18 genes sequenced include AKT1, AKT2, AKT3, GNA11, GNAQ, IDH1, IDH2, MAP2K1, MAP3K3, MTOR, PIK3CA, PIK3R2, PTEN, RASA1, SMO, TEK, TSC1 and TSC2.
Somatic Overgrowth & Related Syndromes
Genomics and Pathology Services (GPS) offers somatic variant analysis by next-generation sequencing for segmental overgrowth, skin lesions, vascular malformations, brain abnormalities, McCune Albright and related syndromes.
Results provide physicians with useful information to better manage difficult-to-diagnose patients.
Indications for Testing
Indications for testing include symptoms of any of the following:
- Bannayan-Riley-Ruvalcaba syndrome (BRRS)
- Cowden syndrome
- Congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomalies (CLOVES)
- Curry-Jones Syndrome
- Epidermal nevi and seborrheic keratoses
- Garcia-Hafner-Happle Syndrome
- Hemimegalencephaly Klippel-Trenaunay syndrome (KTS)
- Macrocephaly–capillary malformation (M-CM)
- Maffuci Syndrome
- McCune Albright Syndrome (MAS)
- Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH)
- Ollier Disease
- Proteus syndrome
1 gene sequenced includes PIK3CA.
1 gene sequenced includes GNAS.
9 genes sequenced include FGFR3, GNA11, GNAQ, HRAS, KRAS, MAP3K3, NRAS, PIK3CA and TEK.
1 gene sequenced includes SMO.
2 genes sequenced include IDH1 and IDH2.
Rasopathy Gene Set
14 genes sequenced include BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, RIT1, SHOC2, SOS1 and SPRED1.
All tests are performed using targeted hybridization capture coupled with next-generation sequencing (NGS) in our CAP/CLIA labs for deep, comprehensive coverage of all coding exons of ordered genes.
Types of variation detected include single nucleotide variants (SNVs) small insertions and deletions (indels).
This test is routinely performed using formalin fixed paraffin embedded (FFPE) or fresh tissues and is able to detect alterations at 10% allele frequency in affected tissues. A buccal swab may be tested if affected tissue is not available however sensitivity may be limited.
Results and Interpretation
DNA sequence data are analyzed by GPS’ clinically validated bioinformatics pipeline to identify and annotate genetic variants associated with segmental overgrowth syndromes.
Variants are interpreted by a board-certified clinical genomicists in the context of the patient’s disease. Those that are most likely to account for the observed clinical phenotype based on evidence from the medical literature are highlighted.
Results are returned to the ordering physician in a concise report.
The turnaround time for NGS testing on the primary tissue is 3 weeks from the time a specimen arrives. Positive results are confirmed on blood by Sanger sequencing which may take an additional 4 weeks.
**Primary specimen type required: tissue from the affected area. Please call the laboratory for further information. In addition, 2-5 mL of peripheral blood in a lavender-top EDTA tube is requested to allow for comparative study.
Acceptable materials for submission include disease involved tissue in the form of a formalin fixed paraffin embedded (FFPE) tissue block, fresh tissue in transport or tissue culture media or buccal swab.
Tissue fixation protocols must be compatible with molecular testing; EDTA decalcification is acceptable, acid decalcification is not.
Kits for testing on peripheral blood and buccal cells are available upon request.
While many genetic disorders are caused by variation within DNA at the germline level, meaning that a genetic change occurs in all cells of the body, increasingly scientists are recognizing that variation in a somatic setting, occurring in only a proportion of the body’s cells, can be associated with disease.
Such is the case in disorders associated with somatic variation in the PI3K/AKT/mTOR pathway, a critical regulatory pathway for cellular proliferation, mobility and survival.
The phenotypic consequences of such somatic variation include fibroadipose overgrowth, vascular malformations, epidermal nevi, skeletal abnormalities, and megalencephaly, among other clinical findings. Somatic variation within the PI3K/AKT/mTOR pathway has been described in individuals diagnosed with M-CM, CLOVES, HMEG and Proteus syndrome, among others.
McCune-Albright is rare disorder characterized by a triad of clinical features including fibrous dysplasia, café au lait spots, and precocious puberty. Somatic variation within the GNAS gene, which encodes the stimulatory alpha subunit for a guanine nucleotide binding protein (G protein), results in the observed clinical features associated with McCune-Albright due to constitutive activation of adenylate cyclase.
Due to the somatic nature of these disorders testing is strongly recommended from affected tissue.
Next-generation sequencing provides clinicians with a powerful tool to manage patients with these diagnostically challenging disorders.