Invitae Cornelia de Lange Syndrome Panel

Ordering
  • Test code: 04727
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
Billing

Test description

The Invitae Cornelia de Lange Syndrome Panel analyzes up to six genes associated with Cornelia de Lange syndrome (CdLS), a multiple-congenital-malformation disorder. These genes were selected based on the available evidence to date to provide Invitae’s broadest test for Cornelia de Lange Syndrome.

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

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Primary panel (5 genes)

HDAC8 NIPBL RAD21 SMC1A SMC3

Add-on Preliminary-evidence Gene for Cornelia de Lange Syndrome (1 gene)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include a gene which does not currently have a definitive clinical association, but which may prove to be clinically significant in the future. This gene can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more. The EP300 gene is also associated with autosomal dominant Rubinstein-Taybi syndrome (PMID: 24352918).

EP300

  • Cornelia de Lange Syndrome (CdLS)
    • classic CdLS
    • mild CdLS

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, SMC and EP300-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
  10. Woods, SA, et al. Exome sequencing identifies a novel EP300 frame shift mutation in a patient with features that overlap Cornelia de Lange syndrome. Am. J. Med. Genet. A. 2014; 164A(1):251-8. PMID: 24352918

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
EP300 NM_001429.3
HDAC8 NM_018486.2
NIPBL NM_133433.3
RAD21 NM_006265.2
SMC1A NM_006306.3
SMC3 NM_005445.3