| Category | Key points | Key sources |
|---|---|---|
| Identifiers/Synonyms | • Microlissencephaly is linked to NDE1 with definitive genetic evidence. • Related names in evidence: microlissencephaly, NDE1-related extreme microcephaly with lissencephaly, Norman–Roberts syndrome / Lissencephaly syndrome, Norman-Roberts type. • Database identifiers present in evidence: MONDO_0015204 (microlissencephaly), Orphanet_89844, HP:0001339 (lissencephaly), NDE1 ENSG00000072864. (pqac-00000002, pqac-00000006) | Open Targets 2025, NDE1–microlissencephaly association, https://platform.opentargets.org (pqac-00000006); Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (pqac-00000002) |
| Inheritance | • Autosomal recessive / biallelic autosomal disease mechanism. • Reported families were consanguineous in seminal reports, with homozygous loss-of-function alleles segregating with disease. • Open Targets/Gene2Phenotype evidence labels allelic requirement as biallelic_autosomal and consequence as absent_gene_product. (pqac-00000002, pqac-00000006, pqac-00000015) | Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (pqac-00000002); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (pqac-00000015); Open Targets 2025, https://platform.opentargets.org (pqac-00000006) |
| Core clinical | • Congenital or birth-presenting extreme microcephaly, profound/global developmental delay, and profound intellectual disability are core findings. • Hypertonia/abnormal tone, abnormal reflexes, and in some reports early-onset seizures/epilepsy occur. • Overall somatic growth may be relatively preserved despite severe brain growth failure. (pqac-00000009, pqac-00000011, pqac-00000012, pqac-00000014) | Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (pqac-00000009); Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (pqac-00000011, pqac-00000012); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (pqac-00000014) |
| Neuroimaging | • Severe microcephaly with extremely simplified gyral pattern / microlissencephaly; in one description, almost no detectable sulci other than the Sylvian fissure. • Frequent agenesis of the corpus callosum and ventricular enlargement. • Cerebellar hypoplasia/small cerebellum is common; additional findings reported include reduced brainstem size and unfused thalami. (pqac-00000010, pqac-00000011, pqac-00000012, pqac-00000014, pqac-00000024) | Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (pqac-00000011, pqac-00000012, pqac-00000024); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (pqac-00000014); Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (pqac-00000010) |
| Case counts/rarity | • Severe congenital microcephaly due to NDE1 is described as very rare. • Tan et al. reported that “To date, 14 patients from 8 families” had been described at that time. • Early seminal papers documented multiple families (2 families in Alkuraya; 3 families in Bakircioglu). (pqac-00000009, pqac-00000012, pqac-00000014) | Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (pqac-00000009); Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (pqac-00000012); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (pqac-00000014) |
| Genetics/variant types | • Pathogenic alleles in evidence are predominantly biallelic loss-of-function variants: homozygous frameshift and splice-site mutations. • Representative variants reported: c.83+1G>T, c.684_685del, c.733dupC; a compound state combining a 16p13.11 deletion with a truncating sequence variant was also reported. • Mutant proteins are unstable and/or fail to localize to the centrosome. (pqac-00000002, pqac-00000008, pqac-00000010) | Alkuraya 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.04.003 (pqac-00000002); Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (pqac-00000008); Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (pqac-00000010) |
| Mechanism highlights | • NDE1 is a centrosomal/dynein-pathway protein required for neuroepithelial/radial glial progenitor function. • Human and model-system data support failure of prenatal neuron production plus defective cortical lamination as central mechanisms. • Mechanistic studies show arrests during apical interkinetic nuclear migration, G2-to-M transition, and primary-cilia/G1-S regulation; 2023 work showed Nde1 promotes Lis1-mediated dynein activation. (pqac-00000003, pqac-00000016, pqac-00000020) | Bakircioglu 2011, AJHG, https://doi.org/10.1016/j.ajhg.2011.03.019 (pqac-00000003); Doobin 2016, Nat Commun, https://doi.org/10.1038/ncomms12551 (pqac-00000020); Zhao 2023, Nat Commun, https://doi.org/10.1038/s41467-023-42907-x (pqac-00000016) |
| Diagnostics | • Diagnosis relies on neuroimaging plus molecular testing. • Evidence-based recommendation from case literature: sequence NDE1 and perform chromosomal microarray in severe congenital microcephaly, especially because 16p13.11 deletions can unmask recessive NDE1 disease. • In CNV-positive patients, 2022 evidence supports adding WES because a predisposing CNV may not fully explain the phenotype. (pqac-00000009, pqac-00000025, pqac-00000026) | Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (pqac-00000009); Granata 2022, Front Genet, https://doi.org/10.3389/fgene.2022.798607 (pqac-00000025); Tropeano 2014, clinical utility card (pqac-00000026) |
| Treatment/supportive | • No disease-modifying therapy or disease-specific interventional trial was identified in the evidence snippets. • Management in available evidence is therefore supportive and symptom-directed, guided by severe neurodevelopmental impairment and seizure risk/epilepsy where present. • Clinical-trial search in this session found no relevant interventional trials. (pqac-00000009, pqac-00000010) | Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (pqac-00000009, pqac-00000010) |
| Prevention/counseling | • Because the disorder is autosomal recessive, recurrence-risk counseling for families is important. • Molecular confirmation enables carrier testing and family-based reproductive counseling; CNV + sequence analysis may both be needed in some families. • No primary environmental prevention factors were identified in the evidence snippets. (pqac-00000006, pqac-00000009, pqac-00000025) | Open Targets 2025, https://platform.opentargets.org (pqac-00000006); Tan 2017, BMC Med Genet, https://doi.org/10.1186/s12881-017-0501-9 (pqac-00000009); Granata 2022, Front Genet, https://doi.org/10.3389/fgene.2022.798607 (pqac-00000025) |


*Table: This table compiles the key disease-definition, clinical, genetic, mechanistic, diagnostic, and counseling points for NDE1-related microcephaly-lissencephaly using only the evidence snippets available in the conversation. It is designed as a compact reference for downstream knowledge-base curation.*