Multiple genomic copy number variants associated with periventricular nodular heterotopia indicate extreme genetic heterogeneity

Abstract

Periventricular nodular heterotopia (PNH) is a brain malformation in which nodules of neurons are ectopically retained along the lateral ventricles. Genetic causes include FLNA abnormalities (classical X-linked PNH), rare variants in ARFGEF2, DCHS1, ERMARD, FAT4, INTS8, MAP1B, MCPH1, and NEDD4L, as well as several chromosomal abnormalities. We performed array-CGH in 106 patients with different malformations of cortical development (MCD) and looked for common pathways possibly involved in PNH. Forty-two patients, including two parent/proband couples, exhibited PNH associated or not with other brain abnormalities, 44 had polymicrogyria and 20 had rarer MCDs. We found an enrichment of either large rearrangements or cryptic copy number variants (CNVs) in PNH (15/42, 35.7%) vs polymicrogyria (4/44, 9.1%) (i.e., 5.6 times increased risk for PNH of carrying a pathogenic CNV). CNVs in seven genomic regions (2p11.2q12.1, 4p15, 14q11.2q12, 16p13.3, 19q13.33, 20q13.33, 22q11) represented novel, potentially causative, associations with PNH. Through in silico analysis of genes included in imbalances whose breakpoints were clearly detailed, we detected in 9/12 unrelated patients in our series and in 15/24 previously published patients, a significant (P < 0.05) overrepresentation of genes involved in vesicle-mediated transport. Rare genomic imbalances, either small CNVs or large rearrangements, are cumulatively a frequent cause of PNH. Dysregulation of specific cellular mechanisms might play a key pathogenic role in PNH but it remains to be determined whether this is exerted through single genes or the cumulative dosage effect of more genes. Array-CGH should be considered as a first-line diagnostic test in PNH, especially if sporadic and non-classical.

Fig. 1

Brain magnetic resonance imaging (MRI) scan of the reported patients. Patient 1 (16p13.3p13.2 deletion): T2–weighted (W) axial (a) and T1W coronal (b) sections showing a single heterotopic nodule (arrows) on the right occipital horn, enlarged lateral ventricles, and dilated subarachnoid spaces. Patient 2 (19q13.33q13.43 duplication and 20q12.33 deletion): T1W axial (c) and T2W coronal (d) sections showing few, small, and non-contiguous nodules of gray matter (white arrows) lining the walls of the lateral ventricles, mostly on the left, simplified gyral pattern, enlarged dysmorphic lateral ventricles, and subarachnoid spaces. Patient 3 (7q33q34 duplication and 7q34qter mosaic duplication): T2W axial section (e) showing a nodule (white arrow) located along the body of left lateral ventricle, asymmetric lateral ventricles, and diffuse periventricular white matter hyperintensities; T1W sagittal section (f) revealing four non-contiguous nodules of heterotopic gray matter (white arrows) protruding into the lumen of left lateral ventricle, thin corpus callosum, white matter hyperintensities, and enlarged subarachnoid spaces, mainly in the frontal region. Patient 4 (2p11.2q12.1 mosaic amplification and 2q12.2 duplication): T2W axial (g) and T2W coronal (h) sections showing multiple, small, non-contiguous, asymmetrical nodules of gray matter (white arrows) lining the wall of the right lateral ventricle and the left frontal horn. Patient 5 (14q11.2q12 duplication and 15q11.1q14 deletion): T1W axial sections (i, j) demonstrating few scattered, bilateral, and asymmetric nodules of heterotopic gray matter (black arrows) along the walls of lateral ventricles, hypomyelination, and bilateral parietal-temporal polymicrogyria (black asterisk); Patient 6a (22q11.22q11.23 duplication): T2W axial (k) and T1W coronal (l) sections showing multiple, bilateral, asymmetrical, scattered nodules of heterotopic gray matter in the lateral ventricles and enlargement of the left lateral ventricle (arrows). Patient 6b (22q11.22q11.23 duplication): T1W coronal (m, n) sections showing bilateral, diffuse subependymal PNH along both lateral ventricles. Patient 7 (4p15 deletion in a complex rearrangement): T1W axial sections (o, p) showing multiple bilateral nodules of gray matter (black arrows) located along the walls of lateral ventricles, most evident prominent on lateral and superior walls of the right side. For this patient, MRI images were not previously published