Noonan Spectrum Disorders Panel (12 Genes) Details
Noonan syndrome (NS) is a genetically heterogeneous condition. Several other conditions, which share overlapping genotypes and phenotypes with Noonan syndrome are cardio-facio-cutaneous (CFC) syndrome, LEOPARD syndrome, and Costello syndrome. Together, these four syndromes make up Noonan Spectrum Disorders. Clinical features of Noonan Spectrum Disorders include short stature, cardiovascular defects (pulmonary valve stenosis and hypertrophic cardiomyopathy being the most common), development delays, and characteristic facies. Skeletal, hematologic, and cutaneous findings also can be associated with Noonan syndrome and its related disorders. The comprehensive approach of the Noonan Spectrum Panel covers 12 genes associated with Noonan, CFC, LEOPARD, and Costello syndromes. These genes include PTPN11, SOS1, RAF1, KRAS, HRAS, BRAF, MEK1/MAP2K1, MEK2/MAP2K2, NRAS, SHOC2, CBL, and SPRED1. As shown below, these genes are involved in the Ras-MAPK pathway and gain-of–function variants result in the phenotype associated with Noonan spectrum disorders. CBL and SPRED1 variants in individuals with Noonan syndrome-like features have been reported with additional hematologic or cutaneous features, respectively.Read More...
Individuals with a Noonan spectrum disorder can have very 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 Noonan spectrum disorders 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 Noonan spectrum disorders. Therefore, this comprehensive approach of simultaneously testing all of these 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, thus reducing the likelihood of missed molecular diagnoses.
Noonan syndrome (NS; OMIM #163950) is an autosomal dominant disorder occurring in about 1 in 1,000–2,500 live births. It is characterized by short stature, distinct facial features, congenital heart disease, motor delay, learning difficulties or mild intellectual disability, hearing loss, chest deformity, scoliosis, undescend testes, pubertal delay, and varied coagulation defects and lymphatic dysplasias (http://www.genetests.org/by-genereview/). Although these are common manifestations of the condition, this syndrome exhibits both inter- and intrafamilial variation.
Noonan syndrome is genetically heterogeneous. Variants in PTPN11 have been detected in 50% of individuals with a clinical diagnosis of Noonan syndrome (Tartaglia et al. 2001, 2002). Of the remaining individuals, variants in RAF1, SOS1, and KRAS have been observed in 3–17%, 10%, and 1%, respectively (Pandit et al. 2007, Razzaque et al. 2007, Roberts et al. 2007, Tartaglia et al. 2007, Carta et al. 2006, Schubbert et al. 2006). BRAF and NRAS variants have been reported in individuals with a clinical diagnosis of Noonan syndrome, and SHOC2 variants have been reported in individuals with a clinical diagnosis of Noonan syndrome with loose anagen hair. However, the detection rates for BRAF, NRAS, and SHOC2 are unknown at this time (Nystrom et al. 2008, Cordeddu et al. 2009, Cirstea et al. 2010). In addition, variants in CBL and SPRED1 have been identified in a subset of individuals with overlapping features of Noonan syndrome (Martinelli et al. 2010, Niemeyer et al. 2010, Denayer et al. 2011). PTPN11, RAF1, NRAS, and SOS1 variants have occurred de novo and have co-segregated with Noonan syndrome within families. However, variable expressivity has been observed. All KRAS and SHOC2 variants described to date have occurred de novo.
LEOPARD syndrome (OMIM# 151100) is an autosomal dominant disorder, whose clinical features include multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness (Digilio et al. 2002, Pandit et al. 2007). There is clinical overlap with features of Noonan syndrome (facial anomalies, distinct congenital heart defects, pectus deformity, hearing loss, and growth retardation). Variants in exons 7, 12, and 13 of PTPN11 have been detected in the majority of individuals with LEOPARD syndrome (90–100%) (Digilio et al. 2002; Legius et al. 2002). As many as 33% of individuals with PTPN11-negative LEOPARD syndrome have variants in RAF1 (Pandit et al. 2007).
Cardio-Facio-Cutaneous syndrome (CFC; OMIM# 115150) is characterized by congenital heart defects and ectodermal anomalies. Sparse, curly, or slow-growing hair and skin abnormalities, such as atopic dermatitis and hyperkeratosis with ichthyosis-like lesions, are distinguishing. Cardiac features occur in 77% of cases and include atrial septal defects, pulmonic stenosis, and hypertrophic cardiomyopathy. Characteristic facial features include macrocephaly, a large prominent forehead, bitemporal narrowing, down-slanting palpebral fissures, epicanthal folds, hypertelorism, ptosis, exophthalmos, short upturned nose, prominent philtrum, posteriorly rotated, low-set ears, and webbed neck. Mild-to-severe intellectual disability is observed in 80% of Cardio-facio-cutaneous syndrome cases. Postnatal growth deficiency is common. Cardio-facio-cutaneous syndrome has been reported to share features with Noonan syndrome, Costello syndrome, and Kabuki syndrome. An increased risk of malignancy has not been reported in individuals with Cardio-facio-cutaneous syndrome.
Costello syndrome (CS; OMIM# 218040) is characterized by typical craniofacial features, failure to thrive, developmental delay, cardiac anomalies, skeletal anomalies, and a predisposition to neoplasia. Facial features are coarse and typically include macrocephaly with a prominent forehead, epicanthal folds, down-slanting palpebral fissures, a short nose with a depressed nasal bridge and broad tip, and low-set posteriorly rotated ears with thickened helices and lobes. The cheeks may be full and the mouth large with full lips. The hair is typically curly. Deep palmar and plantar creases, hyperpigmentation, and nasal papillomas are evident. Cardiac features are observed in up to 52% of cases and include pulmonary valve stenosis, ventricular septal defect, atrial septal defect, thickening of the intraventricular septum, hypertrophic cardiomyopathy, or rhythm disturbances. Developmental delay ranges from mild to severe and feeding difficulties (poor suck and swallow) are common. Predisposition to malignancy has been observed, with the most common being rhabdomyosarcoma, transitional cell carcinoma of the bladder, and neuroblastoma. Costello syndrome has been reported to share features with Noonan syndrome and Cardio-facial cutaneous syndrome.
- Noonan syndrome: 1/1000–1/2500
- LEOPARD, Cardio-facio-cutaneous and Costello syndromes: rare, unknown
- Both males and females are affected in equal frequency.
There is no known association with ethnic origin.
- Autosomal dominant
- Children of an affected individual with an identified pathogenic variant have a 50% (1 in 2) risk of inheriting the same variant
Read More for expanded gene table.Read More...
|PTPN11||PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE 11||176876||12q24.1|
|SOS1||SON OF SEVENLESS, DROSOPHILA, HOMOLOG 1||182530||2p22-p21|
|RAF1||V-RAF-1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1||164760||3p25|
|KRAS||KIRSTEN RAT SARCOMA VIRAL ONCOGENE HOMOLOG||190070||12p12.1|
|NRAS||NEUROBLASTOMA RAS VIRAL ONCOGENE HOMOLOG||164790||1p13.2|
|HRAS||HARVEY RAT SARCOMA VIRAL ONCOGENE HOMOLOG||190020||11p15.5|
|BRAF||V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1||164757||7q34|
|MEK1||MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1||176872||15q21|
|MEK2||MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2||601263||19p13.3|
|SHOC2||SUPPRESSOR OF CLEAR, C. ELEGANS, HOMOLOG OF; SHOC2||602775||10q25|
|CBL||CAS-BR-M MURINE ECOTROPIC RETROVIRAL TRANSFORMING SEQUENCE HOMOLOG||165360||11q23.3|
|SPRED1||SPROUTY-RELATED EVH1 DOMAIN-CONTAINING PROTEIN 1||609291||15q14|
This test is indicated for:
- Diagnostic testing for individuals with a clinical diagnosis or suspicion of Noonan, LEOPARD, Costello, or CFC syndromes
- Familial single site testing for parents and siblings who may be at risk for carrying a variant when a familial variant has been identified
- Prenatal diagnosis when a familial variant has been identified
- Prenatal testing when cystic hygroma or increase nuchal translucency is noted on ultrasound. Pathogenic variants in PTPN11 have been found in 16% and 2% of pregnancies with a cystic hygroma or increased nuchal translucency, respectively, when chromosome abnormalities have been ruled out (Lee et al, 2008).
Loss-of-function variants in PTPN11 have been identified in individuals with metachondromatosis syndrome (MC).
- 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, Cardio-facio-cutaneous, or Costello Syndrome. Additional genes that have not yet been identified also may be associated with these syndromes.
This test is performed by next generation sequencing using Agilent SureSelect capture followed by sequencing of the coding regions and splice sites using Illumina sequencing technologies. Variant calls are generated using the Burrows-Wheeler Aligner followed by GATK analysis. Detection of copy number variants (CNVs) encompassing 1 or more exons is performed using VisCap™ analysis. Sanger sequencing is used to fill in regions with insufficient coverage. All clinically significant variants are confirmed by Sanger sequencing or droplet digital PCR. Variants classified as likely benign or benign are not confirmed. This test does not detect variants in non-coding regions that could affect gene expression, aside from the splice junctions, and a few exons have been excluded due to technical difficulties. CNV analysis is only performed when data meets necessary quality standards and may not be available for all cases.
Analytical and Clinical Sensitivity
This assay is greater than 99% sensitive for detecting substitution variants in the sequence analyzed. In addition, this assay is 95% sensitive for detecting small insertions or deletions (InDels) (100% for 1–2 bp indels, 92.3% for 3–5 bp indels and 87.5% for >10 bp indels). Indels are not a described variant type for Noonan spectrum syndromes.
This test detects pathogenic variants in at least 63% of individuals with a clinical diagnosis of Noonan syndrome, as well as 90% of pathogenic variants in individuals with LEOPARD, Cardio-facio-cutaneous, or Costello syndromes.Read More...
|Gene||Noonan Syndrome||CFC Syndrome||LEOPARD Syndrome||Costello Syndrome|
PTPN11 variants have been identified in 16% of fetuses with cystic hygroma and 2% of fetuses with increased nuchal translucency. The incidence of variants in the other genes analyzed is unknown at this time (Lee et al. 2008).Less