Atlas / Deep research
Microcephaly Genomics Literature Map
This page is the research layer that wraps the inherited MCPH heatmap. It asks: what is the current genomic state of the art for primary microcephaly, and how does that Mendelian developmental biology connect to psychiatric, cognitive, cortical, and neurodegenerative disease genetics?
Answered with reviews, cohort sequencing, gene-specific mechanisms, HGNC aliases, PanelApp/G2P/OMIM/ClinGen, and recent functional papers.
Answered with fetal brain development, neural stem cell expression, cross-disorder GWAS, MPRA, and single-cell regulatory-genomics papers.
Research protocol
How I would run the literature review if this were a thesis chapter.
Start from the local scientific object
Use Mario's 33-gene MCPH list, the original bundle databases, the R heatmap, and Mario's Master's thesis bibliography as the seed. This prevents the review from becoming a generic microcephaly essay: every paper must help explain the exact plot, the exact genes, or the exact disease intersections in this project.
Normalize names before searching
Search both current and historical symbols: KNL1/CASC5/D40/Blinkin and TRAPPC14/C7orf43/MAP11. Do the same for every MCPH gene with HGNC aliases. Otherwise, the older literature and older databases appear falsely incomplete.
Use PubMed for biomedical precision
PubMed is the backbone for curated biomedical metadata: PMID, journal, title, authors, publication year, MeSH-like discoverability, abstracts, and links to PubMed Central where available. The core queries combine primary microcephaly, MCPH, exome/genomics, mechanisms, and each gene symbol.
Use Google Scholar for citation chasing
Google Scholar is excellent for "cited by" exploration and locating preprints, theses, conference abstracts, and institutional repositories. I would not scrape it automatically; I would use it manually to check whether anchor papers have newer citing papers not yet obvious in PubMed.
Use OpenAlex, Crossref, and Semantic Scholar as reproducible layers
OpenAlex gives citation counts, DOI-normalized metadata, publication venues, and open web identifiers. Crossref is useful for DOI verification. Semantic Scholar is useful for topic-sensitive relevance and citation neighborhoods. These do not replace reading papers; they make the bibliography traceable.
Use Connected Papers for conceptual topology
For visual mapping, seed Connected Papers with one recent anchor paper, especially Mato-Blanco et al. 2025 on neural stem cells and cortical disorders, then separately with Phan and Holland 2021 or Zaqout and Kaindl 2022 for MCPH mechanisms. The graph should guide reading clusters, not replace source evaluation.
Separate causal evidence from intersection evidence
MCPH gene causality comes from families, exome/genome sequencing, biallelic variant interpretation, model systems, and clinical gene-disease validity. Psychiatric or cognitive intersections usually come from common-variant GWAS, gene-set enrichment, fetal brain expression, chromatin accessibility, MPRA, and single-cell annotations.
Rank papers by thesis utility
A paper can be important because it is highly cited, very recent, directly about one of our confusing genes, or methodologically close to the heatmap. The bibliography below labels each paper by role so we do not confuse popularity with relevance.
First synthesis
The field is converging on one big idea: small brains are often progenitor problems.
Primary microcephaly is not simply "a list of genes that make the head small." The most coherent modern view is that many MCPH genes are dosage-sensitive components of the machinery that lets neural stem and progenitor cells expand safely before they generate neurons. Centrosomes, centrioles, kinetochores, spindle orientation, DNA repair, RNA processing, chromatin state, cilia, and cell-cycle timing all matter because early cortical growth is an amplification problem: a small change in progenitor survival, mitotic timing, or symmetric/asymmetric division can produce a large change in final neuron number.
This is why Gabriel Santpere's developmental-genomics line is so relevant to the old heatmap. The inherited plot is asking whether genes selected from one developmental phenotype, microcephaly, occupy biologically meaningful positions in fetal progenitor expression and in other disease gene sets. The modern version of that question should not only count intersections; it should ask when the genes are active, which progenitor states they perturb, which mechanisms they share, and which disease categories are genuinely connected rather than merely sharing broad neurodevelopmental vocabulary.
Lane A: define MCPH genes
Reviews and cohort papers establish the causal landscape, inheritance patterns, core mechanisms, and the difference between classic MCPH genes and syndromic/candidate microcephaly genes.
Lane B: explain KNL1/CASC5
The KNL1 alias story is not clerical. It tells us that older databases, older scripts, and current HGNC nomenclature can disagree while referring to the same biological object.
Lane C: connect to progenitors
Human neural stem cell and fetal cortex papers translate gene lists into developmental timing, cell type, chromatin state, and regulatory-network context.
Lane D: connect to psychiatric genomics
Cross-disorder GWAS and MPRA papers show how ASD, ADHD, schizophrenia, bipolar disorder, depression, and other traits share regulatory architecture, often active during fetal brain development.
Gene-by-gene evidence matrix
For each MCPH gene: papers, PanelApp, ClinGen, Open Targets, and live database trails.
This is the bibliographic evidence pass requested after the first literature map. It is generated from public sources on June 17, 2026: PanelApp Severe microcephaly, PubMed, ClinGen gene-disease validity downloads, Open Targets Platform, and direct links to HGNC, G2P, OMIM, and ClinGen searches.
Reasoned bibliography
Curated anchor papers for the next version of the atlas.
Citation-network metadata were checked during curation, but the visible bibliography keeps the paper byline clean: authors, journal, year, DOI, and direct source links.
1. State-of-the-art reviews: what MCPH means biologically
Time is of the essence: the molecular mechanisms of primary microcephaly
This is probably the best conceptual entry point for the thesis because it explains why timing of progenitor expansion, centrosomes, mitosis, and developmental checkpoints are central to MCPH.
The Genetics of Primary Microcephaly
A high-value foundation for classic MCPH genes, cortical development, centrosome/cell-cycle mechanisms, and why brain size is especially sensitive to progenitor biology.
Dissecting the Genetic and Etiological Causes of Primary Microcephaly
Useful for separating inherited primary microcephaly, secondary/environmental causes, syndromic presentations, and gene discovery logic.
Autosomal Recessive Primary Microcephaly: Not Just a Small Brain
Important because it pushes beyond the simplistic idea of MCPH as isolated small brain size and emphasizes broader neurodevelopmental and systemic features.
Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size
A focused review for the centrosome/centriole axis, especially useful for interpreting genes such as ASPM, WDR62, CDK5RAP2, CEP135, CEP152, and CENPJ.
DNA damage and repair: underlying mechanisms leading to microcephaly
Essential for genes whose microcephaly mechanism is genome maintenance rather than only spindle/centrosome biology. It helps frame PNKP, ATR, NBS1-like pathways, and p53-mediated progenitor loss.
2. Recent discovery and mechanism papers: where the field is now
Expanding the genetic spectrum of autosomal recessive microcephaly in Pakistani families
Very recent family-based sequencing paper. It is useful for showing that MCPH gene discovery and variant interpretation remain active in consanguineous/founder-enriched populations.
Elucidating the Genetic Landscape, Phenotypic Spectrum, and Pathogenic Mechanisms in a Turkish Cohort with Primary Microcephaly
Important because a cohort design can distinguish frequent, rare, syndromic, and candidate mechanisms better than a single-family report. This should be checked closely for genes overlapping Mario's list.
Distinct pathophysiological mechanisms of CEP152 variants in microcephaly and brain abnormalities
Strong example of why two variants in the same gene can produce different developmental consequences. This is a good model for the atlas gene profiles: gene name alone is not enough.
EXOSC10 haploinsufficiency causes primary microcephaly by derepression of Sonic hedgehog signalling
Valuable because it extends the mechanistic vocabulary beyond the classic centrosome list into RNA exosome biology and Sonic hedgehog signalling. It should be considered when deciding whether Mario's list is "MCPH only" or broader microcephaly.
3. KNL1 / CASC5 lineage: the alias problem becomes biology
Kinetochore KMN network gene CASC5 mutated in primary microcephaly
This is the key origin paper for CASC5/KNL1 as an MCPH gene. It explains why the old bundle contains CASC5 while current HGNC terminology points us to KNL1.
A novel homozygous splicing mutation of CASC5 causes primary microcephaly in a large Pakistani family
Useful for showing that the CASC5/KNL1 association is not a one-family curiosity and that splicing/disrupted kinetochore function is a recurrent mechanism.
Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype
This paper is especially educational: it asks why a general mitotic/kinetochore component can produce a brain-predominant phenotype, which is one of the central puzzles of MCPH biology.
Robust elimination of genome-damaged cells safeguards against brain somatic aneuploidy following Knl1 deletion
Connects KNL1 loss to genome damage, aneuploidy surveillance, and brain progenitor elimination. It strengthens the bridge between kinetochore biology and progenitor survival.
A novel KNL1 intronic splicing variant likely destabilizes the KMN complex, causing primary microcephaly
Low citation count but high thesis value: it uses the modern KNL1 symbol and directly supports our decision to label rows with current HGNC terminology while running old data with CASC5.
4. Gabriel/Santpere developmental-genomics line: the modern cousin of the heatmap
Early developmental origins of cortical disorders modeled in human neural stem cells
This is the most important modern bridge to the inherited plot. It studies expression dynamics of cortical and neuropsychiatric disorder genes in human neural stem cells across telencephalic fate transitions. It covers diseases from microcephaly/hydrocephaly to ASD, bipolar disorder, depression, anorexia, schizophrenia, Alzheimer disease, and Parkinson disease.
Integrative functional genomic analysis of human brain development and neuropsychiatric risks
A major PsychENCODE/BrainSpan-style paper linking human brain development, transcriptomics, regulation, and neuropsychiatric risk. It gives the larger intellectual background for crossing developmental expression with disease genetics.
NeMO Analytics: a compendium of transcriptomic data for the exploration of neocortical development
A very recent atlas/resource paper that consolidates transcriptomic data for neocortical development. For our project, it is a candidate source for a future, richer expression layer beyond the original CoGAPS matrices.
The impact of human accelerated regions on neuronal development
Short but conceptually relevant: it points toward human-specific regulatory evolution, developmental enhancers, and how brain developmental programs may be especially exposed to regulatory change.
5. Psychiatric, cognitive, and neurodevelopmental intersections
Mapping the genetic landscape across 14 psychiatric disorders
A major cross-disorder GWAS synthesis. It identifies five genomic factors, 238 pleiotropic loci, and broad enrichment for neurobiological processes. This is not an MCPH paper, but it is central for explaining the psychiatric side of the heatmap.
Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders
Strong because it moves from association to function: which shared psychiatric risk variants actually alter regulatory activity? This is the kind of evidence that a future atlas should prefer over simple gene overlap.
A genome-wide association study of shared risk across psychiatric disorders implicates gene regulation during fetal neurodevelopment
This paper gives a direct rationale for why a developmental microcephaly analysis can legitimately compare against psychiatric disorders: shared genetic risk points toward fetal neurodevelopmental regulatory programs.
Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
A heavily cited cross-disorder reference. It helps explain the logic of comparing ASD, ADHD, schizophrenia, bipolar disorder, depression, and related traits at the genetic level.
Rare coding variation provides insight into the genetic architecture and phenotypic context of autism
Useful for the ASD side of the atlas because it brings rare coding variation into the same broad interpretive space as de novo and inherited neurodevelopmental disorders.