Neural tube defects (NTD) are among the most common birth defects in humans and yet their molecular etiology remains poorly understood. NTD are believed to result from the complex interaction of environmental factors with a multitude of genetic risk factors in a classical multifactorial disease model. Mendelian forms of NTD in which single variants are sufficient to cause the disease are extremely rare. We report a monozygotic twin with severe NTD (occipital encephalocele and myelomeningocele) and a shared de novo likely truncating variant in SMARCC1. RTPCR analysis suggests the potential null nature of the variant due to NMD. SMARCC1 is extremely constrained in humans and encodes a highly conserved core chromatin remodeler BAF155. Mice that are heterozygous for a null allele or homozygous for a hypomorphic allele develop severe NTD in the form of exencephaly. This is the first report of SMARCC1 mutation in humans and it shows a critical and conserved requirement for intact BAF chromatin remodeling complex in neurulation. This article is protected by copyright. All rights reserved.