Cornelia de Lange Syndrome via the NIPBL Gene

Classic Cornelia de Lange syndrome (CdLS) is characterized by distinctive facial features, growth retardation, hirsutism, and upper limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly. Craniofacial features include synophrys; arched eyebrows; long eyelashes; small, upturned nose; small, widely spaced teeth; and microcephaly. IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement but often have facial features consistent with CdLS (Deardorff et al. GeneReview 2011).

CdLS can be caused by variants in NIPBL, SMC1A, and SMC3. NIPBL-related CdLS (OMIM#122470) is inherited in an autosomal dominant manner. Variants in this gene account for about 60% of CdLS (Gillis et al. Am J Hum Genet 75:610-623, 2004). NIPBL encodes Nipped-B-like protein, which plays a role in sister chromatid cohesion and in regulating long-range enhancer-promoter interactions, possibly through interactions with the cohesin complex (Dorsett Curr Biol 14:R834-836, 2004). The majority of affected individuals have a de novo NIPBL variant; fewer than 1% of individuals with NIPBL-related CdLS have an affected parent. It has been suggested that milder forms of CdLS are more likely to be caused by missense variants and more severe forms by truncating variants (Gillis et al. 2004).

This test is predicted to detect disease variants in ~60% of individuals with clinical features of CdLS (Gillis et al. 2004; Deardorff et al. 2011).

This test provides full coverage of all coding exons of the NIPBL gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).