The Invitae Costello Syndrome Test analyzes HRAS, a gene that is associated with Costello syndrome. Costello syndrome is one of the RASopathies, which are a class of pediatric disorders associated with genes that are members of the 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.
Costello syndrome is characterized by coarse facial features, congenital heart defects, failure to thrive and feeding difficulties, developmental delay and intellectual disability, deep palmar and plantar creases, and increased risk of malignancies; however, the RASopathies have several overlapping phenotypic features due to their common underlying Ras/MAPK pathway dysregulation. Distinguishing Costello syndrome from other phenotypically similar syndromes, such as CFC syndrome and Noonan syndrome, is important for proper medical management.
The RASopathies are multisystemic disorders whose clinical 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 and can be ordered at no additional charge.
Costello syndrome is a pediatric multisystemic and developmental disorder caused by pathogenic variants in the HRAS gene. Characteristic features include intellectual disability, failure to thrive and feeding difficulties, cardiac malformations, short stature, loose skin with deep palmar and plantar creases, cerebellar overgrowth, papillomata of the face and perianal region, predisposition to malignancy, and dysmorphic facial features including coarse facies, epicanthal folds, long eyelashes, sparse/curly hair, full lips, and a wide nasal bridge.
Pathogenic variants in the HRAS gene are identified in approximately 80%-90% of individuals with a clinical diagnosis of Costello syndrome. A mutation hotspot in exon 2 at amino acid position p.Gly12 or p.Gly13 accounts for nearly 95% of pathogenic variants identified in HRAS.
A small number of individuals have been identified with a clinical diagnosis of Costello syndrome and pathogenic variants in the KRAS gene, so an expansion of the phenotypic and genotypic spectrum caused by KRAS variants may be considered. Depending on the clinical presentation of the patient, clinicians may wish to order Invitae RASopathies Comprehensive panel, which includes both HRAS and KRAS, for a broader analysis.
Costello syndrome is inherited in an autosomal dominant pattern.
Costello syndrome is a completely penetrant pediatric-onset disorder.
Individuals with Costello syndrome have a lifetime risk of approximately 15%-17% of malignant solid tumors, including neuroblastoma and rhabdomyosarcoma. Acoustic neuroma and bladder carcinoma have also been reported in adults with Costello syndrome.
Cardiac abnormalities, including malformations, arrhythmias, and hypertrophy, are present in approximately 63% of individuals with Costello syndrome and are the leading cause of morbidity and mortality.
Costello syndrome is rare, and the birth prevalence has been estimated in the UK population at 1:500,000.
Costello syndrome testing is indicated for any individual with clinical features that are consistent with Costello syndrome or who has a first-degree relative with Costello syndrome.
Because the clinical phenotype overlaps among other RASopathies, Costello syndrome testing is also indicated in cases in which the clinical phenotype is consistent with Noonan syndrome or CFC 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|