Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA and saliva are also acceptable.
Specimen Preparation
Please provide detailed clinical history and features. For more information contact the lab at 6-1447 or by sending an email to DGDGeneticCounselor@chop.edu.
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
For CHOP Phlebotomy: Samples can be collected throughout the week. Samples collected on weekends or holidays are held in Central Labs and sent to the Genomic Diagnostic Lab the following business day.
For External Clients: Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday, optimally within 24 hours of collection.
Please contact the lab (267-426-1447) with questions regarding non-blood specimens.
Volume Required
2-3 mL of blood or 3 ug of DNA with a concentration of at least 50 ng/ul
Minimum Required
1 mL of whole blood
Phlebotomy Draw
Yes
Clinical Features
Noonan spectrum disorders are a genetically heterogeneous group of autosomal dominant conditions: Costello syndrome, LEOPARD syndrome, cardiofaciocutaneous syndrome (CFC), Noonan syndrome, and Noonan-like syndrome with loose anagen hair. The clinical features of each condition overlap and vary in terms of complexity and severity. The typical features seen in all disorders includes distinct facies, short stature, pulmonic stenosis, chest wall malformations, and varying degrees of developmental delays/intellectual disability. The genes involved in Noonan spectrum disorders are all part of the Ras-mitogen activated protein kinase (MAPK) signaling pathway which is involved in cell growth, differentiation, and apoptosis [GeneReviews 2022, PMID: 20301303].
Performing Lab
Division of Genomic Diagnostics
Performed
Mon - Fri 9:00am to 4:00pm
Reported
28 days
Detection Rate
The clinical sensitivity for comprehensive next generation sequencing panels is not yet well-established and is dependent on the panel's gene content and the patient's clinical features. The estimated detection rates are provided for pathogenic variants that can be identified for probands meeting the clinical diagnostic criteria for specific disorders based on the gene content of this panel: ~65-75% for Noonan syndrome [GeneReviews 2022, PMID: 20301303], ~90% for LEOPARD syndrome [Gelb 2015, PMID: 20301557], ~80-90% for Costello syndrome [Gripp 2012, PMID: 20301680], and ~98% for CFC [Rauen 2016, PMID: 20301365].
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.
Genomic DNA is extracted from patient tissue following standard DNA extraction protocols. Whole genome sequencing is performed on the Illumina NovaSeq 6000 platform using the Illumina DNA PCR-Free Library Prep with 150bp paired-end reads. Mapping and analysis is based on the GRCh38 reference sequence. Sequencing data is processed using the Dragen pipeline (Illumina) to call both sequence and copy number variants.
Molecular Testing Notes
The genes involved in the Noonan syndrome spectrum of disorders are all part of the Ras-mitogen activated protein kinase (MAPK) signaling pathway which is involved in cell growth, differentiation, and apoptosis. Pathogenic variants in the LZTR1 are inherited in an autosomal recessive fashion, while all other genes associated with the Nonan syndrome spectrum of diseases are inherited in an autosomal dominant pattern, although many cases are de novo. This panel includes sequencing and copy number analyses of the following genes or regions of interest, unless otherwise noted: A2ML1*, BRAF*, CBL*, HRAS*, KRAS*, LZTR1, MAP2K1*, MAP2K2*, MRAS*, NF1*, NRAS*, PPP1CB*, PTPN11*, RAF1*, RASA2*, RIT1*, RRAS*, SHOC2*, SOS1*, SOS2*, and SPRED1.
* Sequence analysis only is performed for these genes.
CPT Codes
81442
Collection
Collect
Collect whole blood in a purple top (EDTA) tube (preferred). Extracted DNA and saliva are also acceptable.
Specimen Preparation
Please provide detailed clinical history and features. For more information contact the lab at 6-1447 or by sending an email to DGDGeneticCounselor@chop.edu.
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
For CHOP Phlebotomy: Samples can be collected throughout the week. Samples collected on weekends or holidays are held in Central Labs and sent to the Genomic Diagnostic Lab the following business day.
For External Clients: Refrigerate sample until shipment. Send the sample at room temperature with overnight delivery for receipt Monday through Friday, optimally within 24 hours of collection.
Please contact the lab (267-426-1447) with questions regarding non-blood specimens.
Volume Required
2-3 mL of blood or 3 ug of DNA with a concentration of at least 50 ng/ul
Minimum Required
1 mL of whole blood
Phlebotomy Draw
Yes
Ordering
Clinical Features
Noonan spectrum disorders are a genetically heterogeneous group of autosomal dominant conditions: Costello syndrome, LEOPARD syndrome, cardiofaciocutaneous syndrome (CFC), Noonan syndrome, and Noonan-like syndrome with loose anagen hair. The clinical features of each condition overlap and vary in terms of complexity and severity. The typical features seen in all disorders includes distinct facies, short stature, pulmonic stenosis, chest wall malformations, and varying degrees of developmental delays/intellectual disability. The genes involved in Noonan spectrum disorders are all part of the Ras-mitogen activated protein kinase (MAPK) signaling pathway which is involved in cell growth, differentiation, and apoptosis [GeneReviews 2022, PMID: 20301303].
Performing Lab
Division of Genomic Diagnostics
Performed
Mon - Fri 9:00am to 4:00pm
Reported
28 days
Detection Rate
The clinical sensitivity for comprehensive next generation sequencing panels is not yet well-established and is dependent on the panel's gene content and the patient's clinical features. The estimated detection rates are provided for pathogenic variants that can be identified for probands meeting the clinical diagnostic criteria for specific disorders based on the gene content of this panel: ~65-75% for Noonan syndrome [GeneReviews 2022, PMID: 20301303], ~90% for LEOPARD syndrome [Gelb 2015, PMID: 20301557], ~80-90% for Costello syndrome [Gripp 2012, PMID: 20301680], and ~98% for CFC [Rauen 2016, PMID: 20301365].
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.
Genomic DNA is extracted from patient tissue following standard DNA extraction protocols. Whole genome sequencing is performed on the Illumina NovaSeq 6000 platform using the Illumina DNA PCR-Free Library Prep with 150bp paired-end reads. Mapping and analysis is based on the GRCh38 reference sequence. Sequencing data is processed using the Dragen pipeline (Illumina) to call both sequence and copy number variants.
Molecular Testing Notes
The genes involved in the Noonan syndrome spectrum of disorders are all part of the Ras-mitogen activated protein kinase (MAPK) signaling pathway which is involved in cell growth, differentiation, and apoptosis. Pathogenic variants in the LZTR1 are inherited in an autosomal recessive fashion, while all other genes associated with the Nonan syndrome spectrum of diseases are inherited in an autosomal dominant pattern, although many cases are de novo. This panel includes sequencing and copy number analyses of the following genes or regions of interest, unless otherwise noted: A2ML1*, BRAF*, CBL*, HRAS*, KRAS*, LZTR1, MAP2K1*, MAP2K2*, MRAS*, NF1*, NRAS*, PPP1CB*, PTPN11*, RAF1*, RASA2*, RIT1*, RRAS*, SHOC2*, SOS1*, SOS2*, and SPRED1.
* Sequence analysis only is performed for these genes.
