GeneSeq®: Cardio Noonan Syndrome and Related Conditions Profile

CPT: 81404; 81405; 81406(x6); 81479
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Test Details

Test Includes

This test covers all coding nucleotides of eight genes: BRAF, HRAS, KRAS, MAP2K1, MAP2K2, PTPN11, RAF1, and SOS1; plus at least two and typically 10 flanking intronic nucleotides upstream and downstream of each coding exon, covering the conserved donor and acceptor splice sites, as well as typically 10 flanking nucleotides in the 5′ and 3′ UTR. This test also covers the region of SHOC2 where all disease associated mutations have been found.

Use

Confirm a clinical diagnosis of Noonan syndrome and identify presymptomatic family members, guiding prophylactic measures.

Limitations

This analysis does not rule out: germline mosaicism, the presence of large chromosomal aberrations, including deletions, insertions, and rearrangements, mutations in regions or genes not included in this test, and possible inter/intragenic interactions between sequence variants. False-positive results or false-negative results may occur for reasons that include genetic variants, blood transfusions, bone marrow transplantation, mislabeled specimens, or erroneous representation of family relationships.

Methodology

Mutation analysis is performed using the Agilent Sure Select XT® enrichment method and the Illumina® next-generation sequencing platform. Regions of the interest include all exons and splice junctions for each gene and limited regions for the following: SHOC2 (exon 2), APOB (556bp of exon 26), and AKAP9 (exon 18). Sequencing reads are aligned with the hg19 build of the human genome reference sequence. Analytical sensitivity is based on the depth of coverage across the regions of the interest and is provided separately for each gene. Greater than 98% of target bases are synonymous variants not previously recorded at greater than or equal to 20x coverage. Sanger sequencing is used to confirm mutation identity and analyze regions with low coverage. Variants are reported using numbering and nomenclature recommended by the Human Genome Variation Society (HGVS). Variants known to be benign and synonymous variants not previously recorded in our internal variant data bases are not reported.

Additional Information

Noonan syndrome and Noonan-like syndromes tend to be associated predominantly with different genes or different variants within the same genes. Clinical overlap of the various syndromes is explained by the fact that all of these genes code for components of the same intracellular signaling pathway, namely the RAS/MAPK signaling cascade.

Genetic testing for Noonan syndrome and related disorders may:

• Establish or confirm a clinical diagnosis of Noonan syndrome, Leopard syndrome, Costello syndrome, or cardiofaciocutaneous syndrome.

• Identify previously undiagnosed parents, siblings, and other relatives of patients with Noonan syndrome or Leopard syndrome.

• Facilitate appropriate genetic counseling for family members.

Specimen Requirements

Specimen

Whole blood

Volume

10 mL, or 30 mL if ordering multiple tests

Container

Yellow-top (ACD) tube or lavender-top (EDTA) tube

Storage Instructions

Maintain specimen at room temperature.

Causes for Rejection

Frozen or hemolyzed specimen; container broken or leaking; container not labeled or label not legible

Clinical Information

Special Instructions

Test orders must include an attestation that the provider has the patient's informed consent for genetic testing. See sample physician office consent form: Consent for Genetic Testing. For family testing, please call customer service at 866-647-0735 before submitting specimens for family testing (ie, known mutations).

References

Allanson JE, Roberts AE. Noonan syndrome. [GeneReviews Web site]. August 4, 2011. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=noonan. Accessed September 7, 2011. 20301303
Gelb BD, Tartaglia M. LEOPARD syndrome. [GeneReviews Web site]. November 16, 2012. Available at: http://www.ncbi.nlm.nig.gov/bookshelf/br.fcgi?book=gene&part=leopard. Accessed September 7, 2011. 20301557
Gripp KW, Lin AE. Costello syndrome. [GeneReviews Web site]. January 12, 2012. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=costello. Accessed May 11, 2012. 20301680
Jorge AA, Malaquias AC, Arnhold IJ, Mendonça BB. Noonan syndrome and related disorders: A review of clinical features and mutations in genes of the RAS/MAPK pathway. Horm Res. 2009: 71(4):185-193. 19258709
Rauen KA. Cardiofaciocutaneous syndrome. [GeneReviews Web site]. December 23, 2010. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=cfc. Accessed September 7, 2011. 20301365
Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009 Jun; 19(3):230-236. 19467855

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
451441 GeneSeq: Noonan Syndrome 451331 Specimen Type: 31208-2
451441 GeneSeq: Noonan Syndrome 451403 Results: 48003-8
451441 GeneSeq: Noonan Syndrome 451438 Key Findings 53037-8
451441 GeneSeq: Noonan Syndrome 451439 Additional Information 49549-9
451441 GeneSeq: Noonan Syndrome 451694 Gene Information 51968-6
451441 GeneSeq: Noonan Syndrome 451772 Tech Spec Results 51958-7
451441 GeneSeq: Noonan Syndrome 451773 Seq Variants Detected 69548-6
451441 GeneSeq: Noonan Syndrome 451409 Disclaimer N/A
451441 GeneSeq: Noonan Syndrome 451774 Director Review: 48672-0
451441 GeneSeq: Noonan Syndrome 451775 PDF 51969-4
451441 GeneSeq: Noonan Syndrome 451414 GeneSeq:Noonan Syndrome N/A

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The LOINC® codes are copyright © 1994-2017, Regenstrief Institute, Inc. and the Logical Observation Identifiers Names and Codes (LOINC) Committee. Permission is granted in perpetuity, without payment of license fees or royalties, to use, copy, or distribute the LOINC® codes for any commercial or non-commercial purpose, subject to the terms under the license agreement found at https://loinc.org/license/. Additional information regarding LOINC® codes can be found at LOINC.org, including the LOINC Manual, which can be downloaded at LOINC.org/downloads/files/LOINCManual.pdf