Brain Small Vessel Disease 2 via the COL4A2 Gene

COL4A2-related brain small vessel disease 2 a rare neurological disorder that affects the small, deep, penetrating arteries and arterioles of the brain. The age onset is variable, ranging from prenatal to adult onset. The major symptoms include lacunar ischemic strokes, hemiplegia, spasticity, cerebral palsy, seizures, intellectual disability, and leukoencephalopathy. Brain MRI shows deep intracerebral hemorrhages, porencephaly, intracranial aneurysms, and reduced white matter volume. The minor features include cognitive impairment, memory loss, and ophthalmological signs (Jeanne and Gould. 2017. PubMed ID: 27794444; Ha et al. 2016. PubMed ID: 26708157; Gunda et al. 2014. PubMed ID: 24390199; Cavallin et al. 2018. PubMed ID: 30315939).

As brain small vessel disease can be caused by defects in many genes with variable and overlapping presentations, it is difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, and prediction of recurrence risk as well as future family planning.

COL4A2-related brain small vessel disease 2 is inherited in an autosomal dominant manner. The vast majority of pathogenic variants in COL4A2 are missense variants at conserved Gly residues in the Gly-X-Y repeats of the triple-helical domain, leading to alterations of the α1α1α2 heterotrimers (Human Gene Mutation Database; Fidler et al. 2018. PubMed ID: 29632050). Only a few truncating variants, including splicing and a small frameshift deletion, have been reported. A large deletion has also been reported at the COL4A2 locus (HGMD). De novo pathogenic variants are common and the disorder has variable severity with incomplete penetrance (Yoneda et al. 2012. PubMed ID: 22209246).

COL4A2 encodes the alpha-2 chain of type IV collagen. COL4A2 combined another subunit COL4A1 forms heterotrimers with 1:2 stoichiometry (alpha-1/alpha-1/alpha-2). Type IV collagen is then associated with laminin, entactin, and heparan sulfate proteoglycans to form basement membranes that separate epithelium from connective tissue (Jeanne and Gould. 2017. PubMed ID: 27794444). A mouse model heterozygous for the Col4a2 p.Gly646Asp variant showed complete penetrance of intracerebral hemorrhage and the retention of COL4A1/COL4A2 heterotrimers within the endoplasmic reticulum (Jeanne et al. 2012. PubMed ID: 22209247).

Analytical sensitivity of COL4A2 testing is high. However, brain small vessel disease caused by defects in COL4A2 is rare (Rannikmäe et al. 2015. PubMed ID: 25653287).

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

This test provides full coverage of all coding exons of the COL4A2 gene 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 full 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).