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Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (>2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15). Eight unrelated patients with ventriculomegaly, developmental delay, and dysmorphic features harbored loss-of-function DNVs that truncate LDB1's carboxy-terminal LIM interaction domain, which regulates assembly of LIM homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through it's binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging DNVs in our cohort, with SMARCC1 (p = 5.83 x 10-9) and ARID1B (p = 1.80 x 10-17) surpassing exome-wide significance thresholds. These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest an LDB1-regulated transcriptional program is essential for human brain morphogenesis.