NIPBL was first reported in relation to autosomal dominant Cornelia de Lange syndrome (CdLS) in 2004 (Tonkin et al., PMID: 15146185; Krantz et al., PMID: 15146186). Thirteen variants (frameshift, nonsense, splice site, and missense) that have been reported in 13 probands in 2 publications (PMIDs: 15146185, 15146186) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants in this gene generally occur de novo. The mechanism of pathogenicity is known to be loss of function. A total of 243 unique variants have been classified as pathogenic in ClinVar, 193 of which are frameshift, nonsense or consensus splice changes.
Classical CdLS features can be prenatally identified by fetal imaging; these include fetal growth restriction, limb reduction defects, hand anomalies including clinodactyly, oligodactyly, or ectrodactyly, diaphragmatic hernia, heart defects, microcephaly, and abnormal facial features including micrognathia, depressed nasal bridge, anteverted nares, long and smooth philtrum, thin upper lip and downturned corners of the mouth. Unusually long hair, synophrys with arched eyebrows and long eyelashes have been observed by two dimensional and three-dimensional ultrasound. CdLS can be prenatally suspected with any combination of fetal growth restriction, limb defects, facial abnormalities, heart defects, or diaphragmatic hernia (PMIDs: 19242925, 24218399, 24918291, 29995837, 30890023, 33478103, 33633789, 34394191, 35506482). Congenital heart disease is reported in about 30% of patients with CdLS, with pulmonic/peripheral pulmonic stenosis, ventricular septal defect and atrial septal defect being the most commonly found (PMID: 22965847).
This gene-disease relationship is also supported by expression, protein interactions and animal models that recapitulate the human disease.
In summary, there is definitive evidence supporting the relationship between NIPBL and autosomal dominant Cornelia de Lange syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This relationship was evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on June 20, 2018 (SOP 5), the Prenatal Gene Curation Expert Panel on June 28, 2023 (SOP 9), and the Congenital Heart Disease Gene Curation Expert Panel on August 11, 2025 (SOP 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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