| Item | Key details | Evidence/PMID/DOI/URL | Publication date | Context citation id(s) |
|---|---|---|---|---|
| Disease spectrum / definition | Lissencephaly spectrum disorders are malformations of cortical development caused chiefly by defective neuronal migration; the spectrum includes agyria, pachygyria, and subcortical band heterotopia (SBH, “double cortex”). Clinical comorbidity commonly includes developmental delay/intellectual disability, hypotonia progressing to spasticity, and seizures. | Uctepe et al., *Eur J Hum Genet* 2024, DOI: 10.1038/s41431-023-01461-2, https://doi.org/10.1038/s41431-023-01461-2 | 2024-10 | (pqac-00000020) |
| Spectrum subtypes / pathology | Classic lissencephaly is linked to cortical dyslamination genes such as **PAFAH1B1, DCX, ARX**; cobblestone lissencephaly shows distinct neuropathology associated with glycosylation pathway genes such as **POMGNT1, POMT1, POMT2**. | Brock et al., systematic review; summarized neuropathology of genetically defined MCDs | n/a | (pqac-00000008) |
| Standardized disease concept | MONDO includes **lissencephaly spectrum disorders = MONDO:0018838**; Open Targets links high-confidence associated targets including **DCX, PAFAH1B1, TUBA1A, ARX, RELN, CEP85L, LAMB1, MACF1**. | Open Targets disease-target association, https://platform.opentargets.org | current platform query | (pqac-00000000) |
| Key genes / common established causes | The most common established genes across classic lissencephaly are **PAFAH1B1 (LIS1)** and **DCX**; major additional genes include **TUBA1A, DYNC1H1, TUBG1, ARX, RELN, CEP85L, LAMB1, MACF1, KATNB1**. | Open Targets; Proepper et al., *Orphanet J Rare Dis* 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z | 2026-05; platform current | (pqac-00000000, pqac-00000009) |
| Inheritance pattern: AD / de novo | Many lissencephaly-spectrum disorders are **autosomal dominant, often de novo**, especially tubulinopathies. **TUBA1A** is reported as the most commonly mutated tubulin gene; “most cases” show **de novo autosomal dominant inheritance**. | Ren et al., *Front Pediatr* 2024, DOI: 10.3389/fped.2024.1367305, https://doi.org/10.3389/fped.2024.1367305 | 2024-05 | (pqac-00000015) |
| Inheritance pattern: X-linked | **DCX** is an X-linked cause: males often show classic lissencephaly, while females may show SBH/double cortex; mosaic/non-coding variation can yield milder phenotypes. | Gao et al., *Heliyon* 2023, DOI: 10.1016/j.heliyon.2023.e22323, https://doi.org/10.1016/j.heliyon.2023.e22323; Open Targets | 2023-11 | (pqac-00000000) |
| Inheritance pattern: AR | Recessive forms are increasingly recognized, including **CASP2**, **CLASP1**, **TUBGCP2**, and earlier **CRADD/PIDD1**-related anterior-predominant LIS. | Uctepe et al. 2024; Alsafh et al. 2024; Yu et al. 2025 | 2024-10; 2024-08; 2025-02 | (pqac-00000020, pqac-00000019, pqac-00000014) |
| Inheritance pattern: somatic mosaic | **NDEL1 p.Arg105Pro** was identified as a **de novo somatic mosaic** cause of pachygyria with or without SBH, establishing mosaic dynein-pathway disease within the lissencephaly spectrum. | Tsai et al., *Acta Neuropathol* 2024, DOI: 10.1007/s00401-023-02665-y, https://doi.org/10.1007/s00401-023-02665-y | 2024-01 | (pqac-00000004, pqac-00000016) |
| Quantitative stat: exome diagnostic yield | In 102 children with brain malformations, singleton clinical exome had **36%** diagnostic yield, increasing to **43%** after research follow-up/reanalysis; **one** additional diagnosis came from trio exome. Lissencephaly represented **10%** of the cohort, and the **highest phenotype-based yields** were for cobblestone malformation, tubulinopathy, and lissencephaly. | Kooshavar et al., *Brain Communications* 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056 | 2024-02-28 | (pqac-00000017) |
| Quantitative stat: malformation subtype mix | Among the Kooshavar cohort, commonest subtypes were **polymicrogyria 36%**, **pontocerebellar hypoplasia 14%**, **periventricular nodular heterotopia 11%**, **tubulinopathy 10%**, **lissencephaly 10%**, **cortical dysplasia 9%**. | Kooshavar et al., *Brain Communications* 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056 | 2024-02-28 | (pqac-00000017, pqac-00000018) |
| Quantitative stat: recurrent gene in diagnostics | In the Kooshavar series, the **most frequent genetic diagnosis was TUBA1A**. | Kooshavar et al., *Brain Communications* 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056 | 2024-02-28 | (pqac-00000017) |
| Quantitative stat: prenatal genetics | In prenatal MCD literature synthesized by Hu et al., **de novo mutations accounted for 50.6%** of pathogenic alterations, and **up to 75.1%** of pathogenic mutations were not detectable by routine prenatal screening; proliferation-phase abnormalities were **62.9%** of prenatal MCD phenotypes. | Hu et al., *Biomedicines* 2026, DOI: 10.3390/biomedicines14010107, https://doi.org/10.3390/biomedicines14010107 | 2026-01 | (pqac-00000006) |
| Quantitative stat: incidence / mortality | A recent long-term cohort summary cites classic lissencephaly incidence of **11.7–40 per million births**, infantile epileptic spasms syndrome in **57%**, and approximately **50% mortality by age 10 years**. | Proepper et al., *Orphanet J Rare Dis* 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z | 2026-05 | (pqac-00000009) |
| Quantitative stat: prenatal abnormalities and age at recognition | In the Proepper cohort, prenatal abnormalities were seen in **14/37 (38%)** of **PAFAH1B1/LIS1** and **2/5 (40%)** of **DCX** cases; median age at suspected diagnosis was **5 months** for LIS1-related and **9 months** for DCX-related disease. | Proepper et al., *Orphanet J Rare Dis* 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z | 2026-05 | (pqac-00000009, pqac-00000010) |
| Quantitative stat: complications / feeding / respiratory | In the Proepper cohort, frequent complications included recurrent respiratory infections **14/38 (37%)** in LIS1 and **1/4 (25%)** in DCX; dysphagia/vomiting **23/37 (62%)** in LIS1 and **2/4 (50%)** in DCX; tube feeding required in **15/38 (40%)** in LIS1 and **1/5 (20%)** in DCX. | Proepper et al., *Orphanet J Rare Dis* 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z | 2026-05 | (pqac-00000009) |
| Quantitative stat: supportive care burden / QoL | Families reported a median of **8 supportive therapies** per patient (range **1–17**); physiotherapy and respiratory therapy were rated most effective. Parental HRQL mean was **61.23 (SD 16.79)**, indicating substantial caregiver burden. | Proepper et al., *Orphanet J Rare Dis* 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z | 2026-05 | (pqac-00000009) |
| Recent expansion: NDEL1 | First lissencephaly-associated **NDEL1** variant: two unrelated patients with pachygyria ± SBH carried the same **de novo somatic mosaic p.Arg105Pro**; mechanism implicated failure of nucleokinesis via disrupted **NDEL1–LIS1** interaction. | Tsai et al., *Acta Neuropathol* 2024, DOI: 10.1007/s00401-023-02665-y, https://doi.org/10.1007/s00401-023-02665-y | 2024-01 | (pqac-00000004, pqac-00000016) |
| Recent expansion: CASP2 | **CASP2** added to the PIDDosome-related lissencephaly genes: **7 patients from 5 families** with biallelic truncating/splice variants had anterior/frontotemporal LIS and pachygyria resembling **CRADD/PIDD1** disease. | Uctepe et al., *Eur J Hum Genet* 2024, DOI: 10.1038/s41431-023-01461-2, https://doi.org/10.1038/s41431-023-01461-2 | 2024-10 | (pqac-00000020) |
| Recent expansion: CLASP1 | **CLASP1** emerged as a candidate recessive lissencephaly gene in a multiplex consanguineous family; **3 siblings** had homozygous **c.4442G>A p.Arg1481His** with classic lissencephaly, microcephaly, severe developmental delay, and early refractory epilepsy. | Alsafh et al., *Neurology Genetics* 2024, DOI: 10.1212/NXG.0000000000200172, https://doi.org/10.1212/NXG.0000000000200172 | 2024-08 | (pqac-00000005, pqac-00000019) |
| Diagnostic approach: imaging | Brain **MRI** remains the core diagnostic modality for defining the malformation pattern and guiding gene prioritization. Recognizable signatures include anterior/frontotemporal LIS in **CASP2/CRADD/PIDD1**, posterior>anterior classic LIS plus thin splenium/pontine hypoplasia in **CLASP1**, and pachygyria ± SBH in mosaic **NDEL1**. | Uctepe et al. 2024; Alsafh et al. 2024; Tsai et al. 2024 | 2024 | (pqac-00000020, pqac-00000019, pqac-00000016) |
| Diagnostic approach: genetics | Recommended workflow supported by recent evidence: **CMA first** to detect CNVs; then **exome sequencing**; then **periodic reanalysis** because reanalysis contributed more to added diagnoses than trio expansion in a real-world MCD cohort. | Kooshavar et al., *Brain Communications* 2024, DOI: 10.1093/braincomms/fcae056, https://doi.org/10.1093/braincomms/fcae056 | 2024-02-28 | (pqac-00000017, pqac-00000018) |
| Diagnostic approach: prenatal | For suspected fetal cortical malformations, **fetal neurosonography + fetal MRI + NGS/WES** are increasingly emphasized; routine prenatal screens miss many pathogenic variants. | Hu et al., *Biomedicines* 2026, DOI: 10.3390/biomedicines14010107, https://doi.org/10.3390/biomedicines14010107 | 2026-01 | (pqac-00000006) |
| Management / supportive therapies | No disease-modifying therapy is established; current care is multidisciplinary and supportive: **antiepileptic therapy**, feeding support including tube feeding/PEG when needed, **physiotherapy**, **respiratory therapy**, developmental therapies, and caregiver support. Physiotherapy and respiratory therapy were reported as most effective in family surveys. | Proepper et al., *Orphanet J Rare Dis* 2026, DOI: 10.1186/s13023-026-04398-z, https://doi.org/10.1186/s13023-026-04398-z; Ren et al. 2024 | 2026-05; 2024-05 | (pqac-00000009, pqac-00000015) |


*Table: This table condenses high-yield definitions, genetics, quantitative clinical statistics, recent gene discoveries, and current diagnostic/management points for lissencephaly spectrum disorders. It is useful as a structured reference for building a disease knowledge-base entry with linked evidence.*