Prenatal Noonan Syndrome

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

Test Includes

Genes tested: BRAF, HRAS, KRAS, MAP2K1, MAP2K2, PTPN11, RAF1, and SOS1. This test covers all coding nucleotides 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, typically 10 flanking nucleotides in the 5′ and 3′ UTR. Testing covers exon 2 of SHOC2.

Use

Prenatal diagnosis for at-risk pregnancies when a parent is affected or when abnormalities are seen on fetal ultrasound. Noonan syndrome and Noonan-like syndromes tend to be predominantly associated 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.

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 positives or 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 (NGS) platform. Regions of 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 ≥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. Variants known to be benign and synonymous variants not previously recorded in our internal variant databases are not reported.

Specimen Requirements

Specimen

Amniotic fluid, chorionic villus sample (CVS), cultured amniocytes, cultured villi. (Cultured cells are required for testing. Direct specimen can be submitted, but a culture fee may be included.) Submission of maternal blood is required for analysis of Maternal Cell Contamination (511402), which should be ordered on a separate test request form.

Volume

Amniotic fluid: 20 cc, CVS: 20 mg, or amniotic fluid and CVS culture: Two confluent flasks

Container

Sterile plastic conical tube or two confluent T-25 flasks for fetal testing

Storage Instructions

Maintain specimen at room temperature or refrigerate at 4°C.

Causes for Rejection

Frozen specimen; hemolysis; quantity not sufficient for analysis; improper container

Clinical Information

Special Instructions

Please call CMBP genetic coordinators at 800-345-4363 prior to submitting a fetal sample. Test orders must include attestation that the provider has the patient's informed consent for genetic testing. See sample physician office consent form: Consent for Genetic Testing. In the case of a family test (ie, known mutation), family tests will only be accepted from family members of index cases tested at LabCorp. Please order test 451385 to submit family testing for Noonan syndrome.

References

Allanson JE, Roberts AE. Noonan syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al. GeneReviews. 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. Available at: http://www.ncbi.nlm.nig.gov/bookshelf/br.fcgi?book=gene&part=leopard. Accessed September 7, 2011.
Gripp KW, Lin AE. Costello syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al. GeneReviews.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. In: Pagon RA, Adam MP, Ardinger HH, et al. GeneReviews. 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
451890 Prenatal Noonan Syndrome 451892 Specimen Type: 31208-2
451890 Prenatal Noonan Syndrome 451891 Result: 48003-8
451890 Prenatal Noonan Syndrome 451893 Key Findings 53037-8
451890 Prenatal Noonan Syndrome 451894 Additional Information 49549-9
451890 Prenatal Noonan Syndrome 451895 Gene Information 51968-6
451890 Prenatal Noonan Syndrome 451896 Tech Spec Results 51958-7
451890 Prenatal Noonan Syndrome 451897 Seq Variants Detected 69548-6
451890 Prenatal Noonan Syndrome 451898 Disclaimer N/A
451890 Prenatal Noonan Syndrome 451899 Director Review: 48672-0
451890 Prenatal Noonan Syndrome 451904 PDF 51969-4

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The LOINC® codes are copyright © 1994-2018, 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