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Congenital Hydrocephalus Exome Study Reveals Mutations in Early Brain Development Genes

NEW YORK – Researchers have uncovered genetic alterations associated with sporadic congenital hydrocephalus that help explain how the condition may arise in some patients. 

While some cases of hydrocephalus, which is marked by the accumulation of cerebrospinal fluid in the brain, stem from infection or other causes, others have no associated trigger. Studies have suggested some of these cases are genetic in origin, and previous studies have tied a handful of mutations in genes like L1CAM, MPDZ, CCDC88C, and AP1S2 to the condition. 

To find additional genetic factors, researchers led by Yale University School of Medicine's Kristopher Kahle conducted a whole-exome sequencing study of patients with sporadic hydrocephalus that had been treated neurosurgically. While surgical treatment can benefit some patients, others continue to have enlarged cerebral ventricles and neurodevelopmental symptoms even after surgery.

The researchers uncovered de novo mutations in a dozen genes, five of which harbored a high burden of mutations, as they reported Monday in Nature Medicine. As many of these alterations affect genes involved in stem cell biology or neural development, the findings suggest that the disruption of early brain development may drive a portion of sporadic congenital hydrocephalus cases.

"In the longer term, we speculate that WES of patients with [congenital hydrocephalus], coupled with deep clinical and neuroradiographical phenotyping, might improve precision of classification schemes to prognosticate neurocognitive outcomes and stratify patients to specific treatments," the researchers wrote in their paper.

They performed whole-exome sequencing of 381 individuals with sporadic congenital hydrocephalus who were treated with neurosurgery, a cohort that included 232 parent-offspring trios. Another 1,798 trios of unaffected siblings and parents of individuals with autism spectrum disorder were analyzed in parallel as a control group.

The researchers uncovered 12 genes with two or more de novo mutations each that were predicted to be protein damaging. Five of these genes — TRIM71, SMARCC1, PTEN, PIK3CA, and FOXJ1 — had significantly more mutations than expected. The researchers further estimated that about 22 percent of sporadic congenital hydrocephalus are due to rare, damaging mutations.

Because of distinctive phenotypic features found among individuals with TRIM71 and SMARCC1 alterations, the researchers suggested that these may represent new Mendelian congenital hydrocephalus syndromes. Individuals with mutations in TRIM71, which maintains stem cell pluripotency, are more likely to have cranial nerve defect, nonobstructive interhemispheric cysts, and hearing loss. Meanwhile, individuals with mutations in SMARCC1, which regulates gene expression needed for neural stem cell proliferation, differentiation, and survival during telencephalon development, are more likely to have aqueductal stenosis and cardiac and skeletal abnormalities.

The researchers' analysis additionally implicated a number of genes in the PI3K signaling pathway in congenital hydrocephalus. These genes regulate cell growth, proliferation, and differentiation in numerous tissues, including developing neural stem cells. In particular, they uncovered three de novo mutations in PI3KCA, three in PTEN, and two in MTOR. 

All together, the known, high-confidence, and probable risk genes for congenital hydrocephalus converge in gene co-expression networks of the mid-gestational human cortex, the researchers noted. In particular, the congenital hydrocephalus risk genes converge on a network previously linked to autism spectrum disorder that is enriched for neuronal differentiation and RNA processing gene ontology terms. 

This suggests that genetic disruptions affecting early brain development may drive sporadic congenital hydrocephalus. "Our data implicate genetically encoded neural stem cell dysregulation and an associated impairment of fetal neurogliogenesis as primary pathophysiological events in a significant number of [congenital hydrocephalus] cases," the investigators wrote in their paper.