Collect

Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is also acceptable.

Unacceptable Conditions

Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.

Storage/Transport Temperature

Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday within 24 hours of collection.

Performed

Mon - Fri 9:00am to 4:00pm

Volume Required

5 ml whole blood or 8 ug extracted DNA

Minimum Required

3 ml whole blood

Phlebotomy Draw

Yes

Performed

Mon - Fri 9:00am to 4:00pm

Reported

4-6 weeks

Synonyms

  • A2ML1, BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS, SHOC2, SOS1, SOS2, SPRED1, PPP1CB

LIS Mnemonic

NOONP

Performed By

Division of Genomic Diagnostics

Available STAT

No

Test Notes

This test is performed by next generation sequencing of the coding regions and splice sites of the targeted genes. Sanger sequencing is used to confirm clinically significant variants and to fill in regions with insufficient coverage. Variants that are classified as benign or likely benign will not be confirmed or reported.

Clinical Features

Noonan Spectrum disorders include Costello syndrome [OMIM #218040], LEOPARD syndrome [OMIM #151100], cardiofaciocutaneous syndrome (CFC) [OMIM #115150], Noonan syndrome [OMIM #163950], Noonan-like syndrome with loose anagen hair [OMIM# 607721], and Legius syndrome [OMIM #611431]. Noonan syndrome is characterized by short stature, pulmonic stenosis, congenital heart defects, often chest malformations, and a short and webbed neck. Patients with Noonan syndrome also present with distinct facial features including deep philtrums, hypertelorism, ptosis, down slanted and widely spaced eyes, epicanthal folds, and low-set posteriorly rotated ears, and delayed puberty in males [PMID: 1446772, 11992261]. LEOPARD syndrome is an autosomal dominant disorder that demonstrates significant overlap with Noonan syndrome [PMID: 23239957], characterized by lentigines, hypertrophic cardiomyopathy, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness. Costello syndrome shares features with CFC and Noonan syndrome. The facial features of patients with Costello syndrome are coarse and include a bulbous nose, thick eyebrows, full cheeks, a large mouth and tongue, a depressed nasal bridge, and strabismus, macrocephaly, and sparse, curly hair [PMID: 19206176]. Infants born with Costello syndrome experience postnatal growth retardation [PMID: 19288554]. Other features of Costello syndrome include hypotonia, short stature, intellectual disability, congenital heart defects, redundant skin, and malignancies, including rhabdomyosarcoma and neuroblastoma [PMID: 11857556, 16443854]. CFC syndrome is characterized by coarse facial features, dysmorphism including macrocephaly, a high forehead, bitemporal narrowing, ptosis, a depressed nasal bridge, sparse, curly hair, sparse or absent eyelashes and eyebrows, similar to Costello syndrome patients. Affected patients also present with intellectual disability, congenital heart defects, short stature, and skin abnormalities, including xerosis, eczema, and ichthyosis [PMID: 16474404, 18042262]. Noonan-like syndrome with loose anagen hair is similar to classic Noonan syndrome. The most distinct difference is thin, sparse, slow-growing hair that is easy to pluck. Other phenotypic differences include growth hormone deficiency, dark, pigmented skin with ichthyosis or eczema and hyperactive behavior [PMID: 19684605]. Legius syndrome, also known as neurofibromatosis type 1 (NF1) -like syndrome, is an autosomal dominant disorder characterized by cafe au lait spots, axillary and/or inguinal freckling, macrocephaly, and a Noonan-like dysmorphology. Most patients with Legius syndrome do not have impaired intelligence, but some experience attention deficit disorders [PMID: 17704776]. Although there is some phenotypic overlap with NF1, several key features such as cutaneous neurofibromas, Lisch nodules, skeletal abnormalities, and malignant peripheral nerve sheath tumors are absent [PMID: 22753041].

Detection Rate

Pathogenic mutations are identified in ~65-75% of individuals with a clinical diagnosis of Noonan syndrome, 90% of individuals with LEOPARD syndrome, 85% of cases with Costello syndrome and 90% of mutations in Cardiofaciocutaneous syndrome. The detection rate for Noonan-like syndrome with loose anagen hair is still unknown. Nonsense, frameshift, missense and large deletions have been identified in approximately 6-10% of patients with a NF-1 like phenotype in SPRED1.

Utility

The clinical utility of the assay is to support a clinical diagnosis of the disease, facilitate genetic counseling, and assess the risk to other first degree relatives and to facilitate testing of at-risk family members. Molecular confirmation of a diagnosis may help guide recommendations for medical management and screening, and may help avoid unnecessary procedures.

Molecular Testing Notes

The genes involved in the Noonan Spectrum of disorders include PTPN11, RAF1, SOS1, KRAS, BRAF, HRAS, NRAS, CBL, SHOC2, MAP2K2, MAP2K1, SPRED1, A2ML1, LZTR1, MRAS, PPP1CB, RASA2, RIT1, RRAS, SOS2. These genes are all part of the Ras-mitogen activated protein kinase (MAPK) signaling pathway which is involved in cell growth, differentiation, and apoptosis. A recurrent pathogenic variant in the SHOC2 gene (p.Ser2Gly) has been identified in the subgroup of patients with Noonan-like syndrome with loose anagen hair. Mutations in these disorders are all inherited in an autosomal dominant pattern, although many cases are de novo.

CPT Codes

81442
Collection

Collect

Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA is also acceptable.

Unacceptable Conditions

Heparinized specimens, severely hemolyzed specimens, frozen, clotted or possibly commingled specimens, blood in non-sterile or leaky containers, mislabeled or inappropriately labeled specimens.

Storage/Transport Temperature

Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday within 24 hours of collection.

Performed

Mon - Fri 9:00am to 4:00pm

Volume Required

5 ml whole blood or 8 ug extracted DNA

Minimum Required

3 ml whole blood

Phlebotomy Draw

Yes
Ordering

Performed

Mon - Fri 9:00am to 4:00pm

Reported

4-6 weeks

Synonyms

  • A2ML1, BRAF, CBL, HRAS, KRAS, LZTR1, MAP2K1, MAP2K2, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS, SHOC2, SOS1, SOS2, SPRED1, PPP1CB

LIS Mnemonic

NOONP

Performed By

Division of Genomic Diagnostics

Available STAT

No

Test Notes

This test is performed by next generation sequencing of the coding regions and splice sites of the targeted genes. Sanger sequencing is used to confirm clinically significant variants and to fill in regions with insufficient coverage. Variants that are classified as benign or likely benign will not be confirmed or reported.

Clinical Features

Noonan Spectrum disorders include Costello syndrome [OMIM #218040], LEOPARD syndrome [OMIM #151100], cardiofaciocutaneous syndrome (CFC) [OMIM #115150], Noonan syndrome [OMIM #163950], Noonan-like syndrome with loose anagen hair [OMIM# 607721], and Legius syndrome [OMIM #611431]. Noonan syndrome is characterized by short stature, pulmonic stenosis, congenital heart defects, often chest malformations, and a short and webbed neck. Patients with Noonan syndrome also present with distinct facial features including deep philtrums, hypertelorism, ptosis, down slanted and widely spaced eyes, epicanthal folds, and low-set posteriorly rotated ears, and delayed puberty in males [PMID: 1446772, 11992261]. LEOPARD syndrome is an autosomal dominant disorder that demonstrates significant overlap with Noonan syndrome [PMID: 23239957], characterized by lentigines, hypertrophic cardiomyopathy, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, deafness. Costello syndrome shares features with CFC and Noonan syndrome. The facial features of patients with Costello syndrome are coarse and include a bulbous nose, thick eyebrows, full cheeks, a large mouth and tongue, a depressed nasal bridge, and strabismus, macrocephaly, and sparse, curly hair [PMID: 19206176]. Infants born with Costello syndrome experience postnatal growth retardation [PMID: 19288554]. Other features of Costello syndrome include hypotonia, short stature, intellectual disability, congenital heart defects, redundant skin, and malignancies, including rhabdomyosarcoma and neuroblastoma [PMID: 11857556, 16443854]. CFC syndrome is characterized by coarse facial features, dysmorphism including macrocephaly, a high forehead, bitemporal narrowing, ptosis, a depressed nasal bridge, sparse, curly hair, sparse or absent eyelashes and eyebrows, similar to Costello syndrome patients. Affected patients also present with intellectual disability, congenital heart defects, short stature, and skin abnormalities, including xerosis, eczema, and ichthyosis [PMID: 16474404, 18042262]. Noonan-like syndrome with loose anagen hair is similar to classic Noonan syndrome. The most distinct difference is thin, sparse, slow-growing hair that is easy to pluck. Other phenotypic differences include growth hormone deficiency, dark, pigmented skin with ichthyosis or eczema and hyperactive behavior [PMID: 19684605]. Legius syndrome, also known as neurofibromatosis type 1 (NF1) -like syndrome, is an autosomal dominant disorder characterized by cafe au lait spots, axillary and/or inguinal freckling, macrocephaly, and a Noonan-like dysmorphology. Most patients with Legius syndrome do not have impaired intelligence, but some experience attention deficit disorders [PMID: 17704776]. Although there is some phenotypic overlap with NF1, several key features such as cutaneous neurofibromas, Lisch nodules, skeletal abnormalities, and malignant peripheral nerve sheath tumors are absent [PMID: 22753041].

Detection Rate

Pathogenic mutations are identified in ~65-75% of individuals with a clinical diagnosis of Noonan syndrome, 90% of individuals with LEOPARD syndrome, 85% of cases with Costello syndrome and 90% of mutations in Cardiofaciocutaneous syndrome. The detection rate for Noonan-like syndrome with loose anagen hair is still unknown. Nonsense, frameshift, missense and large deletions have been identified in approximately 6-10% of patients with a NF-1 like phenotype in SPRED1.

Utility

The clinical utility of the assay is to support a clinical diagnosis of the disease, facilitate genetic counseling, and assess the risk to other first degree relatives and to facilitate testing of at-risk family members. Molecular confirmation of a diagnosis may help guide recommendations for medical management and screening, and may help avoid unnecessary procedures.

Molecular Testing Notes

The genes involved in the Noonan Spectrum of disorders include PTPN11, RAF1, SOS1, KRAS, BRAF, HRAS, NRAS, CBL, SHOC2, MAP2K2, MAP2K1, SPRED1, A2ML1, LZTR1, MRAS, PPP1CB, RASA2, RIT1, RRAS, SOS2. These genes are all part of the Ras-mitogen activated protein kinase (MAPK) signaling pathway which is involved in cell growth, differentiation, and apoptosis. A recurrent pathogenic variant in the SHOC2 gene (p.Ser2Gly) has been identified in the subgroup of patients with Noonan-like syndrome with loose anagen hair. Mutations in these disorders are all inherited in an autosomal dominant pattern, although many cases are de novo.
Result Interpretation
Administrative

CPT Codes

81442