Lissencephaly-6 with Microcephaly via the KATNB1 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-6 with microcephaly (LIS6) is characterized by developmental delay, severe microcephaly, simplified gyral pattern, thin corpus callosum, and partial agenesis of the corpus callosum. Additional MRI findings include heterotopia of the gray matter and dilated ventricles (Mishra-Gorur. 2014. PubMed ID: 25521378).

Lissencephaly-6 with microcephaly is inherited in an autosomal recessive manner. It has been shown to be caused by homozygous pathogenic variants in the KATNB1 gene in three unrelated Middle Eastern families with a history of the disease. They include 2 missense variants and one splicing variant (Hu et al. 2014. PubMed ID: 25521379).

The KATNB1 gene encodes a regulatory subunit of katanin, a microtubule severing enzyme that is involved in several cellular processes including mitosis, meiosis, and neuronal morphogenesis, function and plasticity (Sharp and Ross. 2012. PubMed ID: 22595526).

Pathogenic variants in the KATNB1 gene appear to be rare. To date, only three pathogenic variants have been implicated in lissencephaly-6 with microcephaly (Hu et al. 2014. PubMed ID: 25521379). All reported pathogenic variants are detectable by sequencing.

This test provides full coverage of all coding exons of the KATNB1 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).