NIPBL, also known as Delangin, appears to have two critical functions: (1) it is essential for loading the cohesin complex onto sister chromatids during meiosis I and DNA double-stranded break repair (Peters et al., 2008) and (2) it may influence gene expression during development (Zuin et al., 2014). Variants in NIPBL are associated with Cornelia de Lange syndrome (CdLS), a developmental disorder characterized by slow growth, moderate to severe intellectual disability, and abnormalities of bones in the arms, hands, and fingers (Brachmann, 1916; De Lange, 1933). Many affected individuals also have behavior problems, including compulsive repetition, anxiety, OCD, and ADHD (Mulder et al., 2017; Oliver et al., 2008). Given that approximately 60% of CdLS cases have a heterozygous NIPBL variant (Mannini et al., 2013), we were surprised to observe variants in this gene in our subjects. However, we only observed Mis3 variants, perhaps suggesting that these variants have less severe consequences. Indeed, cdLS severity is highly correlated to the expression levels of NIPBL (Kaur et al., 2016), and the de novo Mis3 variants that we observed were in exons 29
