COL4A1/2 CNVs and cerebral small vessel disease: Narrowing in on the critical chromosomal region.

A nonsmoking 39-year-old man was referred to Medical Genetics for recurrent cerebrovascular accidents (CVAs). He presented at 34 years of age with isolated left-sided weakness. Brain MRI and CT revealed acute infarction in the right medulla over a background of extensive lacunar infarcts and hyperintense periventricular white matter signals. Cerebral angiogram, transesophageal echocardiogram, Holter monitor, thrombotic workup, glucose, cholesterol, lipid profile, and blood pressure were normal. The patient was started on Plavix, Lipitor, and Baclofen. Four months later, he developed new symptoms with MRI showing novel acute infarction in the right anterior medulla. Family history revealed a significant incidence of recurrent CVAs (figure). The patient's parents were first cousins of French Canadian descent. His medical history was noncontributive: he was myopic, with normal scarring and bruising, and had no epistaxis nor hyperflexibility. Physical examination was significant for scarce nose and thorax telangiectasia, and a mild scoliosis. Neurologic examination revealed the sequelae of his previous infarctions and neuropsychological assessment was normal. After an extensive negative metabolic workup, molecular investigations using a custom next-generation sequencing panel revealed 4 copies of COL4A1 and COL4A2 confirmed by array comparative genome hybridization (aCGH), due to an amplification of 749 kb within chromosome 13 (arr [UCSC 2009 hg19] 13q34 [110,723,731-111,472,467] x4). This copy number variant (CNV) encompasses the OMIM genes COL4A1, COL4A2, CARS2, and ING1 and non-OMIM genes RAB20 and CARKD. Familial aCGH studies of 11 members showed 3 or 4 copies of this region with identical breakpoints segregating with disease, except for the proband's 33-year-old sister and one maternal aunt (figure).