Base by Base

Watkins WS et al et al., Nature Communications - A prospective observational study of 2,253 Pediatric Cardiac Genomics Consortium patients shows that whole-exome sequencing combined with AI genome interpretation and Bayesian networks improves prediction of adverse outcomes after congenital cardiac surgery. Damaging de novo variants in chromatin-modifying genes and recessive/biallelic variants in cilia-related genes increase risk of mortality, cardiac arrest, and prolonged ventilation, especially when combined with specific CHD phenotypes, surgical complexity, and extracardiac anomalies. Key terms: congenital heart disease, genome sequencing, chromatin-modifying genes, cilia genes, Bayesian networks.

Study Highlights:
In 2,253 CHD patients the AI tool GEM identified putative damaging genotypes in 10.6% of individuals. Damaging de novo chromatin variants increased probabilities of mortality, cardiac arrest, and prolonged ventilation (≈1.6–1.8-fold), while recessive cilia genotypes showed similar relative risk increases. Risks were amplified in specific contexts (LVO/HLHS, HTX, STAT4/5 surgeries and presence of extracardiac anomalies) and absence of damaging genotypes was associated with reduced risk. Bayesian network models quantified these conditional dependencies to enable personalized risk estimates.

Conclusion:
Genome sequencing, interpreted with AI and integrated into probabilistic clinical models, enriches outcome forecasting after congenital cardiac surgery and can inform preoperative risk stratification and targeted perioperative strategies.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Genome sequencing is critical for forecasting outcomes following congenital cardiacsurgery

First author:
Watkins WS et al

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61625-0

Reference:
Watkins WS et al., Genome sequencing is critical for forecasting outcomes following congenital cardiacsurgery. Nature Communications (2025) 16:6365. https://doi.org/10.1038/s41467-025-61625-0

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/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/base-by-base-80-genome-sequencing-chd

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-19.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections covering CHD outcome prediction, AI-based phenotyping and GEM genomic interpretation, Bayesian network linkage of genotype to phenotype to outcomes, chromatin- and cilia-associated variant effects, ECAs, surgical complexity, rapid sequencing implications, and study limitations.
- transcript topics: CHD post-surgical outcome prediction; AI-based phenotyping using Fyler codes (LVO, HTX, AVC, CTD, OTH); GEM damaging variants in chromatin-modifying and cilia genes; Bayesian networks linking genotype to phenotype and outcomes; Impact of extracardiac anomalies and surgical complexity; Clinical implications of rapid genome sequencing for perioperative care

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Cohort of 2,253 CHD patients analyzed with exome sequencing and perioperative outcomes
- GEM identified damaging genotypes in 238 participants (10.6%)
- Damaging de novo chromatin-modifying variants associated with ~1.8x mortality, ~1.7x cardiac arrest, and ~1.6x prolonged ventilation
- Damaging recessive/biallelic cilia variants associated with ~1.4x mortality, ~1.5x cardiac arrest, and ~1.4x prolonged ventilation
- Absence of damaging genotypes associated with reduced risk: mortality RR ~0.55 and prolonged ventilation RR ~0.70
- ECAs increase risk: mortality ~2.8x and prolonged ventilation ~1.7x; damaging genotypes enriched in probands with ECAs

QC result: Pass.

Nature Communications - A large cross-population GWAS meta-analysis (168,007 AF cases) integrated with proteomic data identifies hundreds of AF loci, implicates cardiac and TGF-β pathways, finds causal risk factors and proteins via Mendelian randomization, and shows improved prediction when combining polygenic and protein scores. Key terms: atrial fibrillation, cross-population GWAS, proteomics, polygenic risk score, Mendelian randomization.

Study Highlights:
The cross-population meta-analysis identified 525 genome-wide significant loci for atrial fibrillation and prioritized likely causal genes. Pathway analyses implicated muscle development, heart contraction, TGF-β signaling and vascular and cytoskeletal processes. Mendelian randomization highlighted modifiable risk factors (obesity, blood pressure, diabetes, smoking, insomnia, lipids, alcohol) and implicated 28 circulating proteins with potential causal roles. Combining a polygenic risk score and a proteomic score substantially improved AF risk prediction compared with either alone.

Conclusion:
Integrating diverse GWAS with proteomics refines AF genetic architecture, reveals mechanistic pathways and candidate protein targets, and materially improves risk prediction when polygenic and protein scores are combined.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Cross-population GWAS and proteomics improve risk prediction and reveal mechanisms in atrial fibrillation

Journal:
Nature Communications

DOI:
10.1038/s41467-025-61720-2

Reference:
https://doi.org/10.1038/s41467-025-61720-2

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/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/ep-79-cross-population-gwas-proteomics-af

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-18.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the spoken content describing cross-population AF GWAS, shared PITX2/ZFHX3 loci, Mendelian randomization of modifiable risk factors, NT-proBNP direction, proteomics (ProS) and polygenic scores (PGS), and risk-prediction improvements; included limitations and clinical implications.
- transcript topics: Cross-population GWAS meta-analysis for atrial fibrillation; Shared PITX2 and ZFHX3 loci across ancestries; Gene prioritization and AF pathways (muscle development, cardiogenesis, TGF-β signaling); Mendelian randomization of modifiable AF risk factors (BMI, insomnia, etc.); Proteomics integration and protein scoring (ProS) with polygenic scores (PGS); NT-proBNP paradox and causal direction in MR

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 4
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Cross-population GWAS meta-analysis included 168,007 AF cases and 1,959,739 controls across multiple ancestries
- Identified 525 genome-wide significant loci; 483 Europeans, 29 East Asians, 5 Africans, 2 admixed Americans; PITX2 and ZFHX3 shared across ancestries
- Pathway enrichment implicates muscle development, cardiogenesis, TGF-β signaling, arterial morphogenesis, electrical coupling
- Mendelian randomization identified modifiable AF risk factors: BMI, waist-to-hip ratio, visceral adiposity, childhood BMI, LDL, type 2 diabetes, blood pressure, smoking initiation,
- 28 circulating proteins with potential causal associations to AF; NT-proBNP inversely related to AF risk in MR
- Proteomic score (ProS) built from 87 proteins; ProS AUC = 0.792; combined PGS+ProS AUC = 0.823; top-decile AF risk >6-fold

QC result: Pass.

Sukalskaia A et al., Nature - This Nature study identifies APOE as an interaction partner of human TTYH2, maps their endosomal colocalization and binding site by cryo-EM, and shows that TTYH2 accelerates lipid transfer from APOE-containing lipoproteins to membranes in vitro. Key terms: TTYH2, APOE, lipid transfer, endosomes, cryo-EM.

Study Highlights:
Using sybody pull-downs and mass spectrometry the authors identified APOE as a TTYH2 interaction partner and showed both proteins colocalize in endosomal fractions and by confocal microscopy. Single-molecule force spectroscopy and competitive sybody displacement localized the APOE-binding site to the extracellular tip of TTYH2. Cryo-EM of complexes and lipoprotein discs positioned APOE and lipids near a hydrophobic cavity that links the membrane and lumen, and high-resolution maps revealed a continuous lipid path into the cavity. In DPPC-enriched proteoliposomes, TTYH2 markedly accelerated transfer of fluorescent lipids from APOE-containing particles while no convincing scramblase activity was detected.

Conclusion:
TTYH2 binds APOE in endosomal compartments and functions as a paralogue-specific facilitator that brings lipids from APOE-containing lipoproteins into the membrane via a hydrophobic extracellular cavity; further cellular studies are needed to define physiological and pathological roles.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Interactions between TTYH2 and APOE facilitate endosomal lipid transfer

First author:
Sukalskaia A

Journal:
Nature

DOI:
10.1038/s41586-025-09200-x

Reference:
Sukalskaia A., Karner A., Pugnetti A., Weber F., Plochberger B. & Dutzler R. Interactions between TTYH2 and APOE facilitate endosomal lipid transfer. Nature. doi:10.1038/s41586-025-09200-x (2025).

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/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/ttyh2-apoe-endosomal-lipid-transfer

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-17.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript's portrayal of the primary mechanistic claims and experimental evidence from the Nature article, including interaction evidence, endosomal localization, binding site, structural interpretation, lipoprotein-disc binding, lipid transfer kinetics, scramblase tests, and brain relevance.
- transcript topics: APOE–TTYH2 interaction and pull-down evidence; Endosomal colocalization of APOE and TTYH2; Extracellular tip epitope binding and cryo-EM mapping; APOE-containing lipoprotein discs and lipids near the hydrophobic cavity; Single-molecule force spectroscopy (SMFS) and koff measurements; In vitro lipid-transfer assays and DPPC liposome results

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 7
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- APOE identified as interaction partner of TTYH2; both proteins colocalize in endosomes
- TTYH2–APOE interactions observed across lipidation states; extracellular tip epitope implicated
- Cryo-EM shows APOE/lipids near a hydrophobic cavity in TTYH2; lipid belt/pathway described
- Lipid transfer from APOE-containing lipoproteins accelerated by TTYH2 in DPPC liposomes (14-fold)
- TTYH2 not acting as a scramblase; no convincing scramblase activity detected
- TTYH3 binds APOE poorly or not at all and does not accelerate lipid transfer

QC result: Pass.

Bower G et al., Nature - This paper identifies a conserved cis element, REX, and a [C/T]AATTA homeodomain motif signature that are necessary and sufficient to convert short- and medium-range limb enhancers into megabase-range regulators of Shh during mouse limb development. Key terms: enhancer, long-range regulation, REX element, homeodomain motifs, Shh.

Study Highlights:
Transplanted short- and medium-range limb enhancers failed to activate Shh when placed at the endogenous ZRS location, despite maintaining open chromatin. A conserved adjacent sequence, named REX, lacks standalone enhancer activity but is necessary and sufficient to extend enhancer range, in one case increasing activity from 73 kb to 848 kb. The REX element and long-range enhancers are enriched for conserved [C/T]AATTA homeodomain motifs (LHX-like), and mutating these motifs in REX or in the endogenous ZRS abolishes long-range but not short-range activity, producing severe limb truncation in knock-in mice.

Conclusion:
Long-range enhancer–promoter communication can be genetically encoded by separable cis-elements and motif signatures: REX and conserved [C/T]AATTA motifs enable enhancers to act over megabase distances, uncoupling spatial specificity from genomic reach.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Range extender mediates long-distance enhancer activity

First author:
Bower G

Journal:
Nature

DOI:
10.1038/s41586-025-09221-6

Reference:
Bower G. et al., Nature (2025) doi:10.1038/s41586-025-09221-6

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/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/rex-long-range-enhancer-activity

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-16.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcription of the article's central claims: discovery and necessity of REX, the role of CTATA/LHX/LEF1 motifs, long-range vs short-range enhancer behavior at Shh, in vivo enhancer-replacement and mutagenesis experiments, and the modular enhancer model.
- transcript topics: 3D genome organization and enhancer-promoter communication; ZRS/Shh regulatory architecture and long-range activation; REX element discovery and characterization; MM1492 and HS72 enhancer replacements at the Shh locus; CTATA/LHX/LEF1 motif roles in long-range regulation; ZRS HD motif mutagenesis and rescue experiments with REX

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- REX element is adjacent to a long-range limb enhancer (near HS72) and confers long-distance activity when added to short-range enhancers
- ZRS is located ~848 kb from Shh; short-range enhancers fail to activate Shh at this distance
- MM1492 (short-range enhancer, ~73 kb native range) can be extended to long-range activation when fused with REX (MM1492+REX) and placed at 848 kb from Shh
- REX alone lacks enhancer activity but is necessary for long-range activation; ZRS+REX experiments show long-range activation of Shh
- CTATA ([C/T]AATTA) homeodomain motifs are enriched in long-range enhancers and are required for long-range but not short-range activity
- Disrupting ZRS [C/T]AATTA motifs abolishes long-range activity but not short-range expression; adding REX can partially rescue long-range activation

QC result: Pass.

️ Episode 76: Whole-genome Ancestry of an Old Kingdom Egyptian

In this episode of PaperCast Base by Base, we explore the first 2× coverage whole-genome sequence recovered from a high-status individual of the Old Kingdom excavated at the Nuwayrat necropolis and examine the evidence for multi-regional ancestry during early Dynastic Egypt.

Study Highlights:

The research team extracted and authenticated ancient DNA from a pot-burial dating to 2855–2570 cal BCE and generated a 2.02× coverage genome allowing comprehensive ancestry inference. Population genetic analyses revealed that approximately 78% of the genome traces back to North African Neolithic populations and 22% to Neolithic Mesopotamian sources, demonstrating early contacts between Egypt and the eastern Fertile Crescent. Radiocarbon dating, osteological examination, and isotopic profiling confirmed the individual’s timeline, physiological attributes, and Nile Valley upbringing. Uniparental marker and admixture modeling provided further resolution of complex migration and continuity patterns predating known Bronze Age expansions.

Conclusion:

This study establishes the feasibility of whole-genome sequencing for early Dynastic Egyptians and uncovers direct genetic links between ancient Egypt and West Asia, reshaping our understanding of population dynamics in the Old Kingdom.

Reference:

Jacobs AM et al. Whole-genome ancestry of an Old Kingdom Egyptian. Nature. 2025. DOI:10.1038/s41586-025-09195-5

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/

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Lemke O et al., Nature - A deep structural and evolutionary analysis of 11,269 enzyme structures across Saccharomycotina reveals how metabolic context sculpts protein architecture. The study integrates AlphaFold2 models, proteomics and metabolic models to map hierarchical constraints on enzyme evolution. Key terms: enzyme evolution, metabolism, AlphaFold2, structural conservation, yeast.

Study Highlights:
The authors analyzed 11,269 predicted and experimental enzyme structures across 424 orthogroups in 27 yeast species to link structural divergence to metabolic properties. They show that metabolism constrains structural evolution at species, pathway and molecular scales, with substrate-binding sites being the most conserved and surface residues evolving fastest. Metal-binding, number of intracellular inhibitors, flux variability, protein abundance and biosynthetic cost each influence conservation. Cost optimization acts primarily on surface residues while catalytic and small-molecule interactions limit substitutions in binding sites.

Conclusion:
Enzyme structural evolution is governed primarily by catalytic function and metabolic context, producing a hierarchy of conservation that informs enzyme annotation and strategies for metabolic engineering.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
The role of metabolism in shaping enzyme structures over 400 million years

First author:
Lemke O

Journal:
Nature

DOI:
10.1038/s41586-025-09205-6

Reference:
Lemke O., Heineike B.M., Viknander S., et al. The role of metabolism in shaping enzyme structures over 400 million years. Nature (2025). https://doi.org/10.1038/s41586-025-09205-6

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/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/metabolism-shapes-enzyme-structures-75

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-14.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited core scientific claims about structural evolution in enzymes under metabolic constraints, MR/CR metrics, abundance-cost effects, thiamine suicide enzymes, binding-site clusters, and AlphaFold2-based methodology as presented in the transcript.
- transcript topics: AlphaFold2-based structure prediction in Saccharomycotina; Mapping ratios (MR) and conservation ratios (CR) and their interpretation; Metabolic context: fermentation vs respiration and pathway effects; Enzyme abundance, flux, and cost optimization; Thiamine biosynthesis suicide enzymes and conservation; Binding-site clusters as predictive features for binding and PPIs

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Reported number of enzyme structures analyzed: 11,269 (AlphaFold2-predicted and experimentally determined).
- Orthogroups: 424; species: 27; reactions: 361 across 225 pathways.
- Binding sites are highly conserved; surface residues evolve fastest; core remains conserved.
- Abundance and cost influence evolution: high-abundance enzymes favor cheap amino acids; low-abundance enzymes show greater diversity and use of more expensive amino acids.
- Thiamine biosynthesis enzymes Thi5p/Thi11p/Thi12p/Thi13p are conserved despite low abundance due to suicide reactions and high chemical costs.
- AlphaFold2 predictions are integrated with evolutionary data; limitations acknowledged for loops/random coils; Saccharomycotina focus.

QC result: Pass.

Drost F et al., Cell Genomics - Drost et al. integrated 21 pre-trained sequence-based TCR-epitope predictors into ePytope-TCR and benchmarked them on a viral single-cell repertoire and deep mutational scans, revealing performance biases and limited generalization to rare and mutated epitopes. Key terms: T cell receptor, epitope prediction, ePytope-TCR, benchmarking, cross-reactivity.

Study Highlights:
The authors unified 21 sequence-based TCR-epitope predictors inside ePytope-TCR and evaluated them on two challenging datasets: a viral single-cell repertoire and deep mutational scans. Models predicted binding reliably for frequently observed epitopes but failed for less-represented targets. Strong biases in prediction scores between epitope classes were evident and most methods could not predict effects of single-residue epitope mutations. ePytope-TCR provides interoperable interfaces and a standardized benchmark to guide tool selection and method development.

Conclusion:
Pre-trained TCR-epitope predictors can annotate well-studied epitopes but do not generalize to rare or mutated epitopes; ePytope-TCR standardizes access and benchmarking to help researchers choose tools and accelerate development of improved models.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Benchmarking of T cell receptor-epitope predictors with ePytope-TCR

First author:
Drost F

Journal:
Cell Genomics

DOI:
10.1016/j.xgen.2025.100946

Reference:
Drost F., Chernysheva A., Albahah M., Kocher K., Schober K., Schubert B. Benchmarking of T cell receptor-epitope predictors with ePytope-TCR. Cell Genomics. 2025;5:100946. doi:10.1016/j.xgen.2025.100946

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/

Support:
Base by Base is independent and ad-free — no sponsors, no paywall. If an episode was worth your time, chip in and keep the papers audited and the original songs coming:
❤️ Support monthly: https://buy.stripe.com/cNifZhclVebvagk2JDgEg01
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More at basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/epytope-tcrbenchmark-suite-corrupted-pdf

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-13.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections describing the Epitope-TCR benchmarking framework, data formats and ingestion, viral benchmarking dataset, deep mutational scanning dataset, performance metrics, bias observations, and practical implications.
- transcript topics: Benchmarking framework and Epitope-TCR architecture; Data format interoperability and unified interface; Categorical vs general predictors; Viral benchmarking dataset (638 TCRs, 14 epitopes, 5 MHC backgrounds); Deep mutational scanning dataset (epitope mutations VPSVWRSSL and NLVPMVATV); Performance metrics (AUC, recall@K, APS, F1) and results

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- ePytope-TCR provides a unified interface ingesting six common data formats and 21 pre-trained models
- Two benchmarking datasets used: a viral dataset and a deep mutational scanning dataset
- Viral dataset composition: 638 distinct TCRs, 14 epitopes, 5 MHC backgrounds
- Mutation dataset comprises deep mutational scans with 132 mutations for VPSVWRSSL and 172 mutations for NLVPMVATV; evaluated on 26 TCRs
- top performance: four general and two categorical methods exceed AUC 0.6; best AUC ~0.63 (MixTCRpred)
- Recall@1 results: approximately 0.24–0.26 across evaluated models

QC result: Pass.

König T et al., Genetics in Medicine - A retrospective study of 701 memory clinic patients tested whether stratifying by age at onset and family history enriches for diagnostically relevant genetic findings. Using an adapted Goldman-score classification with exome sequencing and targeted genotyping in high-risk cases, the authors increased diagnostic yield and evaluated implications for APOE and C9ORF72 testing. Key terms: Alzheimer's disease, Exome sequencing, APOE, Genetic risk, Diagnostic yield.

Study Highlights:
In 701 dementia patients, 34–48% reported a positive family history depending on diagnosis. Applying an adapted age-at-onset (≤65 years) and Goldman-score stratification identified 51 high-risk patients, 38 of whom had complete genetic data. Among those 38, 39% carried diagnostically relevant variants including APP, PSEN1, MAPT, GRN, C9ORF72 repeat expansions and APOE4/4. Using a stricter ≤60-year cutoff increased yield but missed several APOE4/4 and one C9ORF72 case, showing trade-offs between sensitivity and specificity.

Conclusion:
A standardized classification by age at onset and family history improves selection for genetic testing in memory clinics, raising diagnostic yield to 39% among high-risk patients and supporting routine APOE and C9ORF72 testing while cautioning that overly strict onset cutoffs can miss clinically important cases.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
Assessing family history and approaches for identifying dementia patients with diagnostically significant genetic findings

First author:
König T

Journal:
Genetics in Medicine

DOI:
10.1016/j.gim.2025.101517

Reference:
König T, Silvaieh S, Parvizi T, Wurm R, Goeschl S, Uhlik E, Farr C, Berger-Sieczkowski E, Untersteiner H, Zimprich A, Stögmann E. Assessing family history and approaches for identifying dementia patients with diagnostically significant genetic findings. Genetics in Medicine. 2025. https://doi.org/10.1016/j.gim.2025.101517

License:
© 2025 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/family-history-genetic-dementia-s2e73

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-12.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of the transcript's presentation of the article's methods and results, including: AAO cutoff change (60→65) and its impact on yield; Goldman score integration; cohort/genetic testing approach (ES + APOE genotyping + C9ORF72 testing); key pathogenic variants; C9ORF72 repeat testing; APOE4/4 onset and t
- transcript topics: Overview of dementia genetics and testing landscape; Goldman score and age-at-onset integration; Cohort design and sequencing approaches (ES, APOE, C9ORF72); C9ORF72 repeat expansions testing and limitations of ES; APOE4/4 genotype and age-at-onset interactions; Anti-amyloid therapies, ARIA risk, and regulatory considerations

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 8
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Cohort size: 701 dementia patients (490 AD spectrum, 29 FTD, 182 other/mixed).
- 51 high-risk patients identified; 38 had complete data and underwent genetic analysis.
- Among analyzed high-risk patients, 15/38 (39%) carried diagnostically relevant variants (APP, PSEN1, MAPT, GRN, C9ORF72, APOE4/4).
- C9ORF72 repeat expansions detected via specialized testing (two-step PCR and Southern blotting).
- 65-year AAO cutoff (instead of 60) increased capture of APOE4/4 cases; missed 4 APOE4/4 and 1 C9ORF72 with 60-year cutoff.
- APOE4/4 carriers had a later median onset (~68 years), illustrating semi-dominant effects and limits of a strict 60-year cutoff.

QC result: Pass.

Vulto-van Silfhout AT et al., Genetics in Medicine - A cohort study of twelve families shows that bi-allelic loss-of-function variants in POC5 cause a multisystem syndrome characterized by rod-cone dystrophy, early-onset insulin-resistant diabetes with partial lipodystrophy, renal disease and muscle cramps. Cellular studies in patient fibroblasts reveal reduced POC5 expression due to nonsense-mediated decay and mislocalization at centrioles, supporting a ciliopathy mechanism. Key terms: POC5, ciliopathy, retinitis pigmentosa, insulin resistance, lipodystrophy.

Study Highlights:
Twelve families with bi-allelic POC5 loss-of-function variants were characterized clinically and molecularly, revealing a consistent multisystem phenotype including rod-cone dystrophy, insulin-resistant diabetes with partial lipodystrophy, kidney disease and muscle cramps. RNA studies showed reduced POC5 transcript levels consistent with nonsense-mediated decay for predicted truncating variants. Immunofluorescence in proband-derived fibroblasts showed loss or reduction of POC5 centriolar localization and altered centrin distribution with largely preserved ciliogenesis and SHH signaling. These data support that POC5 LoF causes a pleiotropic ciliopathy that includes metabolic and adipose tissue dysfunction.

Conclusion:
Bi-allelic loss-of-function variants in POC5 cause an autosomal recessive multisystem ciliopathy marked by retinal dystrophy, insulin-resistant diabetes with partial lipodystrophy, renal disease and neuromuscular symptoms, and are associated with reduced POC5 expression and mislocalization at centrioles.

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Article title:
Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine and neuromuscular ciliopathy

First author:
Vulto-van Silfhout AT

Journal:
Genetics in Medicine

DOI:
10.1016/j.gim.2025.101513

Reference:
Vulto-van Silfhout AT, Jazet IM, Yzer S, et al. Bi-allelic loss-of-function variants in POC5 cause a syndromic retinal, endocrine and neuromuscular ciliopathy. Genetics in Medicine (2025). doi: 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 License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/poc5-ciliopathy-retinal-endocrine-neuromuscular

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-11.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited transcript sections covering POC5/ciliopathy background, identification of variants and NMD analysis, centriolar localization and ciliogenesis SHH results, and comprehensive clinical phenotype (retinal dystrophy, diabetes with insulin resistance, lipodystrophy, renal disease, muscle cramps) with translational i
- transcript topics: POC5 and ciliopathy overview; Bi-allelic LoF variants in POC5; NMD and CHX RNA analysis; POC5 centriolar localization and centrin; Ciliogenesis and SHH signaling in fibroblasts; Clinical phenotype: retinal dystrophy and metabolic features

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- POC5 bi-allelic loss-of-function variants identified across 12 families.
- Rod-cone dystrophy observed in 11/12 probands.
- Early-onset diabetes mellitus with high insulin resistance observed in 10/12 participants.
- Partial lipodystrophy observed in six participants; ectopic fat accumulation in liver/abdomen.
- Renal insufficiency reported in 4/12 participants.
- POC5 transcripts reduced with evidence of nonsense-mediated decay; CHX treatment increases detectable transcript.

QC result: Pass.

Dore R et al., Genetics in Medicine - This episode reviews a multi-center study that defines ELFN1 deficiency as a recessive neurodevelopmental disorder. The authors report new patients with biallelic ELFN1 variants, show that pathogenic variants impair ELFN1 surface trafficking and mGlu receptor binding, and present mouse and zebrafish models that reproduce hyperactivity and epileptiform activity. Key terms: ELFN1, synaptic adhesion, epilepsy, neurodevelopmental disorder, loss of function.

Study Highlights:
The study describes eight new patients from five unrelated families with homozygous ELFN1 variants and integrates clinical data from previously reported cases to define a consistent spectrum of developmental delay, epilepsy and movement disorders. Functional assays in HEK293 cells showed that multiple ELFN1 variants severely reduce plasma membrane trafficking and abolish interaction with group III metabotropic glutamate receptors. Structural modelling of an in-frame Val159 deletion predicts local disruption of the LRR domain consistent with trafficking and binding defects. Elfn1 knockout mice and zebrafish morphants display hyperactivity and epileptiform brain activity, supporting loss of function as the disease mechanism.

Conclusion:
Biallelic ELFN1 variants cause a loss-of-function recessive neurodevelopmental disorder—proposed as ELFN1 Deficiency Disorder—characterized by developmental delay, epilepsy and movement abnormalities, driven by impaired ELFN1 trafficking and disrupted mGlu receptor interactions.

Music:
Enjoy the music based on this article at the end of the episode.

Article title:
ELFN1 Deficiency: the mechanistic basis and phenotypic spectrum of a neurodevelopmental disorder with epilepsy

First author:
Dore R

Journal:
Genetics in Medicine

DOI:
10.1016/j.gim.2025.101506

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

License:
© 2025 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00

Official website https://basebybase.com

On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Episode link: https://basebybase.com/episodes/elfn1-deficiency-mechanisms-phenotype

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-10.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing ELFN1 function, variant impact on trafficking and mGlu binding, Val159del structural effects, cell-surface trafficking assays, mouse and zebrafish models, human clinical phenotype, and potential therapeutic directions.
- transcript topics: ELFN1 function as trans-synaptic synaptic adhesion and mGlu receptor anchoring; Variants causing ELFN1 loss of function and trafficking defects; Val159del structural impact and loss of mGlu binding; Cell surface trafficking assays (biotinylation) and ectodomain pull-downs; Mouse Elfn1 knockout and haploinsufficiency hyperactivity; Zebrafish elfn1a/elfn1b morpholino knockdown, locomotor changes and LFP seizures

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- ELFN1 functions as a synaptic cell adhesion molecule that binds and anchors group III mGlu receptors at synapses, with allosteric modulation of mGlu receptor function
- Biallelic ELFN1 variants disrupt ELFN1 trafficking to the cell surface, causing loss of function
- Val159del (c.475_477del) disrupts the LRR domain, severely impairs surface trafficking, and abolishes mGlu receptor binding
- Elfn1-/- mice show hyperactivity; Elfn1+/− mice also display hyperactivity (haploinsufficiency effect observed)
- Zebrafish elfn1a/b morphants show seizure-like behavior and increased epileptiform brain activity measured by LFP and PSD changes
- Epilepsy is present in the majority of patients (12/14) with onset ranging from neonatal to several years

QC result: Pass.