Cornelia de Lange Syndrome via the RAD21 Gene

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 mutations in NIPBL, SMC1A, SMC3, RAD21 and HDAC8. RAD21-related Cornelia de Lange syndrome (OMIM#614701) is inherited in an autosomal dominant manner.  RAD21 (also called nuclear matrix protein 1) coded by RAD21 is a component of four core cohesion proteins which play a key role in sister chromatid cohesion, DNA repair and transcriptional control (Nasmyth, K. and Haering, C.H. Annu Rev Genet 43:525-558, 2009; Deardorff, M. A. et al. Am J Hum Genet 90(6): 1014-1027, 2012). To date, two de novo missense mutations and two large deletion involving RAD21 were identified in four unrelated individuals affected with growth retardation, minor skeletal anomalies, facial features, and very mild cognitive impairment (Deardorff, M. A., et al., 2012).

A small portion of the Cornelia de Lange syndrome cases are caused by mutations in RAD21. Mutations were identified in four out of 258 unrelated individuals without NIPBL mutations (Deardorff, M. A. et al. Am J Hum Genet 90(6): 1014-1027, 2012; Human Gene Mutation Database).

This test provides full coverage of all coding exons of the RAD21 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).