Lissencephaly 1 and Subcortical Band Heteropia via the PAFAH1B1 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 1 can be distinguished by MRI findings consistent with a posterior greater than anterior gradient of lissencephaly. Neurological symptoms include severe developmental delay, severe motor impairment including axial hypotonia and spastic quadripareis, no language development, autistic features, sleep disorders, postnatal microcephaly, and seizures (Saillour et al. 2009. PubMed ID: 19667223).

Heterozygous pathogenic variants in the PAFAH1B1 gene have been implicated in lissencephaly 1 and SBH (Cardoso et al. 2000. PubMed ID: 11115846; Pilz et al. 1999. PubMed ID: 10441340). To date, ~150 pathogenic variants have been reported. The majority of variants are truncating and include nonsense, splice site, small frameshift deletions or insertions, and large copy number variants. Large pathogenic deletions are the major genetic cause of lissencephaly 1 (Human Gene Mutation Database). All pathogenic PAFAH1B1 variants have been documented to be de novo (Dobyns et al. 2014. PubMed ID: 20301752). Germline and somatic pathogenic variants have been reported (González-Morón et al. 2017. PubMed ID: 28953922; Sicca et al. 2003. PubMed ID: 14581661).

The PAFAH1B1 protein (platelet-activating factor acetylhydrolase IB alpha subunit) is required for the normal migration of neurons in the cerebral cortex during brain development (Reiner et al. 1993. PubMed ID: 8355785; Albrecht et al. 1996. PubMed ID: 8954729).

Pathogenic variants in the PAFAH1B1 gene have been detected in about 40% 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 PAFAH1B1 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).