care pathway into assessment, pre-testing, laboratory, and post-testing stages, and identify key variables influencing model selection . The framework outlines six categories of variables—patient characteristics, disease features, test complexity, clinician expertise, report design, and health-system context—that determine the appropriateness of different mainstreaming models . It describes four generalizable models—“to-test,” “to-result,” “to-navigation,” and fully mainstreamed—that reflect progressively shifting responsibilities from the genetics service to non-geneticist clinicians . Designed for adaptability, the taxonomy facilitates standardized evaluation of accessibility, sustainability, diagnostic yield, and patient satisfaction across diverse clinical settings .

🧠 Conclusion:
This conceptual framework provides a unified roadmap for designing, implementing, and evaluating mainstreaming initiatives in clinical genetics, optimizing scopes of practice while improving patient access to genomics-informed care .

📖 Reference:
Mackley MP, Richer J, Guerin A, et al. Mainstreaming of clinical genetic testing: a conceptual framework. Genetics in Medicine. 2025. https://doi.org/10.1016/j.gim.2025.101465

📜 License:
This episode is based on an open access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

🎙️ Episode 65: Uncovering Hidden Splice Defects — Genome Sequencing and Group-Enrichment in Marfan Syndrome

🧬 In this episode of Base por Base, we delve into a groundbreaking study by Walker et al. (2025) in Genetics in Medicine that leverages whole-genome sequencing from the 100,000 Genomes Project alongside advanced in silico prediction and targeted RNA assays to reveal the contribution of non-canonical FBN1 splice variants to undiagnosed Marfan syndrome.

🔍 Key Highlights of the Study:
The authors systematically screened over 78,000 genomes, identifying 20 ultra-rare FBN1 variants in 23 families that lie beyond the ±8-base canonical splice regions; enrichment analysis showed these deep intronic and pseudoexon-creating variants account for approximately 3% of Familial Thoracic Aortic Aneurysm Disease cases previously lacking a molecular diagnosis; 70% of the variants were predicted to generate novel pseudoexons or extend exons, often introducing premature termination codons; experimental confirmation via RT-PCR, minigene constructs, and limited RNA-seq validated splicing aberrations for 16 of the 20 variants; replication in UK Biobank participants coded for Marfan syndrome supported a significant enrichment of predicted splice defects; these findings underscore the power of integrating genome sequencing, SpliceAI predictions, and bespoke RNA testing to uncover cryptic splice mutations that standard clinical assays may miss .

🧠 Conclusion:
This work inaugurates a new paradigm in Marfan diagnostics, demonstrating that systematic intronic analysis and confirmatory RNA assays can lift the veil on cryptic splice variants, thereby enhancing diagnostic yield and guiding more precise surveillance strategies for individuals at risk.

📖 Reference:
Walker S., Bunyan D.J., Thomas H.B., et al. (2025). Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome. Genetics in Medicine. https://doi.org/10.1016/j.gim.2025.101477

📜 License:
This episode is based on a journal pre-proof published by Elsevier Inc. on behalf of the American College of Medical Genetics and Genomics. All rights reserved.