X-Linked Lissencephaly-1 and Subcortical Band Heterotopia via the DCX Gene

Lissencephalies and subcortical band heterotopia (SBH) are a group of cerebral malformations due to an 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 X-linked 1 can be distinguished by MRI findings consistent with an anterior greater than posterior gradient of lissencephaly or with SBH. Neurological symptoms include developmental delay, infantile spasms, foot deformities, and variable degrees of intellectual disabilities and behavioral manifestations. The phenotype is usually more severe in male than in female patients (Pilz et al. 1998. PubMed ID: 9817918; Dobyns. 2010. PubMed ID: 20331703). SBH is more common in female compared to male patients (D'Agostino et al. 2002. PubMed ID: 12390976).

Lissencephaly X-linked 1 and SBH are caused by pathogenic variants in the DCX gene (Ross et al. 1997. PubMed ID: 9097958; Sakamoto et al. 2000. PubMed ID: 10807542). To date, ~130 pathogenic variants have been implicated in the two forms of the disease. The majority of variants are missense. Truncating variants that include nonsense, splice site, small framsehift deletions or insertions, and large deletions have also been reported (Human Gene Mutation Database).

De novo pathogenic variants in the DCX gene have been reported in about 25% of affected male patients (Bahi-Buisson et al. 2013. PubMed ID: 23365099). Mosaicism, both somatic and germline, have been reported in ~10% of unaffected mothers (Demelas et al. 2001. PubMed ID: 11468322; D'Agostino et al. 2002. PubMed ID: 12390976; Aigner et al. 2003. PubMed ID: 12552055).

DCX encodes doublecortin, a microtubule-associated protein required for the normal migration of neurons in the cerebral cortex during brain development (Gleeson. 1998. PubMed ID: 9489700).

Pathogenic variants in the DCX gene have been detected in about 23% of patients from a large cohort of children with lissencephaly or SBH (Di Donato et al. 2018. PubMed ID: 29671837).

This test provides full coverage of all coding exons of the DCX 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).