Submission Details

The relationship between NDE1 and microcephaly with lissencephaly and/or hydranencephaly was first reported in 2011 (PMID: 21529752, PMID: 21529751). Microcephaly with lissencephaly and/or hydranencephaly is a brain disorder that is characterized by extreme microcephaly (typically head circumference of less than 10 standard deviations (SD) below the mean), profound motor and intellectual disability, spasticity, and incomplete cerebral formation. Patients demonstrate cortical dysgenesis ranging from simplification to pachygyria/lissencephaly to hydranencephaly. Agenesis of the corpus callosum as well as hypoplasia of the brainstem and cerebellum are typically present. These presentations were lumped into a single disease curation, consistent with shared molecular mechanism and mode of inheritance (Autosomal Recessive, AR).

At least 8 variants in NDE1 have been identified in individuals with microcephaly with lissencephaly and/or hydranencephaly over 14 years (PMID: 21529751, 34562061,21529752, 22526350, 30637988, 29191162, 23704059). These variants include loss of function and missense variants in highly conserved residues. In the literature, patients with severe microcephaly have been identified with deletions of 16p13.11 (including NDE1) and an additional NDE1 variant on the second allele (PMID: 23704059, PMID: 29191162). Due to the prominent phenotype, these cases have been scored. More evidence is available in the literature, but the maximum genetic evidence (12 pts) was reached.

This gene-disease relationship is also supported by animal models and in vitro data. NDE1 was first associated with cerebral cortical size in 2004 (PMID: 15473967). Initially, NDE1 was identified as a LIS1 interacting protein (PMID: 11163258). NDE1 is part of a multiprotein complex that regulates dynein function, playing an essential role in microtubule organization, mitosis and neuronal migration. Experimental data from mouse and yeast studies supports the role of NDE1 in brain malformation. NDE1 is strongly expressed in the developing mouse cerebral cortex (PMID: 11163258). Null mouse models of NDE1 demonstrate neuronal migration defects, resulting in microcephaly, including fewer neurons and a thin superficial cortical layer (PMID: 15473967).

In summary, there is definitive evidence supporting the relationship between NDE1 and microcephaly with lissencephaly and/or hydranencephaly. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen Brain Malformation GCEP on December 10, 2024 (SOP 11).