Structural deviations of the posterior fossa and the cerebellum and their cognitive links in a neurodevelopmental deletion syndrome

Abstract

High-impact genetic variants associated with neurodevelopmental disorders provide biologically defined entry points for etiological discovery. The 3q29 deletion (3q29Del) is one such variant that confers a ~40-fold increased risk for schizophrenia, and a ~30-fold increased risk for autism. However, the specific neural mechanisms underlying this link remain largely unknown. Here, we report the first in vivo quantitative neuroimaging study in 3q29Del subjects (N = 24) and healthy controls (N = 1,608) using structural MRI. Given prior reports of posterior fossa abnormalities in 3q29Del, we focus our investigation on the cerebellum and its primary tissue-types. Additionally, we compare the prevalence of cystic/cyst-like malformations of the posterior fossa between 3q29Del subjects and controls, and examine the association between neuroanatomical findings and standardized behavioral measures to probe gene-brain-behavior relationships. 3q29Del subjects had smaller cerebellar cortex volumes than controls, both before and after correction for intracranial volume (ICV). 3q29Del subjects also had larger cerebellar white matter volumes than controls following ICV-correction. The 3q29Del group displayed an elevated rate of posterior fossa arachnoid cysts and mega cisterna magna findings independent of cerebellar volume. Sex played a moderating role in a subset of findings. Cerebellar white matter volume was positively associated with visual-motor integration skills and cognitive ability, while cystic/cyst-like malformations yielded no behavioral link. Abnormal development of posterior fossa structures may represent neuroimaging-based biomarkers in 3q29Del. Results reveal cerebellar associations with sensorimotor and cognitive deficits in 3q29Del and present a novel point of genetic convergence with cerebellar pathology reported in idiopathic forms of neurodevelopmental disease.

Psychosis spectrum symptoms among individuals with schizophrenia-associated copy number variants and evidence of cerebellar correlates of symptom severity

“…Our group has also shown quantitively that study subjects with 3q29DS exhibit abnormal cerebellar volumes compared with HCs (32). In the current study, we demonstrate that these neuroanatomical phenotypes may have clinical relevance.…”

“…Recent radiological findings by our team have revealed that cerebellar hypoplasia and cystic/cyst-like malformations of the posterior fossa, are significantly elevated in 3q29DS (10). Our group has also shown quantitively that study subjects with 3q29DS exhibit abnormal cerebellar volumes compared with HCs (32). In the current study, we demonstrate that these neuroanatomical phenotypes may have clinical relevance.…”

“…To determine whether the severity of psychotic symptoms in participants with 3q29Del is associated with structural cerebellar abnormalities previously documented in this population (10, 33) (see Fig. 2A for a representative MR image), we first modeled the dimensional relationship between SIPS ratings for three major symptom domains relevant to psychotic disorders (positive, negative, disorganization) and global and tissue-specific cerebellar volumes in participants with 3q29Del.…”

“…T2-weighted 3D images were acquired in the sagittal plane using a SPACE sequence (38) with the following parameters: TE=563ms, TR=3200ms, bandwidth=745Hz/pixel, FOV=256×256mm, resolution=0.8mm isotropic. Further details on neuroimaging parameters have been described (10, 33).…”

Visual-motor integration deficits in 3q29 deletion syndrome

“…These studies indicate that the genomic insults in Williams syndrome and 22q11.2 deletion syndrome impact visual-motor integration ability above and beyond the insult to cognitive ability; the present study suggests the same may be true in the context of the 3q29 deletion. Indeed, previous work by our team has identified a significant association between VMI performance and cerebellar white matter volume (Sefik et al, 2022), suggesting that VMI performance in 3q29del is related to a brain region distinct from those canonically involved in cognition, but likely to contribute to visuo-spatial function.…”