Lissencephaly-4 with Microcephaly via the NDE1 Gene

Lissencephalies and subcortical band heterotopia (SBH) are a group of cerebral malformations involving arrest of neuronal migration during embryogenesis. Lissencephaly is characterized by simplification or absence of the brain convolutions, resulting in a smooth appearance. SBH, also known as double cortex, is characterized by abnormal bands of neurons beneath a normal cortex. Lissencephalies and SBH are characterized by intellectual disability and seizures. Additional features include microcephaly, subtle dysmorphic features, failure to thrive, difficulty feeding and swallowing, malformations of the digits, muscle spasms, myoclonic jerks, cognitive impairment, and poor social interactions (Leventer et al. 2001. PubMed ID: 11502906; Wallerstein et al. 2008. PubMed ID: 18462864; Dobyns. 2010. PubMed ID: 20331703; Di Donato et al. 2017. PubMed ID: 28440899). The incidence of lissencephalies is ~1:100,000 live births (https://www.orpha.net).

Lissencephalies are clinically and genetically heterogeneous. Several forms are recognized. They are distinguished on the basis of the clinical features and the causative genes.

Lissencephaly-4 with microcephaly (LIS4) is characterized by extreme congenital microcephaly, and profound global developmental delay. Additional features include short stature, macrosomia, prominent broad nasal bridge, and hypertonia. MRI findings include grossly simplified cortical gyral structure, agenesis of the corpus callosum and a hypoplastic cerebellum (Alkuraya et al. 2011. PubMed ID: 21529751; Bakircioglu et al. 2011. PubMed ID: 21529752).

Lissencephaly-4 with microcephaly is inherited in an autosomal recessive manner. To date, 3 homozygous pathogenic variants (one splicing, one small frameshift deletion and one small frameshift duplication) in the NDE1 gene have been reported in five consanguineous families from the Middle East (Alkuraya et al. 2011. PubMed ID: 21529751; Bakircioglu et al. 2011. PubMed ID: 21529752).

The NDE1 gene encodes Nude Neurodevelopment protein 1, a member of the nuclear distribution E family. It is involved in several cellular functions, including the development of the cerebral cortex and neuronal migration (Feng and Walsh. 2004. PubMed ID: 15473967; Shu et al. 2004. PubMed ID: 15473966).

Pathogenic variants in the NDE1 gene appear to be rare. To date, only three pathogenic variants have been implicated in five consanguineous families from the Middle East (Alkuraya et al. 2011. PubMed ID: 21529751; Bakircioglu et al. 2011. PubMed ID: 21529752). All reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the NDE1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).