Brain Malformation Testing

Microcephaly-Capillary Malformation syndrome [MICCAP, OMIM#614261] is characterized by severe progressive

microcephaly, early-onset refractory epilepsy, profound developmental delay, and generalized capillary malformations. The

capillary malformations, sometimes referred to as port wine stains, are spread diffusely throughout the body. Other less

common features can include hypoplasia of the distal phalanges and of the fingers and toes, mild heart defects, and

dysmorphic facies [1,2].

Molecular Genetics

Mutations of the STAMBP [OMIM #606247] gene have been identified in patients with MIC-CAP. McDonnell et al., identified

six missense variants, two nonsense mutations, two translational frameshift mutations and three intronic mutations, in a total

of 10 patients with MIC-CAP [3]. STAMBP is involved with endosomal sorting and trafficking machinery and functions in the

regulation of sorting of endosomal sorting complexes required for transport (ESCRTs) machinery and ubiquitinated receptor

cargo [3].

Microcephaly-Capillary Malformation syndrome is characterized by severe progressive microcephaly, early-onset refractory epilepsy, profound developmental delay, and generalized capillary malformations. The capillary malformations, sometimes referred to as port wine stains, are spread diffusely throughout the body. Other less common features can include hypoplasia of the distal phalanges and of the fingers and toes, mild heart defects, and dysmorphic facies.

Mutations of the STAMBP gene have been identified in patients with MIC-CAP. McDonnell et al., identified six missense variants, two nonsense mutations, two translational frameshift mutations and three intronic mutations, in a total of 10 patients with MIC-CAP. STAMBP is involved with endosomal sorting and trafficking machinery and functions in the regulation of sorting of endosomal sorting complexes required for transport (ESCRTs) machinery and ubiquitinated receptor cargo.

STAMBP sequencing

Microcephaly-Capillary Malformation syndrome [MICCAP, OMIM#614261] is characterized by severe progressive

microcephaly, early-onset refractory epilepsy, profound developmental delay, and generalized capillary malformations. The

capillary malformations, sometimes referred to as port wine stains, are spread diffusely throughout the body. Other less

common features can include hypoplasia of the distal phalanges and of the fingers and toes, mild heart defects, and

dysmorphic facies [1,2].

Molecular Genetics

Mutations of the STAMBP [OMIM #606247] gene have been identified in patients with MIC-CAP. McDonnell et al., identified

six missense variants, two nonsense mutations, two translational frameshift mutations and three intronic mutations, in a total

of 10 patients with MIC-CAP [3]. STAMBP is involved with endosomal sorting and trafficking machinery and functions in the

regulation of sorting of endosomal sorting complexes required for transport (ESCRTs) machinery and ubiquitinated receptor

cargo [3].

Autosomal Recessive non-syndromic hydrocephalus sequencing panel

Autosomal recessive non-syndromic hydrocephalus [OMIM#236600] is characterized by onset in utero of enlarged ventricles due to a disturbance of cerebrospinal fluid accumulation. In general, the causes of hydrocephalus are heterogeneous and the majority of cases are secondary to neural tube defects, intracranial hemorrhages, trauma, tumors, teratogens or brain malformations. The remaining cases can be divided into the syndromic (two thirds of cases) and non-syndromic (one third of cases).

Our Autosomal Recessive non-syndromic hydrocephalus sequencing panel includes full gene sequencing for the CCDCC8C and MPDZ genes

Baraitser Winter syndrome sequencing panel

Baraitser-Winter syndrome [BRWS, OMIM #243310 and 614583] is a rare developmental disorder characterized by congenital ptosis, high-arched eyebrows, hypertelorism, ocular colobomata and anterior predominant lissencephaly. Additional features include postnatal short stature, microcephay, intellectual disability, seizures and hearing loss.

Mutations in ACTB and ACTG1 have been identified in patient with BRWS.

Comprehensive Lissencephaly Panel

Classic Lissencephaly (LIS) or Lissencephaly Type 1 is a smooth or nearly smooth cerebral surface caused by deficient neuronal migration. The spectrum of malformations ranges from complete agyria (absent gyri) to regional pachygyria to subcortical band heterotopia (SBH). Cobblestone lissencephaly (COB) previously designated as lissencephaly "type 2", is a brain malformation consisting of a complex cortical dysplasia with glioneuronal heterotopia on the brain surface, moderate to severe lissencephaly, dysmyelination, hypoplastic brainstem, and dysplastic cerebellum with cysts. Our Comprehensive Lissencephaly panel includes sequencing and deletion/duplication analysis of 14 genes (ACTB, ACTG1, ARX, DCX, FKRP, FKTN, LARGE, LIS1, POMT1, POMT2, POMGnT1, RELN, TUBA1A and VLDLR) implicated in both classic and cobblestone lissencephaly

Cobblestone Lissencephaly Sequencing Panel

Cobblestone lissencephaly (COB) previously designated as lissencephaly "type 2", is a brain malformation consisting of a complex cortical dysplasia with glioneuronal heterotopia on the brain surface, moderate to severe lissencephaly, dysmyelination, hypoplastic brainstem, and dysplastic cerebellum with cysts. These findings on brain MRI are pathognomonic of a continuum of autosomal recessive diseases with cerebral, ocular and muscular deficits, Walker-Warburg syndrome, muscle-eye-brain and Fukuyama muscular dystrophy. Our Cobblestone Lissencephaly panel includes sequencing of 6 genes (FKTN, FKRP, LARGE, POMGnT1, POMT1 and POMT2) associated with cobblestone lissencephaly

Classic Lissencephaly Panel

Classic Lissencephaly (LIS) or Lissencephaly Type 1 is a smooth or nearly smooth cerebral surface caused by deficient neuronal migration. The spectrum of malformations ranges from complete agyria (absent gyri) to regional pachygyria to subcortical band heterotopia (SBH). Lissencephaly—“smooth brain" with absent (agyria) or abnormally wide gyri (pachygyria) SBH—“double cortex”; band of heterotopic gray matter below the cortex separated by a thin zone of normal white matter Miller-Dieker syndrome—lissencephaly, characteristic facial features and severe neurologic abnormalities X-linked lissencephaly with abnormal genitalia (XLAG)—lissencephaly and moderately increased thickness of the cortex, absence of the corpus callosum, infantile spasms, hypothalamic dysfunction including deficient temperature regulation, and ambiguous genitalia in males Our Classic Lissencephaly Panel is now available and will include sequencing and deletion/duplication analysis of 8 genes (ACTB, ACTG1, ARX, DCX, LIS1, RELN, TUBA1A and VLDLR) associated with classic lissencephaly.

TUBB3 deletion/duplication analysis

Complex cortical dysplasia with other brain malformations (CDCBM) is a neuronal migration disorder associated with axon guidance defects. Clinically, patients have mild to severe mental retardation, strabismus, axial hypotonia, and spasticity. Cortical malformations seen on brain MRI include: polymicrogyria, gyral disorganization, fusion of the basal ganglia, thin corpus callosum, hypoplastic brainstem, and abnormal cerebellar vermis. Abnormalities of the TUBB3 gene were reported in approximately 10% (12/120) of patients with CDCBM.

TUBB2B deletion/duplication analysis

The hallmark feature seen in patients with TUBB2B mutations is asymmetric polymicrogyria (PMG). PMG is a brain malformation with numerous small gyri separated by shallow sulci, creating a cobblestone appearance. PMG in these patients is usually bilateral, asymmetric, and more striking in the frontal and temporal lobes. Other findings on MRI include absence of the corpus callosum, abnormal basal ganglia and cerebellum, and hypoplasia of the brainstem. Most patients also have microcephaly, severe mental retardation and seizures. Mutations of the TUBB2B gene have been identified in patients with asymmetrical PMG. Jaglin XH, et al [2009] reported four unrelated individuals and one fetus with asymmetrical PMG and de novo mutations in TUBB2B. All mutations were missense mutations in highly conserved residues in exon 4. These mutations result in haploinsufficiency and aberrant heterodimer assembly. Mutations in TUBB2B are autosomal dominant and all mutations, to date, have been de novo. To date, no deletions/duplications in the TUBB2B gene have been reported as causative of polymicrogyria.

TUBA1A deletion/duplication analysis

TUBA1A [OMIM#602529] mutations have been identified in patients with gyral malformations and are generally associated with a p>a gradient (similar to LIS1-associated lissencephaly). Of patients with cortical dysgeneses in whom DCX, LIS1, and ARX mutation analysis is normal, approximately 30-40% have mutations in the TUBA1A gene. To date, no deletions/duplications in the TUBA1A gene have been reported as causative of lissencephaly.

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