Comprehensive Brain Malformation Panel

Brain malformation is a group of complex conditions influenced by both genetic and environmental factors. About 3% of newborns have major central nervous system or systemic malformations (Knupp and Parsons. 2009). This comprehensive panel covers a broad spectrum of brain malformations including tubulinopathies, cortical dysplasia, cortical malformations, periventricular heterotopia, lissencephaly, polymicrogyria, pontocerebellar hypoplasia, muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies, brain small vessel disease, Joubert and Meckel syndrome, holoprosencephaly, and many syndromic and non-syndromic disorders. Most brain malformations have onset before birth. These malformations usually lead to severe intellectual disability and early onset seizures or infantile spasms. Other minor features may include facial diplegia and strabismus, optic nerve hypoplasia and congenital fibrosis of the extraocular muscles, and more (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; Sapir and Karlinski. 2022. PubMed ID: 35626679; Polemic et al. 2024. PubMed ID: 39054600).

Outside of DNA testing, brain imaging techniques such as CT and MRI are the most powerful tools for diagnosis of brain malformations. For example, in the case 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). 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).

As brain malformations can be caused by defect in many genes with variable and overlapping presentations, they can be difficult to diagnose by clinical manifestation and image study only. Therefore, an accurate molecular diagnosis become critical for treatment, prognosis, prediction of recurrence risk, as well as future family planning.

The genetic etiology of brain malformations is extremely heterogeneous, ranging from monogenic causes with little or no influence from modifiers or environmental factors to genetically complex forms. This panel includes genes which are involved in various well documented monogenic brain malformations, as well as many newly-discovered genes (Bahi-Buisson and Cavallin et al. 2016. PubMed ID: 27010057; Spalice et al. 2009. PubMed ID: 19120042; Lange et al. 2015. PubMed ID: 26471271; Barak et al. 2011. PubMed ID: 21572413; Bouchet et al. 2007. PubMed ID: 17559086; Di Donato et al. 2018. PubMed ID: 29671837; Rall et al. 2018. PubMed ID: 29024830; Tantry and Santhakumar. 2023. PubMed ID: 36943622). Following are brief descriptions of these genes and the disorders involved. See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

Cortical dysplasia complex due to defects in structural protein tubulin, actin regulation, neuronal migration microtubule proteins or others (TUBB2A, TUBB2B, TUBB3, TUBB, TUBG1,TUBA8, TUBA1A, CTNNA2, KIF2A, KIF5C, DYNC1H1, CUL4B).

Heterotopia due to defects in neuronal migration and neurogenesis (ARFGEF2, FLNA, NEDD4L, DCHS1, FAT4, ERMARD).

Brain small vessel disease due to defects in collagen structure (COL4A1, COL4A2).

Lissencephaly due to defects in Reelin signaling, structural protein tubulin, doublecortin, Katanin, microtubule-actin cross-linking factor, extracellular matrix laminin, platelet-activating factor acetylhydrolase, mitosis related protein, Aristaless-related homeobox protein or others (RELN, TUBA1A, DCX, KATNB1, MACF1, LAMB1, PAFAH1B1, NDE1, ARX, TMTC3, CRADD).

Baraitser-Winter syndrome due to defects in actin cytoskeleton (ACTB, ACTG1).

Cortical malformations due to defects in epithelial structure laminin (LAMC3).

Cerebellar hypoplasia due to defects in Reelin signaling, calcium/calmodulin- dependent serine protein kinase or others (VLDLR, CASK, DYNC1H1, MAST1).

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (PIK3R2, AKT3, CCND2).

Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies (B3GALNT2, B4GAT1, CRPPA/ISPD, FKRP, FKTN, GMPPB, LARGE1, POMGNT1, POMGNT2, POMK, POMT1, POMT2, RXYLT1).

Pontocerebellar hypoplasia (AMPD2, CHMP1A, CLP1, EXOSC3, RARS2, SEPSECS, TSEN15, TSEN2, TSEN34, TSEN54, VRK1).

Microcephaly with brain malformation (ASPM, CIT, EOMES, IER3IP1, MCPH1, NFIB, RTTN, WDR62, ANKLE2, CDK5RAP2, CDK6, CENPE, CENPJ, CEP135, CEP152, KIF14, etc.).

Intellectual disability with brain malformation (ACTL6B, DDX3X, MEF2C, OPHN1, SRPX2).

Warburg micro syndrome (RAB18, RAB3GAP1, RAB3GAP2, TBC1D20).

Galloway-Mowat syndrome (LAGE3, WDR73).

Hydrocephalus (AKT3, AP1S2, CCDC88C, CCND2, CRB2, DNAI1, EML1, FLVCR2, HDAC6, L1CAM, MPDZ, P4HB, PIK3R2, POMT1, PTEN, WDR81, ZIC3).

Other disorders with brain malformations (L1CAM, ADGRG1, EMX2).

Other syndromes which cause brain malformation or abnormalities (ATP1A2, ATP6V0A2, COL18A1, FH, GPSM2, KIF7, KIFBP, LAMA2, LRP2, MAP1B, MED12, MTOR, NSDHL, OCLN, OFD1, PAX6, PQBP1, SCN3A, SNAP29, SRD5A3, TSC1, TSC2, TUBB4A, ZBTB20, ZIC2).

Brain malformation can be inherited in autosomal dominant, autosomal recessive or X-linked manner or through complex inheritance. The vast majority of pathogenic variants in genes involving tubulinopathies occurr de novo (Bahi-Buisson and Cavallin et al. 2016. PubMed ID: 27010057; Rodan et al. 2017. PubMed ID: 27770045). Germline mosaicism has been seen in a patient with tubulinopathies (Brock et al. 2018. PubMed ID: 29706637).

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, the authors detected pathogenic variants 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). In a study of lissencephaly, analysis of 17 genes (ACTB, ACTG1, ARX, CRADD, DCX, LIS1, TUBA1A, TUBA8, TUBB2B, TUBB, TUBB3, TUBG1, KIF2A, KIF5C, DYNC1H1, RELN, and VLDLR) reached a detection rate of 81% (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 98.3% 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).