Brain Malformation Panel

Brain malformation is a group of complex conditions influenced by both genetic and environmental factors such as chemicals, infections or radiation during pregnancy. This brain malformation panel focuses on important brain malformations including tubulinopathies, cortical dysplasia, cortical malformations, periventricular heterotopia, lissencephaly, polymicrogyria, pontocerebellar hypoplasia, and muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies. Most brain malformations have onset before birth. The symptoms vary with different causes. For example, in tubulinopathies, the major features include lissencephaly, pachygyria, cortical dysplasia, simplified gyral pattern, microlissencephaly, abnormality of corpus callosum, brain stem and cerebellum. These malformations led to severe intellectual disability and early onset seizures or infantile spasms (Brock et al. 2018. PubMed ID: 29706637; Poirier et al. 2013. PubMed ID: 23603762; Di Donato et al. 2018. PubMed ID: 29671837; Romaniello et al. 2017. PubMed ID: 28677066).

For diagnosis of brain malformation, brain imaging techniques such as CT and MRI are the most powerful tools. For example, in the case of tubulinopathies, MRI shows pachygyric cortex with posterior to anterior gradient, enlarged lateral ventricles, 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). In defects of neuronal migration, MRI reveals diffuse periventricular heterotopia, thin corpus callosum, and cortical and hippocampal atrophy (Sheen et al. 2004. PubMed ID: 14647276; Tanyalçin et al. 2013. PubMed ID: 23755938).

The genetic etiology of the brain malformation is extremely heterogeneous, ranging from monogenic causes with little or no influence from modifiers or environmental factors to genetically complex forms. In this panel, we mainly focus on a group of genes causative for certain congenital brain malformations. These selected genes have been well documented, such as cortical dysplasia due to defects in structural protein tubulin (TUBA1A, TUBB2A, TUBB2B, TUBB3, TUBB, TUBG1,TUBA8), cortical dysplasia due to defects in actin regulation and neuronal migration (CTNNA2), cortical dysplasia due to defects in microtubule proteins (KIF2A, KIF5C, DYNC1H1), Baraitser-Winter syndrome or lissencephaly due to defect in actin cytoskeleton and microtubule associated proteins (ACTB, ACTG1, DCX), lissencephaly or cerebellar hypoplasia due to defect in Reelin signaling (RELN, VLDLR), cortical malformations or lissencephaly due to defect in epithelial structures laminin or extracellular matrix laminin (LAMC3, LAMB1), heterotopia due to defect in neuronal migration and neurogenesis (ARFGEF2, FLNA, NEDD4L), and heterotopia and lissencephaly due to defects in platelet-activating factor acetylhydrolase (PAFAH1B1). This panel also include genes involving other various cellular functions which cause lissencephaly (ARX, KATNB, MACF1, NDE1, TMTC3), muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies (FKRP, FKTN, LARGE1, POMGNT1, POMT1, POMT2). In total, this panel covers more than 50 disorders (Bahi-Buisson and Cavallin et al. 2016. PubMed ID: 27010057; Spalice et al. 2009. PubMed ID: 19120042; Lange et al. 2015. PubMed ID: 26471271; Parrini et al. 2006. PubMed ID: 16684786; Barak et al. 2011. PubMed ID: 21572413; Bouchet et al. 2007. PubMed ID: 17559086; Di Donato et al. 2018. PubMed ID: 29671837). Brain malformation can be inherited in autosomal dominant, autosomal recessive and X-linked manner. The type of pathogenic variant varies with different genes. For example, the vast majority of pathogenic variants in genes involving tubulinopathies occurr de novo (Bahi-Buisson and Cavallin. 2016. PubMed ID: 27010057; Rodan et al. 2017. PubMed ID: 27770045). Germline mosaicism has been seen in a patient with tubulinopathy (Brock et al. 2018. PubMed ID: 29706637).

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

Brain malformations are clinically and genetically heterogeneous. The sensitivity is variable depending on different disorders. For example, in analysis of FLNA in 120 patients with classical bilateral periventricular nodular heterotopia and periventricular heterotopia, 25 pathogenic variants were detected in 40 patients (Parrini et al. 2006. PubMed ID: 16684786). In a study of the fetal form of type II lissencephaly, 22 out of 41 unrelated families had positive results in genes causative for muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies (Bouchet et al. 2007. PubMed ID: 17559086). When considering lissencephaly, the four most common genes (PAFAH1B1, DCX, TUBA1A, and DYNC1H1) account for 69% of cases (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 97.5% 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).