Lissencephaly Panel

Lissencephaly comprises a group of cerebral malformations due to a defect of neuronal migration. Lissencephaly is characterized by absent (agyria) or decreased (pachygyria) convolutions, cortical thickening, and a smooth cerebral surface. The symptoms of lissencephaly vary with different causes. The major features of lissencephaly include early developmental delay, early diffuse hypotonia, spastic quadriplegia, intellectual disability, infantile spasms and seizures. Additional features include microcephaly, subtle dysmorphic features, failure to thrive, difficult feeding and swallowing, muscle spasms, myoclonic jerks, and poor social interactions (Leventer et al. 2001. PubMed ID: 11502906; Wallerstein et al. 2008. PubMed ID: 18462864; Di Donato et al. 2017. PubMed ID: 28440899; Barkovich et al. 2012. PubMed ID: 22427329; Dobyns. 2010. PubMed ID: 20331703). The prevalence of classical lissencephaly is estimated around 12 per million births (Parrini et al. 2016. PubMed ID: 27781032).

Outside of DNA testing, brain imaging techniques such as CT and MRI are the most powerful tools for diagnosis of lissencephaly. For example, in the cases of tubulinopathies, MRI shows pachygyric cortex with posterior to anterior gradient, enlarged lateral ventricles, and variable degrees of reduced white matter volume (Brock et al. 2018. PubMed ID: 29706637; Poirier et al. 2013. PubMed ID: 23603762; Romaniello et al. 2017. PubMed ID: 28677066).

As lissencephaly can be caused by defects in many genes with variable and overlapping presentations, they can be difficult to diagnose by clinical manifestation and image studies only. Therefore, an accurate molecular diagnosis is critical for treatment, prognosis, and reproductive planning.

The genetic etiology of the lissencephaly is heterogeneous. Lissencelphay can be inherited in an autosomal dominant, autosomal recessive or X-linked manner.  This panel covers many well documented genes, as well as newly-discovered genes. Genes within the panel include ARX (Aristaless-related homeobox protein), DCX (doublecortin), RELN (reelin signaling), TUBA1A, TUBB2B, TUBB3, TUBB, TUBG1, TUBA8 (tubulins), KATNB1 (Katanin), MACF1 (microtubule-actin cross-linking factor), LAMB1 (extracellular matrix laminin), PAFAH1B1 (platelet-activating factor acetylhydrolase), NDE1 (mitosis-related protein), and a number of others (Di Donato et al. 2018. PubMed ID: 29671837; Parrini et al. 2016. PubMed ID: 27781032). 

The type of pathogenic variant varies with different genes. The vast majority of pathogenic variants in genes involving tubulinopathies occur de novo (Bahi-Buisson and Cavallin et al. 2016. PubMed ID: 27010057; Rodan et al. 2017. PubMed ID: 27770045). Germline mosaicism has been reported in a patient with tubulinopathy (Brock et al. 2018. PubMed ID: 29706637).

See individual gene summaries for information about the molecular biology of gene products and spectra of pathogenic variants.

Lissencephaly is clinically and genetically heterogeneous. The sensitivity is variable depending on different disorders. In one study with analysis of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) a detection rate of 81% was achieved (Di Donato et al. 2018. PubMed ID: 29671837).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.4% coverage of all coding exons of the genes 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 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).