The Invitae Noonan Syndrome Panel analyzes up to 16 genes that are associated with Noonan syndrome (NS). NS is one of the RASopathies, which are a class of pediatric disorders associated with genes that are members of the mitogen-activated protein kinase (Ras/MAPK) pathway. This pathway is involved in a signal transduction cascade that is necessary for the proper formation of several types of tissue during embryonic and postnatal development.
Noonan syndrome is characterized by distinctive facial features, short stature, congenital heart defects (pulmonary valve stenosis), chest deformities, and coagulation and lymphatic deficiencies; however, the RASopathies have several overlapping phenotypic features due to their common underlying Ras/MAPK pathway dysregulation. Distinguishing Noonan syndrome from other phenotypically similar syndromes is important for proper medical management.
A2ML1 BRAF CBL KRAS MAP2K1 MAP2K2 NRAS PTPN11 RAF1 RIT1 RRAS SHOC2 SOS1 SOS2
ACTB ACTG1
Some clinical features of Noonan syndrome overlap with Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome, a rare autosomal dominant developmental disorder characterized by multiple congenital anomalies and intellectual disability. If analysis for Baraitser Winter Cerebrofrontofacial syndrome has not been performed previously, adding this panel to this analysis may be considered. This panel can be ordered at no additional cost.
A2ML1 BRAF CBL KRAS MAP2K1 MAP2K2 NRAS PTPN11 RAF1 RIT1 RRAS SHOC2 SOS1 SOS2
Some clinical features of Noonan syndrome overlap with Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome, a rare autosomal dominant developmental disorder characterized by multiple congenital anomalies and intellectual disability. If analysis for Baraitser Winter Cerebrofrontofacial syndrome has not been performed previously, adding this panel to this analysis may be considered. This panel can be ordered at no additional cost.
ACTB ACTG1
Testing for Noonan syndrome is also included in the broader Invitae RASopathies Comprehensive Panel. Depending on the individual’s clinical and family history, this broader panel may be appropriate. This broader panel can be ordered at no additional charge.
Noonan syndrome is a multisystemic pediatric developmental syndrome with variable expressivity. It is a member of a class of disorders known as the RASopathies.
Characteristic clinical features include:
Additional clinical features observed in affected individuals include but are not limited to:
Noonan syndrome patients are also at increased risk for hematologic abnormalities, including malignancies. The most common hematologic conditions are coagulopathies and factor deficiencies—platelet defects that occur in about one-third of patients. Malignancies including juvenile myelomonocytic leukemia (JMML), acute myelogenous leukemia (AML), and B-cell acute lymphoblastic leukemia are observed more frequently than in the general population. Rhabdomyosarcoma and neuroblastoma have also been described in individual patients.
Pathogenic variants in PTPN11, SOS1, and RAF1 account for the majority (65%-75%) of clinically diagnosed cases of Noonan syndrome. The remaining genes on this panel account for approximately another 10% of cases. See the table below for details.
Gene | Proportion of NS attributed to pathogenic variants in this gene |
---|---|
A2ML1 | unknown |
BRAF | <2% |
CBL | <1% |
KRAS | <5% |
MAP2K1 | <2% |
MAP2K2 | rare |
NRAS | rare |
PTPN11 | 50% |
RAF1 | 5%-10% |
RIT1 | <2% |
RRAS | unknown |
SHOC2 | <1% |
SOS1 | 10%-15% |
SOS2 | rare |
Noonan syndrome is inherited in an autosomal dominant pattern, although many cases are the result of a spontaneous de novo mutation in a proband. Males and females are affected equally.
Noonan syndrome is a highly penetrant condition whose clinical expression is widely variable. The exact penetrance is unclear as more genes are being implicated in the genetic etiology.
Prevalence is reported as 1 in 1000 to 1 in 2500 individuals, but Noonan syndrome may be underdiagnosed because mild phenotypes can escape detection.
Testing for Noonan syndrome is indicated in any individual with a family history of Noonan syndrome or suspected diagnosis in a proband due to clinical features consistent with Noonan syndrome (see the clinical features list above).
Noonan syndrome testing is also indicated in cases in which the clinical phenotype is consistent with cardio-facio-cutaneous syndrome or Costello syndrome, but previous molecular testing for these conditions is negative.
For management guidelines please refer to:
American Management Guidelines
Romano, AA, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010; 126(4):746-59.
European Management Guidelines
Noonan Syndrome Guideline Development Group. Management of Noonan syndrome – a clinical guideline (pdf). University of Manchester: DYSCERNE. Accessed July 2015.
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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
Gene | Transcript reference | Sequencing analysis | Deletion/Duplication analysis |
---|---|---|---|
A2ML1 | NM_144670.4 | ||
ACTB | NM_001101.3 | ||
ACTG1 | NM_001614.3 | ||
BRAF | NM_004333.4 | ||
CBL | NM_005188.3 | ||
KRAS | NM_004985.4 | ||
MAP2K1 | NM_002755.3 | ||
MAP2K2 | NM_030662.3 | ||
NRAS | NM_002524.4 | ||
PTPN11 | NM_002834.3 | ||
RAF1 | NM_002880.3 | ||
RIT1 | NM_006912.5 | ||
RRAS | NM_006270.4 | ||
SHOC2 | NM_007373.3 | ||
SOS1 | NM_005633.3 | ||
SOS2 | NM_006939.2 |