Mehta, Neel H.

Primary enlargement of the cerebrospinal fluid (CSF)–filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the “hand-in-glove” development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

OBJECTIVE Chiari malformation type 1 (CM1) is the most common neurological disorder of the craniocervical junction. CM1 is characterized by cerebellar tonsillar herniation below the foramen magnum, causing CSF obstruction and neural compression. Patients with CM1 suffer from highly variable symptoms, progression, comorbidities, and outcomes, partly due to poor understanding of CM1 pathogenesis. In this paper, the authors present the only familial CM1 cohort study to statistically assess intrafamilial clinical phenotypes to date. METHODS Comprehensive medical, surgical, and family histories and neuroimaging were collected from families with multiple CM1-affected family members. Univariate analysis was performed for each symptom, comorbidity, or surgery to compare observed versus expected frequencies of affected patients with another CM1-affected family member with the same clinical characteristic. RESULTS Twenty-four new familial CM1 cases (totaling 57 patients with CM1) are presented. Intrafamilial similarities were identified for age of onset, symptoms such as headaches (p = 0.007) and neck pain (p = 0.018), neurological comorbidities such as syringomyelia (p = 0.003) and hydrocephalus (p = 0.0001), neurodevelopmental conditions such as dyslexia (p < 0.0001), and connective tissue disorders (CTDs) such as Ehlers-Danlos syndrome (p < 0.0001). CONCLUSIONS These results suggest that CM1 and its associated clinical phenotypes, including age of onset, clinical symptoms, neurological comorbidities, neurodevelopmental conditions, and CTDs, are genetically influenced. Whole-exome sequencing of CM1 patient-parent trios has the potential to identify the genetic determinants of CM1, with implications for neurosurgical management.