October 2019 AND PANEL: INCLUDING CARDIOFACIOCUTANEOUS SYNDROME, COSTELLO SYNDROME AND LEOPARD SYNDROME For More Information The Noonan syndrome and RASopathies panel includes testing for the following disorders: Noonan syndrome, Noonan-like syndrome, Cardio-facio-cutaneous (CFC) syndrome, GeneReviews Costelo syndrome and LEOPARD syndrome. This genetically heterogeneous group of dis- orders is associated with a defect of the RAS/MAPK signalling pathway. The clinical pheno- - http://www.ncbi.nlm.nih.gov/ types overlap and include the following hallmark features: facial dysmorphology, cardiac de- books/NBK1124 - http:// www.ncbi.nlm.nih.gov/books/ fects (such as pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic NBK1507/ - http:// cardiomyopathy, rhythm disturbances), short stature, deafness, motor and cognitive delay of www.ncbi.nlm.nih.gov/books/ varying degrees, predisposition to tumors (including including , neuro- NBK1186/ - http:// blastoma, ALL and transitional cell carcinoma) and prenatal presentation of . www.ojrd.com/content/3/1/13 SickKids Genomic Diag- nostics Laboratory: GENETICS TEST METHODS www.sickkids.ca/genome- The inheritance of Noonan syndrome, CFC Complete sequencing of the coding region diagnostics syndrome, Costello syndrome and LEOPARD and flanking intron/exon boundaries of the To locate a genetics center syndrome is autosomal dominant. Most indi- listed in the table below. This is near you: viduals have the condition as a result of a de done via NGS of a targeted panel of novo pathogenic variant in one of the genes genes associated with Noonan spectrum Canadian Association of Ge- listed below. disorders. Please refer to our “A Guide to netic Counsellors (CAGC): Next-Generation Sequencing” information www.cagc-accg.ca WHO SHOULD BE TESTED? sheet available on our website, for further details. National Society of Genetic  Individuals clinically suspected of being af- Counselors (NSGC): fected with Noonan syndrome, CFC syn- Deletion/duplication analysis is available www.nsgc.org/ drome, Costello syndrome and LEOPARD for the SPRED1 by MLPA. syndrome. Genes on the Condition variants in  The relatives of a proband with identified panel gene are associated with pathogenic variant(s) in one of the Noonan spectrum disorder genes. BRAF Noonan syndrome and CFC syndrome

PRENATAL TESTING CBL Noonan-like syndrome 1. Current molecular testing may not detect all possible mu- Most of the features of Noonan syndrome are Costello syndrome tations for this disease. A nega- not identified in the 1st or 2nd trimester of HRAS tive test does not rule out the pregnancy, although 1st trimester cystic possibility of Noonan, CFC, Cos- hygroma has been associated with a clinical KRAS Noonan syndrome and tello or LEOPARD syndrome. CFC syndrome diagnosis of Noonan syndrome in 1-4% of 2. The clinical course or se- cases with normal karyotype. MAP2K1 CFC syndrome verity of symptoms cannot be predicted by molecular analysis. Fetuses at increased risk due to a family MAP2K2 CFC syndrome history of Noonan syndrome, CFC syndrome, 3. Test results should be in- terpreted in the context of clini- Costello syndrome and LEOPARD syndrome NRAS Noonan syndrome or an ultrasound finding of lymphedema and/or cal findings, family history and other laboratory data. cystic hygroma are eligible for prenatal testing. Noonan syndrome and PTPN11 LEOPARD syndrome 4. This test was developed and its performance characteristics RAF1 Noonan syndrome and LEOPARD syndrome validated by the Genome Diagnostics Laboratory at the RIT1 Noonan syndrome Hospital for Sick Children. It has not been cleared or approved by SHOC2 Noonan-like syndrome the U.S. Food and Drug Administration. The FDA has SOS1 Noonan syndrome determined that such clearance or approval is not necessary. SOS2 Noonan syndrome This test is used for clinical SPRED1 purposes. LZTR1 Noonan syndrome OMG1620BF/04