Introduction: CH is a major cause of childhood morbidity and mortality, affecting 1 in 1,000 live births  and representing up to 3% of all pediatric hospital charges in the U.S. . Accordingly, CH is a major financial burden on health care systems worldwide , and costs the U.S health care system alone greater than $2 billion annually [2, 4]. Over the last few decades, there has been little progress in the prevention or treatment of hydrocephalus. Current therapy consists of life-long, catheter-based CSF shunting and endoscopic third ventriculostomy with or without choroid plexus cauterization, invasive surgeries with high rates of failure and morbidity . Understanding critical genetic drivers underlying human CH holds promise for the development of targeted therapies.
Methods: We exome sequenced DNA isolated from 125 patient-parent trios (affected patient and unaffected parents) and an additional 52 probands for a total of 177 non-L1CAM primary CH. Exome-sequencing data from these 440 individuals was then analyzed to identify rare, de novo and transmitted mutations contributing to CH. Candidate mutations were subsequently confirmed by Sanger sequencing and functionally validated using CRISP/Cas9 gene editing in Xenopus to establish gene causality.
Results: Exome sequencing identified three novel genes with significant burden of rare damaging de novo or transmitted mutations: TRIM71 (p = 2.15 x 10-7), SMARCC1 (p = 8.15 x 10-10), and PTCH1 (p = 1.06 x 10-6). Additionally, two de novo duplications were identified at the SHH locus, encoding the PTCH1 ligand (p = 1.2 x 10-4). Together, these mutations explain 10% of studied congenital hydrocephalus cases. Strikingly, all four genes are required for neural tube development and regulate ventricular zone neural stem cell fate.
Conclusions: These results implicate impaired neurogenesis and not active CSF accumulation in the pathogenesis of a subset of CH patients, with potential diagnostic, prognostic, and therapeutic ramifications.
Patient Care: Our study represents the largest, whole-exome sequencing cohort of patients with well-phenotyped, primary, non-L1CAM congenital hydrocephalus. Exome sequencing data from this investigation has elucidated novel genetic mutations and cellular signaling mechanisms never before implicated in human congenital hydrocephalus, thereby facilitating: 1) a deeper understanding of pathways involved in the development of congenital hydrocephalus, 2) better classification and prognostication schemes, 3) a more efficient path towards designing targeted, effective therapeutic options for patients with congenital hydrocephalus.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the genetic basis of hydrocephalus and recognize the pressing need for studies that aim to advance our primitive understanding of genetic and molecular determinants of this disorder, 2) Understand and appreciate the ability of large cohort, exome sequencing and bioinformatics analyses to elucidate the pathogenesis of heterogeneous disorders, 3) Identify novel, effective treatment targets in hydrocephalus in the light of novel, recurrent mutations in genes required for neural tube development and neural stem cell programming.
References: 1. Munch, T.N., et al., Familial aggregation of congenital hydrocephalus in a nationwide cohort. Brain, 2012. 135(Pt 8): p. 2409-15.
2. Simon, T.D., et al., Hospital care for children with hydrocephalus in the United States: utilization, charges, comorbidities, and deaths. J Neurosurg Pediatr, 2008. 1(2): p. 131-7.
3. Boivin, M.J., et al., Reducing neurodevelopmental disorders and disability through research and interventions. Nature, 2015. 527(7578): p. S155-60.
4. Shannon, C.N., et al., The economic impact of ventriculoperitoneal shunt failure. J Neurosurg Pediatr, 2011. 8(6): p. 593-9.
5. Kahle, K.T., et al., Hydrocephalus in children. The Lancet, 2016. 387(10020): p. 788-799.