ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
15146185 Tonkin et al (Nat Gen 2004) initially described the gene in several patients from their study with NIPBL variants (N = 10 patients, Table 1) detected by direct sequencing and heteroduplex analysis. The patients exhibited with a severe or mild (missense changes) Cornelia de Lange Syndrome (CdLS) phenotype. Phenotypic variation was noted but generally included characteristic face, severe growth restriction, feeding difficulty, and heart murmur. The alterations were small variants, splicing and/or nonsense changes. They were reported as either de novo or parental sample not available for testing.
15146186 Krantz et al. (Nat Gen 2004) identified stop gain, altered start codon, and splice site disruptions among 9 individuals across 12 families (table 2) with CdLS. A 1.1 Mb critical region involving NIPBL was delineated. All variants expected to result in a truncated protein and in three of the four sporadic cases for which samples were available from both parents, the detected variants were de novo.
15318302 Gills et al (AJHG 2004) evaluated 120 individuals with CdLS (including four previously reported, unrelated patients in PMID 15146186) for disruptions in the NIPBL gene. The entire NIPBL coding region (exons 2?47) was screened. The authors identified mutations in 56 patients with CdLS, of which 7 segregated in families and 49 were sporadic (i.e. 47% of tested probands, table 2 and fig. 1). In 25 of the 49 sporadic cases in which both parents were available for screening, all mutations were found to be de novo. The mutation spectrum comprised of 21 frameshift, 12 missense, 10 nonsense, and 8 splice-site mutations. The majority of identified variants were private.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
23085304 Novaro et al (EJMG 2012) performed aCGH (Agilent 180k microarray) and identified a 264kb duplication involving the entire NIPBL gene (no additional genes), confirmed by quantitative PCR . Coordinates (hg19) = chr5:36,809,705-37,073,754. This was indicated as a de novo occurrence following microsatellite analysis of the parents. The patient exhibits delay in psychomotor function, language, dysmorphic features of face, and extremities.
19052029 Yan et al (J Med Gen 2009) presented a study in which they comment on the dosage effect of 5p13 duplications. The patients, whose phenotype was assessed by medical geneticist, in their cohort shared common features including intellectual disability, developmental delay, sleep abnormalities, crainofacial obesity in some, and limb defects. The same systems are affected in CdLS, however clinical manifestations are distinct; namely the absence of the facial gestalt. The authors performed aCGH using a 244k oligo array (Agilent) Notable entry in this publication with respect to triplosensitivity: Patient 4 = 250 kb duplication containing only NIPBL (possibly smallest region of overlap reported). This individual also had a skull deformity. Whether this is a result of the duplication is difficult to assess and complicated the assessment of the phenotype. chr5:36870689-37120908 (hg18 coordinates). Converted to hg19: chr5:36,834,932-37,085,151 Of note, the gains were not detected in parental samples (both parents for two patients and 3 maternal samples for three patient). They were also not found in DGV and were confirmed by interphase FISH.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.