Exome sequencing high-yield test for molecular diagnosis of congenital hydrocephalus: JAMA

The systematic review and meta-analysis including 538 probands with congenital hydrocephalus revealed a higher diagnostic yield of ES in CH than that of the current recommendation for ES as a first-tier test for other neurodevelopmental disorders.

Congenital hydrocephalus is a primary form of hydrocephalus characteristically marked by pathological expansion of the cerebral ventricles. CH is present in about 1 in 1000 live births and is among the most common structural brain disorders and neurodevelopmental disorders.

Exome sequencing has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as autism spectrum disorder and global developmental delay; however, current recommendations are not specific to or inclusive of congenital hydrocephalus. Therefore, Ana B. W. Greenberg, Department of Neurosurgery, Massachusetts General Hospital, Boston, and colleagues aimed to determine the diagnostic yield of ES in CH and whether ES should be considered as a first-line diagnostic test for CH.

For this purpose, the researchers searched online databases to identify studies published in English between 2010 and 2023. Eligible studies included those with at least 10 probands with the defining feature of congenital hydrocephalus and/or severe cerebral ventriculomegaly that had undergone ES.

Studies with less than 10 probands, studies using genetic tests other than ES, and studies of mild or moderate ventriculomegaly were excluded. Two reviewers conducted a full-text review of 68 studies. Discrepancies were resolved by consensus.

The primary outcome was pooled diagnostic yield. Estimation of additional diagnostic yields was done for specific subgroups based on syndromic presentation, clinical features, and parental consanguinity.

Nine studies with a total of 538 CH probands were selected for final inclusion from 498 deduplicated and screened records.

The study led to the following findings:

• The overall diagnostic yield was 37.9%.
• The yield was lower for isolated and/or nonsyndromic cases (21.3%).
• The yield was higher for probands with reported consanguinity (76.3%) than those without (16.2%).

"Our findings underscore the high yield of exome sequencing in congenital hydrocephalus," the researchers wrote. "Given that the percentage of patients receiving a molecular diagnosis by ES in CH is comparable to that of the current recommendation for other neurodevelopmental disorders (NDDs)."

"Exome sequencing should also be recommended as a first-tier clinical diagnostic test for CH," they concluded.

Reference:

Greenberg ABW, Mehta NH, Allington G, Jin SC, Moreno-De-Luca A, Kahle KT. Molecular Diagnostic Yield of Exome Sequencing in Patients With Congenital Hydrocephalus: A Systematic Review and Meta-Analysis. JAMA Netw Open. 2023;6(11):e2343384. doi:10.1001/jamanetworkopen.2023.43384