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Nuclear distribution E-homolog 1 (NDE1) is essential for centrosome function and neurogenic mitosis. Autosomal recessive NDE1-related microhydranencephaly presents with severe microcephaly, motor and cognitive impairment, gross ventricular dilation, and near-complete absence of the cerebral hemispheres (Disease Name).
Homozygous deletion of exon 2 of NDE1 (c.-43-3548_83+622del) abolishing the initiation codon was identified in three related patients with microhydranencephaly (n=3) (PMID:22526350). This null allele segregates with disease in a consanguineous pedigree under an autosomal recessive model, supporting loss-of-function etiology.
Additional NDE1 frameshift variants, c.733dup (p.Leu245fs) and c.684_685del (p.Pro229fs), were reported in four probands with extreme microcephaly and microlissencephaly, expanding the allele spectrum and reinforcing recessive loss-of-function (n=4) (PMID:21529751; PMID:21529752). Patient-derived mutant proteins are unstable, fail to bind cytoplasmic dynein, mislocalize from the centrosome, and disrupt CDK1-dependent cell-cycle progression.
Nde1-null mice recapitulate profound neuronal proliferation defects and cortical lamination failure, mirroring human microcephaly phenotypes and validating haploinsufficiency as the pathogenic mechanism (PMID:21529751). Rescue of cell-cycle arrest and centrosomal localization in patient cells by wild-type NDE1 further corroborates functional concordance.
No studies to date have disputed the loss-of-function model or identified dominant-negative effects. Integration of genetic and experimental data assigns a Moderate ClinGen clinical validity rating for the association between NDE1 and autosomal recessive microhydranencephaly.
Key Take-home: Recessive null mutations in NDE1 cause severe cortical neurogenesis defects, making NDE1 genotyping critical for early diagnosis and genetic counseling in families with microhydranencephaly.
Gene–Disease AssociationModerateRecessive null allele in 3 probands; consistent with autosomal recessive segregation and loss-of-function mechanism Genetic EvidenceModerateHomozygous deletion in 3 related patients; additional frameshift alleles in 4 probands demonstrating allelic heterogeneity Functional EvidenceModerateNde1-null mice recapitulate neurogenic defects; patient proteins unstable and mislocalized; CDK1 phosphorylation disrupted |