The Invitae Cardio-Facio-Cutaneous Syndrome Panel analyzes six genes that are associated with cardio-facio-cutaneous (CFC) syndrome. CFC syndrome 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.
CFC syndrome is characterized by failure to thrive, feeding difficulties, congenital heart defects, distinctive facial features, curly sparse hair, skin rashes, neurologic complications (e.g., hypotonia, motor delay), and developmental delay; however, the RASopathies have several overlapping phenotypic features due to their common underlying Ras/MAPK pathway dysregulation.
CFC syndrome is a multisystemic disorder whose expression is highly variable. Proper management by specialists across a variety of disciplines is critical because CFC syndrome must be correctly identified and comprehensively managed. Distinguishing CFC syndrome from other phenotypically similar syndromes, such as Noonan syndrome or Costello syndrome, is important for proper medical management.
BRAF KRAS MAP2K1 MAP2K2 SHOC2 SOS1
BRAF KRAS MAP2K1 MAP2K2 SHOC2 SOS1
The RASopathies are multisystemic disorders whose expressions are highly variable, even among family members. Many of the clinical features that can differentiate RASopathy conditions manifest later in childhood or change with age, making accurate clinical diagnosis difficult. The phenotypes of many RASopathy conditions are expanding: Individuals are being discovered with a molecular genetic finding in a RASopathy gene but clinical findings that are not typically described in the specific condition associated with that gene. Additionally, some genes are associated with more than one RASopathy syndrome.
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.
Cardio-facio-cutaneous (CFC) syndrome is a multi-system pediatric developmental syndrome that most commonly affects the heart, face, and skin. It is a member of a class of pediatric disorders called the RASopathies. CFC is a phenotypically variable disorder; not all affected individuals will present with every finding. Further, some findings may be evident at birth while others may present later.
The most commonly observed cardiac anomalies are pulmonic stenosis and other valvular defects, septal defects, hypertrophic cardiomyopathy, and arrhythmia.
Classic facial dysmorphology comprises macrocephaly, broad forehead, bitemporal narrowing, hypoplasia of the supraorbital ridges, downslanting palpebral fissures, ptosis, short nose with depressed nasal bridge and anteverted nares, high-arched palate, and low-set, posteriorly rotated ears.
Cutaneous findings usually include sparse, curly hair with sparse eyebrows and lashes, hyperkeratosis, keratosis pilaris, hemangioma, ichthyosis, progressively forming nevi, and flat, broad nails.
Other anomalies are also frequently observed, such as short stature, pectus deformity, kyphosis/scoliosis, and ocular abnormalities (strabismus, nystagmus, myopia,hyperopia, and astigmatism). Failure to thrive during infancy is typical, as are gastrointestinal complications such as reflux, vomiting, oral aversion, and constipation. Neurologic complications are observed in all patients to varying degrees and include hypotonia, hydrocephalus, motor delay, seizures, speech delay, and mild-to-severe developmental delay (there are a few individuals with IQs in the normal range). CFC syndrome is not associated with the increased risk of malignancy that has been observed in such phenotypically similar syndromes as Noonan and Costello, but some malignancies have been reported.
BRAF mutations are the most common and account for an estimated 75% of individuals with CFC syndrome. Mutations in MAP2K1 and MAP2K2 have been reported in nearly 25% of individuals with a clinical diagnosis of CFC syndrome. KRAS mutations have been observed in less than 5% of CFC syndrome individuals. Individuals with pathogenic variants in SHOC2 and SOS1 have been reported with clinical manifestations that overlap with typical Noonan or CFC syndrome features . The Invitae Cardio-Facio-Cutaneous Syndrome panel will identify mutations in nearly 100% of individuals with a clinical diagnosis of CFC syndrome.
Individuals with CFC syndrome rarely reproduce, so cases are generally a result of spontaneous de novo mutation; however, autosomal dominant transmission has been reported.
CFC syndrome is fully penetrant with phenotypic variability.
The exact incidence of CFC syndrome is not known; based on historic accounts, an estimated 200-300 people are affected worldwide. It is possible that CFC syndrome has been under- or misdiagnosed: A nationwide prevalence study conducted in Japan found CFC syndrome in 1 person per 810,000 Japanese individuals. CFC syndrome affects males and females equally and has no ethnic predilection.
Cardio-facio-cutaneous (CFC) syndrome testing may be indicated for any individual with a family history of CFC in a first-degree relative or a suspected diagnosis in a proband due to clinical features consistent with CFC Syndrome (see the clinical description above).
CFC testing may also be indicated in cases where the clinical phenotype is consistent with Noonan syndrome or Costello syndrome, but results from previous molecular testing for these conditions are negative.
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|