Using rare genetic mutations to revisit structural brain asymmetry

Asymmetry between the left and right hemisphere is a key feature of brain organization. Hemispheric functional specialization underlies some of the most advanced human-defining cognitive operations, such as articulated language, perspective taking, or rapid detection of facial cues. Yet, genetic investigations into brain asymmetry have mostly relied on common variants, which typically exert small effects on brain-related phenotypes. Here, we leverage rare genomic deletions and duplications to study how genetic alterations reverberate in human brain and behavior. We designed a pattern-learning approach to dissect the impact of eight high-effect-size copy number variations (CNVs) on brain asymmetry in a multi-site cohort of 552 CNV carriers and 290 non-carriers. Isolated multivariate brain asymmetry patterns spotlighted regions typically thought to subserve lateralized functions, including language, hearing, as well as visual, face and word recognition. Planum temporale asymmetry emerged as especially susceptible to deletions and duplications of specific gene sets. Targeted analysis of common variants through genome-wide association study (GWAS) consolidated partly diverging genetic influences on the right versus left planum temporale structure. In conclusion, our gene-brain-behavior data fusion highlights the consequences of genetically controlled brain lateralization on uniquely human cognitive capacities

Effects of eight neuropsychiatric copy number variants on human brain structure

Many copy number variants (CNVs) confer risk for the same range of neurodevelopmental symptoms and psychiatric conditions including autism and schizophrenia. Yet, to date neuroimaging studies have typically been carried out one mutation at a time, showing that CNVs have large effects on brain anatomy. Here, we aimed to characterize and quantify the distinct brain morphometry effects and latent dimensions across 8 neuropsychiatric CNVs. We analyzed T1-weighted MRI data from clinically and non-clinically ascertained CNV carriers (deletion/duplication) at the 1q21.1 (n = 39/28), 16p11.2 (n = 87/78), 22q11.2 (n = 75/30), and 15q11.2 (n = 72/76) loci as well as 1296 non-carriers (controls). Case-control contrasts of all examined genomic loci demonstrated effects on brain anatomy, with deletions and duplications showing mirror effects at the global and regional levels. Although CNVs mainly showed distinct brain patterns, principal component analysis (PCA) loaded subsets of CNVs on two latent brain dimensions, which explained 32 and 29% of the variance of the 8 Cohen’s d maps. The cingulate gyrus, insula, supplementary motor cortex, and cerebellum were identified by PCA and multi-view pattern learning as top regions contributing to latent dimension shared across subsets of CNVs. The large proportion of distinct CNV effects on brain morphology may explain the small neuroimaging effect sizes reported in polygenic psychiatric conditions. Nevertheless, latent gene brain morphology dimensions will help subgroup the rapidly expanding landscape of neuropsychiatric variants and dissect the heterogeneity of idiopathic conditions

Cerebellar granuloprival degeneration in an Italian Hound

A severe atrophy of the cerebellum was observed in a 7-monthold male Italian hound with a history of progressive ataxia and head tremor from the age of 3 months. On clinical examination, signs included severe hypermetric gait, head tremors and proprioception deficits in all limbs. At necropsy, a pronounced symmetrical reduction in size of the cerebellum was the only gross lesion observed. Histological examination of the cerebellum revealed marked thinning of the granular and molecular layers with almost complete loss of granule cells. Purkinje cells had normal morphology and distribution. These findings differ from those of previous reports of cerebellar cortical abiotrophy in dogs, which were mainly characterized by prominent Purkinje cell degeneration and loss

Clinicopathological features of globoid cell leucodystrophy in cats

Clinical and pathological findings consistent with globoid cell leucodystrophy (GLD) were evaluated in two domestic shorthaired cats, aged 3 and 4 months. Both showed neurological signs mainly characterized by progressive pelvic limb ataxia, paraplegia with loss of deep pain perception in the pelvic limb, and intentional tremors of the thoracic limbs. Pathological changes affecting the central and peripheral nervous systems were characterised by diffuse, bilateral and symmetrical myelin loss, and marked astrogliosis. In the leucodystrophic areas there was perivascular accumulation of large PAS-positive, nonmetachromatic macrophages (globoid cells), with intracytoplasmic accumulation of crystalloid tubular aggregates. Peripheral nerves showed demyelinating features with thin myelin sheaths, myelin splitting, and ballooning; the nerve fibres had bizarre shapes due to the presence of pate inclusions in the Schwann cells. GLD in cats shares clinical and pathological features with the disease described in other animals and human beings. The neurological signs differed from those of other feline inborn neurometabolic diseases and cerebellar hypoplasia