Invitae Cornelia de Lange Syndrome Panel


Test description

The Invitae Cornelia de Lange Syndrome Panel analyzes five genes that are associated with Cornelia de Lange syndrome (CdLS), a multiple-congenital-malformation disorder. These genes were selected based on the available evidence to date.

Analysis of these genes may confirm a clinical diagnosis and help guide management and surveillance decisions. Identification of a disease-causing variant can inform recurrence-risk assessment and genetic counseling.

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Primary panel (5 genes)


Cornelia de Lange syndrome (CdLS) is a multiple-congenital-malformation disorder with a broad spectrum of clinical involvement including characteristic facial features, gastrointestinal disease, growth restriction, intellectual disability, and malformations of the limbs, diaphragm, and cardiac, gastrointestinal, and musculoskeletal systems. Neurodevelopmental findings include developmental delays, anxiety, and depression, as well as obsessive-compulsive, self-injurious, and autistic behaviors. CdLS may present as the more severe classic CdLS subtype or the less severe mild CdLS subtype.

Variants in NIPBL, SMC1A, and SMC3 account for approximately 65% of cases of CdLS.

NIPBL, RAD21 and SMC related CdLS are inherited in an autosomal dominant manner. HDAC8 and SMC1A related CdLS are inherited in an X-linked dominant pattern. The majority of CdLS occurs due to de novo mutations. Somatic and germline mosaicism have been reported.

Both NIPBL- and SMC1A-related forms of CdLS are highly penetrant. The penetrance for SMC3-, RAD21-, and HDAC8-related CdLS is not well-established.

Prevalence of CdLS has most recently been estimated at 1 in 50,000; however, the prevalence may be underestimated due to underdiagnosis of the mild subtype of CdLS.

This panel may be appropriate to confirm a diagnosis in an individual who meets clinical criteria for classic CdLS or to establish a diagnosis in an individual who is suspected to have mild CdLS.

  1. Ansari, M, et al. Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism. J. Med. Genet. 2014; 51(10):659-68. PMID: 25125236
  2. Barisic, I, et al. Descriptive epidemiology of Cornelia de Lange syndrome in Europe. Am. J. Med. Genet. A. 2008; 146A(1):51-9. PMID: 18074387
  3. Borck, G, et al. Father-to-daughter transmission of Cornelia de Lange syndrome caused by a mutation in the 5' untranslated region of the NIPBL Gene. Hum. Mutat. 2006; 27(8):731-5. PMID: 16799922
  4. Deardorff, MA, et al. Cornelia de Lange Syndrome. 2005 Sep 16. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301283
  5. Deardorff, MA, et al. Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am. J. Hum. Genet. 2007; 80(3):485-94. PMID: 17273969
  6. Kline, AD, et al. Cornelia de Lange syndrome: clinical review, diagnostic and scoring systems, and anticipatory guidance. Am. J. Med. Genet. A. 2007; 143A(12):1287-96. PMID: 17508425
  7. Liu, J, Krantz, ID. Cornelia de Lange syndrome, cohesin, and beyond. Clin. Genet. 2009; 76(4):303-14. PMID: 19793304
  8. Musio, A, et al. X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat. Genet. 2006; 38(5):528-30. PMID: 16604071
  9. Niu, DM, et al. Paternal gonadal mosaicism of NIPBL mutation in a father of siblings with Cornelia de Lange syndrome. Prenat. Diagn. 2006; 26(11):1054-7. PMID: 16958143

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
HDAC8 NM_018486.2
NIPBL NM_133433.3
RAD21 NM_006265.2
SMC1A NM_006306.3
SMC3 NM_005445.3