🎙️ 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/