Part 8 — Reference
31. Glossary
Genetics fundamentals
| Term | Meaning |
|---|---|
| Allele | One version of a gene |
| Autosome | Any non-sex chromosome (1–22) |
| Breakpoint | The exact position where a structural change begins/ends |
| Carrier | Someone carrying a variant, often unaffected |
| Chromosome | A packaged bundle of DNA |
| CNV | Copy number variant — a segment in abnormal copy number |
| De novo | New in the child; not inherited |
| Duplication | A segment present in extra copies |
| Expression | How much mRNA/protein a gene produces |
| Gene | A stretch of DNA encoding a protein |
| Genome | The complete DNA set |
| Hemizygous | Having one copy (males, for X-linked genes) |
| Mosaic | Some cells carry the variant, others don't |
| Penetrance | The proportion of carriers who show the trait |
| Phenotype | The observable characteristics |
| Point mutation | A single-letter change |
| Tandem duplication | Extra copy adjacent to the original |
| Variant | Any difference from the reference sequence |
| X-inactivation | Silencing of one X in female cells |
| Xq25 | Chromosome X, long arm, band 25 |
Molecular biology
| Term | Meaning |
|---|---|
| Central dogma | DNA → RNA → protein |
| Chromatin | DNA plus packaging proteins |
| Cohesin | The ring complex containing STAG2 |
| CTCF | Boundary protein defining loop endpoints |
| Enhancer | Distant regulatory element activating a gene |
| Loop extrusion | Cohesin reeling DNA into loops |
| mRNA | The working copy of a gene |
| Paralog | A related gene from duplication (STAG1/STAG2) |
| Promoter | Where transcription of a gene starts |
| TAD | Topologically associating domain — a loop neighborhood |
| Transcription / Translation | DNA→mRNA / mRNA→protein |
Disease-specific
| Term | Meaning |
|---|---|
| Cohesinopathy | Disorder of cohesin function |
| Dosage-sensitive | Amount of product must stay in a narrow range |
| Goldilocks problem | Both too much and too little cause disease |
| Haploinsufficiency | One copy isn't enough |
| MKMS | Mullegama-Klein-Martinez syndrome — STAG2 loss |
| OPHN1 | X-linked ID gene upregulated by STAG2 gain |
| STAG2 / STAG1 | The interchangeable cohesin subunits (SA2/SA1) |
| Triplosensitivity | An extra copy causes disease |
| Tumor suppressor | A gene restraining cancer; STAG2 is one |
Laboratory
| Term | Meaning |
|---|---|
| Assay / readout | The specific measurement |
| Batch effect | Differences from processing, not biology |
| Biological vs technical replicate | Independent samples vs repeated measures |
| Confounder | An alternative explanation |
| Differentiation | Guiding stem cells to a cell type |
| Fibroblast | Skin cell from a biopsy |
| High-content imaging | Automated microscopy at scale |
| Hi-C / CUT&RUN | Map 3D folding / protein-DNA binding |
| iPSC | Induced pluripotent stem cell |
| Isogenic | Identical except the one variant |
| Karyotype | Chromosome check |
| MEA | Multi-electrode array — records neuronal firing |
| NGN2 | Gene forcing rapid neuronal identity |
| Organoid | 3D mini-tissue |
| Passage | One round of splitting cells |
| qPCR / RNA-seq | Measure one mRNA / all mRNAs |
| Yamanaka factors | The four reprogramming genes |
| Z-factor | Assay quality statistic (>0.5 = screenable) |
Therapeutics & translation
| Term | Meaning |
|---|---|
| AAV | Adeno-associated virus; gene therapy vector |
| ASO | Antisense oligonucleotide |
| BBB | Blood-brain barrier |
| Cas13 | CRISPR enzyme targeting RNA |
| CRISPRi | CRISPR adapted to repress genes |
| Expanded access | Unapproved drug outside a trial |
| Hit / Lead | Screen signal / validated candidate |
| ICV / Intrathecal | Into brain ventricles / into spinal fluid |
| IND | FDA application to dose humans |
| Knockdown vs knockout | Partial reduction vs elimination |
| Modality | The class of therapeutic |
| N-of-1 | Formal single-patient trial |
| Off-label | Approved drug, unapproved use |
| Orphan Drug Designation | FDA rare-disease status |
| PK / PD | What body does to drug / drug does to body |
| PRV | Priority review voucher |
| Repurposing | Existing drug, new disease |
| siRNA | Small interfering RNA |
| Target engagement | Evidence the drug hit its target |
| Therapeutic window | Gap between effective and harmful dose |
| Prime editing | Precise CRISPR "find and replace" without cutting both strands |
| Base editing | CRISPR that chemically swaps one DNA letter for another |
| CRISPRa | CRISPR repurposed to switch a gene up |
| Divalent siRNA | Two linked siRNA copies; spreads and persists in brain far better |
| Tool compound | A lab chemical for probing biology — not an approved medicine |
| Dose-responsive | Bigger dose, bigger effect — a hallmark of a real drug effect |
Program, registries & funding
| Term | Meaning |
|---|---|
| 501(c)(3) | US registered charity status; most foundations can only fund one |
| Fiscal sponsor | An existing nonprofit that receives grants on your behalf |
| Advisory board | Outside experts who periodically review and challenge the program |
| Biobank / repository | An organization storing cells and shipping them to researchers |
| Reference line | The publicly deposited cell line everyone in a field studies |
| Single point of failure | If the only cells are in one freezer, one failure ends the work |
| Natural-history registry | Long-term record of how a disease unfolds untreated |
| CoRDS | A free ready-made registry platform for small patient groups |
| Re-curation | Formally asking an expert body to revisit a rating |
| Petition (registry) | A formal request that a registry add your condition |
| Observational baseline protocol | A formal study that measures without treating (FDA now recommends) |
| LINCS / L1000 / CMap | Public dataset of what thousands of drugs do to gene activity |
| Gene set | A named group of genes that behave together |
| GEO | NCBI's free public archive of gene-activity datasets |
| Primary cells | Cells taken directly from a person, not an immortalized line |
| Endogenous | Naturally present in the cell, not added by researchers |
| N=1 Collaborative | Network advancing individualized genetic therapies |
| milasen | The first bespoke ASO made for one named patient |
32. Reference library
The essential papers
- Kumar et al. 2015 — Increased STAG2 dosage defines a novel cohesinopathy — the single most important paper. DOI 10.1093/hmg/ddv414 · full text
- Leroy et al. 2016 — Xq25 duplication: the crucial role of STAG2
- Mullegama et al. 2019 — STAG2 loss-of-function phenotype in males
- Familial STAG2 germline mutation — npj Genomic Medicine 2017
- Different NIPBL requirements of cohesin-STAG1 and STAG2 — Nat Commun 2023
- STAG2-truncating variants and compensatory cohesin remodeling
The MECP2 duplication precedent
- NCT06615206 — HERO trial of HG204
- ASO therapy in humanized MECP2 duplication mice — Sci Transl Med
- ASO therapy in MECP2 duplication iPSC neurons — HMG 2024
- HuidaGene — HG204 Nature Neuroscience publication · FDA designations
Databases
- PubMed · Europe PMC · bioRxiv
- OMIM 300979 — Xq25 duplication syndrome
- ClinGen Xq25 dosage curation
- DECIPHER · gnomAD · ClinicalTrials.gov
Organizations
- n-Lorem Foundation — free bespoke ASOs for nano-rare patients
- Cornelia de Lange Syndrome Foundation — the adjacent cohesinopathy community
- CZI Rare As One · Global Genes
- NCATS · FDA Rare Diseases
33. Further learning
If you want to go deeper, in order of effort:
Set up Google Scholar alerts (2 minutes) —
STAG2 duplication,cohesinopathy therapy,MECP2 duplication treatment. Highest return per unit effort of anything in this document.NHGRI Talking Glossary — genome.gov/genetics-glossary — authoritative, plain-language, with audio explanations from actual scientists.
MedlinePlus Genetics — medlineplus.gov/genetics — written specifically for patients and families.
Read Kumar 2015 properly. Use the method in Module 10. It is the paper about this condition, and reading it yourself changes the character of every conversation you have with a scientist.
Follow the citations forward from Kumar 2015 (Module 13). This is how you find both new science and new collaborators.
Attend a rare disease meeting. The warm-introduction value substantially exceeds the scientific content.
Talk to MECP2 duplication families. They are two decades ahead on a nearly identical problem — including an active first-in-human trial. Their hard-won knowledge about running a program, working with companies, and handling hope transfers almost directly.