| Concept | Evidence-supported details | Key citations (pqac ids) | URL/publication year where available |
|---|---|---|---|
| Core disease label | Reelin-pathway lissencephaly is most directly represented in the evidence as **lissencephaly with cerebellar hypoplasia (LCH)**, a cortical malformation/neurodevelopmental disorder with simplified or smooth gyri plus cerebellar hypoplasia. | (pqac-00000000, pqac-00000004, pqac-00000006) | Hong et al., *Nature Genetics* (2000): https://doi.org/10.1038/79246; Lossi et al., *J Clin Med* (2019): https://doi.org/10.3390/jcm8122088 |
| Alternative disease labels / synonyms | The evidence explicitly states **“Lissencephaly 2 (LIS2)”** and that LIS2 is also referred to as **“lissencephaly syndrome, Norman–Roberts type or Norman–Roberts syndrome.”** | (pqac-00000004) | Lossi et al., *J Clin Med* (2019): https://doi.org/10.3390/jcm8122088 |
| OMIM identifier explicitly present | **OMIM #257320** is explicitly attached in the evidence to **Lissencephaly 2 (LIS2) / Norman–Roberts syndrome**. | (pqac-00000004) | Lossi et al., *J Clin Med* (2019): https://doi.org/10.3390/jcm8122088 |
| Primary causal gene: RELN | Strongest disease-defining gene in the evidence. Autosomal recessive **RELN** mutations were linked to LCH/LIS2; 2022 evidence further shows **biallelic RELN** variants cause severe LIS-CBLH, while **monoallelic RELN** variants can produce milder/intermediate neuronal migration disorders. | (pqac-00000000, pqac-00000002, pqac-00000011, pqac-00000013) | Hong et al. (2000): https://doi.org/10.1038/79246; Di Donato et al. (2022): https://doi.org/10.1093/brain/awac164; Riva et al. (2024): https://doi.org/10.1172/jci153097 |
| Reelin-pathway gene: DAB1 | **Biallelic DAB1** splice variants were reported to cause **mild lissencephaly and cerebellar hypoplasia** with a RELN-like phenotype, supporting inclusion of DAB1-related disease within the Reelin-pathway lissencephaly spectrum. | (pqac-00000001) | Smits et al., *Neurology Genetics* (2021): https://doi.org/10.1212/nxg.0000000000000558 |
| Reelin-pathway gene: VLDLR | **Biallelic VLDLR** loss-of-function variants cause a related recessive Reelin-pathway disorder characterized by cerebellar hypoplasia with **cerebral gyral simplification**; evidence supports overlap with the broader Reelin-pathway lissencephaly/cerebellar hypoplasia spectrum, although some literature distinguishes VLDLR cerebellar hypoplasia from classic RELN-LIS2. | (pqac-00000012, pqac-00000008, pqac-00000009) | Ozcelik et al., *PNAS* (2008): https://doi.org/10.1073/pnas.0710010105; Holling et al. (2024): https://doi.org/10.1038/s10038-024-01279-w; Di Donato et al. (2018): https://doi.org/10.1038/gim.2018.8 |
| Inheritance pattern | **RELN-LIS2/LCH:** autosomal recessive in classic disease. **DAB1-related RELN-like lissencephaly:** recessive in the reported case. **VLDLR-related cerebellar hypoplasia/gyral simplification:** recessive. Newer evidence shows **monoallelic/dominant RELN** variants can also cause neuronal migration disorders, but the classic Norman–Roberts/LIS2 phenotype remains recessive. | (pqac-00000000, pqac-00000001, pqac-00000002, pqac-00000004, pqac-00000012, pqac-00000013) | Hong et al. (2000): https://doi.org/10.1038/79246; Smits et al. (2021): https://doi.org/10.1212/nxg.0000000000000558; Di Donato et al. (2022): https://doi.org/10.1093/brain/awac164; Riva et al. (2024): https://doi.org/10.1172/jci153097 |
| Hallmark MRI / neuroimaging findings | Across the evidence, hallmark imaging includes **moderate lissencephaly/pachygyria**, **thick cerebral cortex (~5–10 mm)**, **simplified gyral pattern** (often frontotemporal/temporal-predominant in RELN-related cases), **profound/very hypoplastic cerebellum with reduced or absent folia**, **hypoplastic inferior vermis and hemispheres**, **malformed or flattened hippocampus**, **thin corpus callosum**, **small pons/brainstem**, and **enlarged lateral ventricles**. VLDLR-related imaging emphasizes **inferior cerebellar vermis/hemisphere hypoplasia**, **simplified cortical gyration**, and **small brain stem**. | (pqac-00000000, pqac-00000004, pqac-00000002, pqac-00000008, pqac-00000012) | Hong et al. (2000): https://doi.org/10.1038/79246; Lossi et al. (2019): https://doi.org/10.3390/jcm8122088; Di Donato et al. (2022): https://doi.org/10.1093/brain/awac164; Holling et al. (2024): https://doi.org/10.1038/s10038-024-01279-w; Ozcelik et al. (2008): https://doi.org/10.1073/pnas.0710010105 |
| Identifier/diagnostic context in sequencing cohorts | In a large lissencephaly cohort, **RELN accounted for ~1%** of diagnosed cases and **VLDLR for <1%**, supporting that Reelin-pathway lissencephaly is genetically rare within the broader lissencephaly spectrum. | (pqac-00000009) | Di Donato et al., *Genetics in Medicine* (2018): https://doi.org/10.1038/gim.2018.8 |


*Table: This table summarizes the evidence-supported disease names, identifiers, causal genes, inheritance patterns, and hallmark imaging findings for Reelin-pathway lissencephaly. It is useful for mapping the disorder across historical labels such as LIS2 and Norman–Roberts syndrome while distinguishing RELN-, DAB1-, and VLDLR-related forms.*