Expanded RASopathy Panel (23 Genes) Test Details
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Background
The RASopathies are a genetically heterogeneous group of conditions with overlapping genotypes and phenotypes, consisting of Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, LEOPARD syndrome, Costello syndrome, Neurofibromatosis type 1, and Legius syndrome. Together these six syndromes make up the RASopathies. Clinical features of the RASopathies include short stature, cardiovascular defects (pulmonary valve stenosis and hypertrophic cardiomyopathy being the most common), cutaneous findings, and characteristic facies. Skeletal, hematological, and developmental delays/intellectual disabilities can also be associated with the RASopathies. The comprehensive approach of the Expanded RASopathy Panel covers 23 genes associated with RASopathies as well as Baraitser-Winter syndrome, Aarskog-Scott syndrome, Genitopatellar syndrome and SBBYSS syndrome, which are conditions that have phenotypic overlap with RASopathies. The genes tested in the Expanded RASopathy panel include: ACTB, ACTG1, BRAF, CBL, FGD1, HRAS, KAT6B, KRAS, LZTR1, MAP2K1, MAP2K2, MRAS, NF1, NRAS, PPP1CB, PTPN11, RAF1, RRAS, RIT1, SHOC2, SOS1, SOS2, and SPRED1. As shown below, these genes are involved in the RAS-MAPK pathway and gain-of–function effects on the pathway result in the phenotype associated with the RASopathies.
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Individuals with a RASopathy can have variable phenotypes, even among family members. Features of these disorders also can change with age, which may make it difficult to make an accurate clinical diagnosis. To this point, individuals with a clinical diagnosis of one of the RASopathies have had a molecular etiology that is not consistent with their clinical diagnosis. For example, BRAF variants have been reported in individuals with a clinical diagnosis of Noonan syndrome and a SOS1 variant has been reported in an individual with cardio-facio-cutaneous syndrome (Nystrom et al. 2008). In addition, some of these genes are associated with more than one syndrome (PTPN11, KRAS, and RAF1). As such, molecular diagnostics can help to distinguish between the different RASopathies. Therefore, this comprehensive approach of simultaneously testing all 23 genes is beneficial because it provides complete testing, while eliminating the need to determine which of these genes to test based on an individual's clinical features.
Epidemiology
- Noonan syndrome: 1/1,000–1/2,500
- Neurofibromatosis type 1: ~1/3,000
- Noonan syndrome with multiple lentigines, cardio-facio-cutaneous, Costello, and Legius syndromes, Baraitser-Winter syndrome, Aarskog-Scott syndrome and SBBYSS syndrome: rare, unknown
- Both males and females are affected in equal frequency.
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There is no known association with ethnic origin.
Inheritance Pattern
- Autosomal dominant except FGD1, which is X-linked recessive
- Children of an affected individual with an identified pathogenic variant have a 50% (1 in 2) risk of inheriting the same variant
Gene Information
Read More for expanded gene table.
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Gene |
Protein |
OMIM# |
Locus |
|
ACTB |
Actin, Beta |
102630 |
7p22.1 |
|
ACTG1 |
Actin, Gamma-1 |
102560 |
17q25.3 |
|
BRAF |
V-RAF Murine Sarcoma Viral Oncogene Homolog B1 |
164757 |
7q34 |
|
CBL |
CAS-BR-M Murine Ecotropic Retroviral Transforming Sequence Homolog |
165360 |
11q23.3 |
|
FGD1 |
FYVE, RhoGEF, and PH Domain-Containing Protein 1 |
300546 |
Xp11.22 |
|
HRAS |
Harvey RAT Sarcoma Viral Oncogene Homolog |
190020 |
11p15.5 |
|
KAT6B |
Lysine Acetyltransferase 6B |
605880 |
10q22.2 |
|
KRAS |
Kirsten RAT Sarcoma Viral Oncogene Homolog |
190070 |
12p12.1 |
|
LZTR1 |
Leucine Zipper-Like Transcriptional Regulator 1 |
600574 |
22q11.21 |
|
MAP2K1 |
Mitogen-Activated Protein Kinase Kinase 1 |
176872 |
15q21 |
|
MAP2K2 |
Mitogen-Activated Protein Kinase Kinase 2 |
601263 |
19p13.3 |
|
MRAS |
Muscle RAS Viral Oncogene Homolog |
608435 |
3q22.3 |
|
NF1 |
Neurofibromatosis; Type 1 |
162200 |
17q11.2 |
|
NRAS |
Neuroblastoma RAS Viral Oncogene Homolog |
164790 |
1p13.2 |
|
PPP1CB |
Protein Phosphatase 1, Catalytic Subunit, Beta Isoform |
600590 |
2p23.2 |
|
PTPN11 |
Protein-Tyrosine Phosphatase, Nonreceptor-Type 11 |
176876 |
12q24.1 |
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RAF1 |
V-RAF-1 Murine Leukemia Viral Oncogene Homolog 1 |
164760 |
3p25 |
|
RRAS |
Related RAS Viral Oncogene Homolog |
165090 |
19q13.33 |
|
RIT1 |
RIC-Like Protein Without CAAX Motif 1; RIT1 |
609591 |
1q22 |
|
SHOC2 |
Suppressor of Clear, C. Elegans, Homolog of: SHOC2 |
602775 |
10q25.2 |
|
SOS1 |
Son of Sevenless, Drosophila, Homolog 1 |
182530 |
2p22-p21 |
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SOS2 |
Son of Sevenless, Drosophila, Homolog 2 |
601247 |
14q21.3 |
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SPRED1 |
Sprouty-Related EVH1 Domain-Containing Protein 1 |
609291 |
15q14 |
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Testing Strategy
This test is indicated for:
- Diagnostic testing for individuals with a clinical diagnosis or suspicion of Noonan, LEOPARD, CFC, Costello, Neurofibromatosis type 1,Legius syndromes, Baraitser-Winter syndrome, Aarskog-Scott syndrome, Genitopatellar syndrome and SBBYSS syndrome.
- Familial single site testing for parents and siblings who may be at risk for carrying a variant when a familial variant has been identified.
- Loss-of-function variants in PTPN11 have been identified in individuals with metachondromatosis syndrome (MC).
Test Outcome
- The detection of a pathogenic variant will offer a definitive diagnosis for an affected individual.
- A negative test result does not rule out a diagnosis of Noonan, LEOPARD, CFC, Costello, Neurofibromatosis type 1,Legius syndromes, Baraitser-Winter syndrome, Aarskog-Scott syndrome, Genitopatellar syndrome or SBBYSS syndrome. Additional genes that have not yet been identified also may be associated with these syndromes.
Methodology
The RASopathy Panel includes 23 genes: ACTB, ACTG1, BRAF, CBL, FGD1, HRAS, KAT6B, KRAS, LZTR1, MAP2K1, MAP2K2, MRAS, NF1 (excludes exon 15 in NM_001128147.2), NRAS, PPP1CB, PTPN11 (excludes exon 11A* in NM_080601.1), RAF1, RRAS, RIT1, SHOC2 (only the p.Ser2Gly variant is reported), SOS1, SOS2 (excludes exon 18 in NM_006939.2), and SPRED1. *Exon from an alternate transcript. For additional information on reference sequences and exon coverage, please click here.
Read More...This assay is performed using the PerkinElmer Sciclone® G3 Workstation combined with the Agilent SureSelect Clinical Research Exome capture kit (#G9496A 5190-7344; targeting coding regions (exons) and canonical splice sites) followed by sequencing on the Illumina NextSeq 550 (High-Output v2 kit). Reads are aligned to the GRCh37 reference sequence using the Burrows-Wheeler Aligner (BWA 0.7.17), and variant calls are made using the Genomic Analysis Tool Kit (GATK v4.0.3.0). Detection of copy number variants (CNVs) encompassing 2 or more exons is performed using next-generation sequencing read data and the VisCap algorithm. CNV analysis is only performed when data meets necessary quality standards and may not be available for all cases. Variant calls are limited bioinformatically to the associated region of interest for the assay (see above for details). Sanger sequencing is used for fill in when bases have <12x coverage. All clinically significant variants are confirmed by Sanger sequencing or droplet digital PCR; variants classified as likely benign or benign are not confirmed.
Variant classifications are based on ACMG/AMP criteria (Richards et al. 2015) with ClinGen rule specifications (https://www.clinicalgenome.org/working-groups/sequence-variant-interpretation/). Variants are reported according to HGVS nomenclature (www.hgvs.org/mutnomen). Likely benign and benign variants are not included in this report but are available upon request.
This test does not routinely detect variants in non-coding regions (aside from the canonical splice sites), triplet repeat expansions, translocations, inversions, and copy number variants encompassing less than 2 consecutive exons. There is reduced detection for larger indels, variants in low complexity regions, and variants in regions with high homology.
This test was developed, and its performance characteristics determined by the Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine (LMM, 65 Landsdowne St, Cambridge, MA 02139; 617-768-8500; CLIA#22D1005307). It has not been cleared or approved by the U.S. Food and Drug Administration (FDA). The FDA has determined that such clearance or approval is not necessary.
LessAnalytical and Clinical Sensitivity
This test is 99.93% sensitive (95% CI =99.92-99.94%) to detect variants changing a single base and 96.75% sensitive to detect insertion/deletions (95% CI =96.28-97.22%) within covered regions. Technical positive predictive value for single nucleotide variant changes is 99.42% (95% CI = 99.37-99.48%) and 94.16% (95% CI = 93.34-94.97%) for insertion/deletion changes within covered regions. There is demonstrated reduced detection for larger indels, especially in low complexity regions with corresponding low sequence coverage and in regions with high homology.
This test detects pathogenic variants in at least 70% of individuals with a clinical diagnosis of Noonan syndrome, ~90% of pathogenic variants in individuals with LEOPARD, cardio-facio-cutaneous, or Costello syndromes, and ~95% of pathogenic variants in individuals with Neurofibromatosis type 1. Please note that this test does not analyze deep intronic sequences of NF1 where there have been some variants reported to cause altered splicing; therefore a negative result reduces but does not eliminate the possibility that the individual has Neurofibromatosis type 1.
