My name is Adam Kundeshora. I'm a PGY4 neurosurgery resident at Yale University and Yale New Haven Hospital. I'd just like to thank the AANS for this opportunity to present in the Young Neurosurgeons Research Forum. Today I want to talk to you about how de novo mutations in TRMM71 cause a novel syndrome of congenital hydrocephalus with consistent clinical and neuroimaging findings. I have no conflicts of interest to disclose and the funding for this work is listed below. So hydrocephalus has been classically defined as enlargement of the cerebral ventricles resulting from inadequate passage of CSF from its point of production to its point of absorption. There are different forms, primary or congenital, secondary which can be acquired from tumor, hemorrhage, infection, etc. and both of these forms have both non-communicating and communicating types. Congenital hydrocephalus impacts 1 in 1,000 live births and is often associated with cortical malformations. The literature supports a genetic basis and estimates that maybe 40% of cases should be explained by genetics but until recently only a few mutations have been identified, namely L1CAM, MPDZ, CCDC88, and AP1S2. We all know about the treatment for congenital hydrocephalus that involves CSF diversion either by endoscopic third ventriculostomy or shunt placement but these treatment modalities have high failure rates and morbidity, especially shunt failure and infection resulting in the need for re-operation. Our group has approached investigating this question of congenital hydrocephalus by leveraging aggressive social media recruitment and whole exome sequencing. In 2018 we published our initial cohort which consisted of 177 probands, 125 of which were case parent trios meaning that we had whole exome sequencing data for both the patient and the parents 47 of them were singleton, which is the patient only, and 5 of the patients were actually part of families where congenital hydrocephalus spanned generations. We were able to identify three new pathogenic mutations in TRMM71, SMARTC1, and PATCH1 and what we've done since then is essentially doubled down on our recruitment efforts focusing on increasing cohort size, doing a deep dive into the complete medical records of the patients who are able to get records for something we like to call deep phenotyping and we have reviewed entire neuroimaging histories of patients for which we found significant mutations. So as it stands now we have about 400 patients, 232 are trios and 149 are singletons. Now we've identified a number of other genes associated with congenital hydrocephalus but I want to focus on one of those genes today, TRMM71 as this gene really illustrates best the subtyping we've been able to do with such a large cohort. Now our prior study had identified three patients with TRMM71 mutation and we've now increased that to 8, 6 of which are de novo, which you can see in this table here and many of the patients actually harbor identical mutations which you can appreciate in the amino acid change column. So what is TRMM71 exactly? TRMM71 encodes the target LIN41 which is a phylogenetically conserved RNA binding protein shown to regulate stem cell fate in C. elegans. Now we've been working with a mouse model to further characterize pathogenesis and have found that mutations in TRMM71 lead to impaired embryonic neurogenesis. You can see a schematic of the gene here and you'll note that almost all of the mutations are in NHL domains which, in a schematic 3D rendering of the protein, disrupt the ability to bind to its mRNA targets. Now in a cohort this size we see a wide variety of hydrocephalic skins. We see typical symmetric dilatation of the ventricles, moderate and sometimes profound white motor volume loss, thinning of the cortical mantle, copal cephalic brains, and even atypical asymmetric intraventricular cysts, etc. Interestingly, what we've been able to note and quantify was the similarities between our TRMM71 mutant patients. Now the two images on the left are pre-shunting images and the two images on the right are post-shunting images, but nevertheless you can appreciate the similarity between these scans. Now all of our scans were read by at least two clinicians, myself and a neuroradiologist, and we had about a 90% concordance in findings and a few discrepancies were discussed until there was an agreement. Now this is a heat map which represents our findings where the red columns represent a trait shared by at least 50% of our probands. Now you can see 100% of our study participants with TRMM71 mutations were shunt responsive, had corpus callosum anomalies, and had white matter volume loss. 86% had septum pellucidum anomalies. 71% had commissural or fornoceal anomalies, malformations of the cingulate gyrus, both anterior and posterior, cerebellar tonsillar arctopia, and 57% had interhemispheric cysts, and that's what was responsible for that large dilatation which you saw in the prior scans. With regard to clinical presentation, we performed a comprehensive review of all medical records, deep phenotyping, quote unquote, and we were able to obtain metrics that 67% had cranial nerve deficits and 50% had hearing loss, developmental delay, and epilepsy. Now this degree of consistency was not seen across hydrocephalic programs with different mutations, and it really starts to make an argument for a specific syndrome defined by these clinical and neuroimaging features. One can even imagine, as the cohort grows, being able to define major and minor criteria that increase the pretest probability that the patient sitting in front of you with congenital hydrocephalus may or may not have a TRMM71-associated mutation. So what's the point here? We have identified a subtype of hydrocephalus that seems to be secondary to impaired embryonic neurogenesis, and this really goes against the conventional wisdom of hydrocephalus being a CSF handling disorder. Rather, it implies that maybe there's improper formation of the, quote unquote, container or the brain. So I'd like to conclude by asserting that mutations in TRMM71 lead to a distinct subtype of congenital hydrocephalus. Whole exome sequencing may be integral for prognostication discussions and therapeutic decision-making in the future, and given the plummeting costs of whole exome sequencing, it should become standard of care. I'd like to thank all the members at the Kali Lab as well as our collaborators in the Lifton Lab at the Rockefeller University, and I'd like to thank again the AANS for putting on the Young Neurosurgeons Research Forum.

neurosurgery

congenital hydrocephalus

TRMM71 mutations

genetic basis

embryonic neurogenesis