Lissencephaly 2 via the RELN 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 2 can be distinguished by MRI findings consistent with severe abnormalities of the cerebellum, hippocampus and brainstem. Additional findings include severe microcephaly, hypotonia, hyperreflexia, growth failure, and craniofacial features in the form of prominent occiput, low sloping forehead, prominent nasal bridge and ocular hypertelorism (Norman et al. 1976. PubMed ID: 175907; Dobyns et al. 1984. PubMed ID: 6476009; Iannetti et al. 1993. PubMed ID: 8368261).

Lissencephaly 2 is inherited in an autosomal recessive manner. It is caused by homozygous or compound heterozygous pathogenic variants in the RELN gene. To date, five truncating pathogenic variants have been reported. They include 2 splicing variants, one small frameshift deletion, one gross deletion and one complex rearrangement (Hong et al. 2000. PubMed ID: 10973257; Alfares. 2017. PubMed ID: 28454995; Zaki et al. 2007. PubMed ID: 17431900; Human Gene Mutation Database).

The RELN gene encodes reelin, a glycoprotein involved in several cellular processes including the proper positioning of neurons during brain development (Quattrocchi et al. 2002. PubMed ID: 11689558).

Pathogenic variants in the RELN gene have been detected in about 1% of patients from a large cohort of children with lissencephaly (Di Donato et al. 2018. PubMed ID: 29671837).

This test provides full coverage of all coding exons of the RELN gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.