PRODUCT UPDATE: New genes added to GPS’ SOMA testing
To better serve our customers and their patients, we have made updates to our SOMA genomic testing, which provides next-generation sequencing of key genes implicated in segmental overgrowth, McCune Albright and related syndromes.
All new orders of SOMA testing will require completion of the updated requisition.
We now offer a new tests for Curry-Jones syndrome and Maffucci syndrome. In addition, we have added genes to the Somatic Overgrowth and the Epidermal Nevus Syndrome Gene Sets.
SMO, the gene shown to be associated with the recently defined Curry-Jones syndrome, demonstrates phenotypic overlap particularly in relation to cerebral phenotypes observed in somatic disorders associated with the PI3K-AKT-MTOR pathway. Inclusion of SMO will expand the clinical reach of the assay and aid in defining the molecular etiology of patient disease (PMID: 27236920).
In addition, genetic testing for Maffucci syndrome and Ollier disease for the detection of somatic alterations associated with cartilaginous tumors and soft tissue hemangiomas is now available. Somatic variation within IDH1 and IDH2 has been described in these disease settings (PMID: 22057236).
Finally, new genes have been added to our Epidermal Nevus syndrome gene set including FGFR3, associated with Garcia-Hafner-Happle syndrome (PMID:24891911) and PIK3CA associated with epidermal nevi and seborrheic keratoses (PMID:17673550).
Ask us about our ability to support somatic analysis of other genes associated with mosaic disease.
PUBLICATION: Utility of Clinical High-Depth Next Generation Sequencing for Somatic Variant Detection in the PIK3CA Related Overgrowth Spectrum
GPS faculty recently published a paper in Clinical Genetics that describes how NGS is being used in PIK3CA related overgrowth syndromes.
Utility of Clinical High-Depth Next Generation Sequencing for Somatic Variant Detection in the PIK3CA Related Overgrowth Spectrum. Hucthagowder V, Shenoy A, Corliss M, Vigh-Conrad KA, Storer C, Grange DK, Cottrell CE. Clin Genet. 2016 Jun 16. PubMedID 27307077
Next-generation sequencing (NGS) has revolutionized the approach of studying sequence variation, and has been well described in the clinical laboratory setting for the detection of constitutional alterations, as well as somatic tumor associated variants. It is increasingly recognized that post-zygotic somatic alteration can be associated with congenital phenotypic abnormalities. Variation within the PI3K/AKT/mTOR pathway, including PIK3CA, has been described in somatic overgrowth syndromes and vascular malformations. Detection of PIK3CA somatic alteration is challenging due to low variant allele frequency (VAF) along with the need to assay involved tissue, thus necessitating a highly-sensitive methodology. Here we describe the utility of target hybrid capture coupled with NGS for the identification of somatic variation in the PIK3CA-Related Overgrowth Spectrum (PROS) among 14 patients submitted for clinical testing. Assay detection of low allelic fraction variation is coverage dependent with >90% sensitivity at 400x unique read depth for VAF of 10%, and approaching 100% at 1000x. Average read depth among the patient dataset across PIK3CA coding regions was 788.4. The diagnostic yield among this cohort was 71%, including the detection of two PIK3CA alterations novel in the setting of PROS. This report expands the mutational scope and phenotypic attributes of PROS disorders.
EVENT: David W. Smith Workshop on Malformations & Morphogenesis – Sept. 9-14 in Lake Arrowhead, CA
WashU physician, and GPS collaborator, Dr. Kathy Grange has been selected for a platform presentation at this prestigious clinical genetics meeting. One of the themes for this year’s meeting is germline and somatic mosaicism, and she will be highlighting data from our SOMA sequencing tests.
For more information about the David W. Smith Workshop, please visit their website.
Abstract
Detection of Somatic Variants in Segmental Overgrowth Syndromes Utilizing Next Generation Sequencing
Dorothy K. Grange MD1, Meagan M. Corliss CGC2, Jonathan W. Heusel MD PhD2,Vishwanathan Hucthagowder PhD2 and Catherine E. Cottrell PhD2,
1Division of Genetics and Genomic Medicine, Department of Pediatrics and 2Division of Laboratory and Genomic Medicine, Department of Pathology and Immunology, Washington University School of Medicine
Next-generation sequencing (NGS) is widely used in the clinical setting for genetic variant analysis in human disease. It is increasingly recognized that somatic genetic variation is associated with congenital malformation syndromes. NGS technology has utility in the detection of somatic alterations present at low variant allele frequency (VAF) due to its ability to achieve high sequencing read depths. Somatic variation has been described in Proteus and PIK3CA-related overgrowth syndromes. Because of the somatic nature of these disorders, the causative alteration is detected only in limited tissues, and is typically not identifiable in blood. Genomics and Pathology Services at Washington University (GPS@WUSTL) performs clinical testing for somatic overgrowth and related disorders, by single gene analysis or by a panel (SOMA gene set) of 11 genes (AKT1, AKT2, AKT3, GNAQ, MTOR, PIK3CA, PIK3R2, PTEN, RASA1, TSC1 and TSC2).
Case Examples: Patient 1 is a 2-year-old boy with a vascular malformation on his right face and scalp present at birth. The right face and body are larger than the left. He has 3-4 syndactyly of the right hand and bilateral 2-3 toe syndactyly. Brain MRI showed an asymmetrically enlarged right cerebral hemisphere and right lateral ventricle consistent with hemi-megalencephaly. Development has been normal. Two tissue sources, swabbed buccal mucosal cells and blood, were subjected to NGS. A PIK3CA alteration, p.P104L, was identified with a variant allele frequency (VAF) of approximately 37% in the specimen derived from buccal cells. Manual review of the sequencing data from the blood sample revealed a VAF of <1%. This mutation has been previously reported in breast cancer, but not in association with somatic overgrowth syndromes. Notably, this mutation has subsequently been identified in a second patient with suspected MCAP and polymicrogyria. Patient 2 is a 6-year-old girl with overgrowth involving her lower torso, specifically the buttocks, lower extremities and feet. She also has lipomatous masses on her back. She had syndactyly and macrodactyly of the toes. She is normal developmentally. Three tissue types were analyzed by NGS including blood, buccal scraping and fresh tissue, the latter representing lipomatous soft tissue from a toe. A PIK3CA p.C420R alteration was identified only in the affected tissue from the foot with a VAF of 29%. Blood and buccal samples yielded no evidence of the variant allele. The p.C420R variant has been observed in many tumors and in CLOVES. Patient 3 is a 16-year-old female with megalencephaly, hydrocephalus, strabismus, generalized overgrowth, body asymmetry, vascular skin lesions, 2-3-4 toe syndactyly and intellectual disabilities. She had a posterior tongue mass excised that was a lymphatic malformation. A PIK3CA p.M1043I variant at a near heterozygous allelic frequency of 46.8% was identified in formalin fixed tissue derived from the tongue mass. Analysis of blood revealed the variant at an estimated frequency of <20%. This variant has been reported in MCAP and in various cancers. Patient 4 is a 6-year-old boy with hemi-megalencephaly with intractable seizures who underwent right hemispherectomy, massive overgrowth of the lower extremities, extensive cutaneous vascular malformations, subcutaneous soft tissue masses and developmental disabilities. NGS on fresh tissue from the legs showed a pathogenic PIK3CA p.E545K variant in a very low percentage of total reads. However, DNA extracted from formalin fixed brain cortical and white matter tissue confirmed the variant in a higher percentage of reads. Patient 5
NGS testing was performed on 39 total cases through the GPS laboratory, 28 with the broader SOMA gene set (7-11 genes including PIK3CA) and 11 cases on PIK3CA only. Of these, 25/39 (64.1%) had a pathogenic or likely pathogenic variant identified, ascertained in 18/28 SOMA cases and 7/11 PIK3CA only cases. The vast majority of disease-causing mutations (23/25; 92%) were identified in PIK3CA. SOMA testing demonstrates clear clinical utility in the setting of overgrowth syndromes and exhibits a high diagnostic yield when performed on appropriate specimen types using a deep sequencing approach.
PUBLICATION: Concurrent MPL W515L and Y591D mutations in a patient with myelofibrosis
This case report in Blood Cells, Molecules and Diseases describes a patient with myelofibrosis who was sequenced with our hematopoietic disorders gene set. Analysis revealed very rare, concurrent pathogenic mutations in MPL.
Concurrent MPLW515L and Y591D mutations in a patient with myelofibrosis. Rashidi A, Heusel JW, Oh ST. Blood Cells Mol Dis. 60 (2016) 1-2. Read the article.
EVENT: Interpretation of Rare and Inherited Disease – June 22
The Intellectual and Developmental Disabilities Research Center, is pleased to organize this symposium featuring the landscape of genetics research at Washington University.
This half-day event includes presentations from a number of WU faculty experts in the field – including GPS Medical Director, Catherine Cottrell – and includes discussion around the challenges and opportunities in variant interpretation across multiple disciplines within the university.
There is no charge for this event, which includes a reception of refreshments and hors d’oeuvres. Please register for this event at http://iddrc.wustl.edu/genes to enable an accurate count for accommodations.
Details
Interpretation of Genetic Variants in Rare and Inherited Disease
A Cross-Disciplinary Symposium on the State of Science, Technology, and Capacity at Washington University in St. Louis
Date/Venue
Wednesday, June 22nd, 1:00 – 6:30 PM in Connor Auditorium (FLTC)
Featured Speakers
Marwan Shinawi: The Role of Clinician Input in Variant Interpretation
F. Sessions Cole: The Value of the Pediatrics Genomics Board and Inter-institutional Data Sharing
Don Conrad: Novel Bioinformatics Approaches to Variant Interpretation
Cathy Cottrell: The GPS Experience in Interpreting “n of 1” Variants in Clinical Disease Sequencing
Christina Gurnett: Scientific Tradeoffs between Clinical and Research Genomic Sequencing
Ira Hall: Putting Variants in Context: Large-scale Genome Sequencing Projects at WUSTL
Shondra Miller: Functional Genomic Validation of Disease-Associated Mutants
Josh Rubin: Disease-Specific Limitations and Cross-Disciplinary Opportunity in Variant Interpretation
Dustin Baldridge: Improving Inventories of Variants, Patients, and Biomaterials at WUSTL
Schedule
1:00 Session 1
2:40 Break/Refreshments
2:50 Interactive Panel Discussion
3:10 Session 2
5:15 Reception (refreshments and hors d’oeuvres) in FLTC 2nd Floor Hearth
EVENT: Women’s Health Event at the Muny – May, 25 2016
GPS Medical Director, Dr. Catherine Cottrell, is one of three panelists at this fantastic community event sponsored by the Siteman Cancer Center at Barnes Jewish Hospital and Washington University School of Medicine. Panelists discuss the most up-to-date recommendations for breast and cervical cancer screenings, prevention and treatment.
PRODUCT UPDATE: Congenital Neutropenia Testing Now Available
GPS is pleased to announce a new test for congenital neurtopenia that sequences 24 genes associated with this disease. For more information or to order a test, please click here.
EVENT: GPS at ACMG 2016 – March 8-12 in Tampa, FL
Several people from GPS are attending and presenting at this year’s ACMG conference.
Our genetic counselor, Meagan Corliss is giving a platform presentation (22) on March 11 at 5PM entitled The Utility of NGS in the Identification of Somatic Variants in Overgrowth Related Syndromes. View her abstract.
Clinical fellow, Vishwanathan Hucthagowder, has a poster presentation (311) entitled Targeted Next-Generation Sequencing Identifies HRAS mutation in Schimmelpenning-Feuerstein-Mims Syndrome. View his abstract.
Find out more about testing for somatic overgrowth and related syndromes offered by GPS.
PRODUCT UPDATE: New reports for constitutional disease testing
GPS is pleased to announce that all constitutional disease testing will now feature an improved clinical report. These include all cardiac disease and renal disease tests including aHUS.
The new report has been redesigned to include easy-to-understand result summaries. Pathogenic and likely pathogenic variants are clearly highlighted on the first page of the report and are accompanied by concise clinical interpretations.
Please take a moment to familiarize yourself with the new clinical report template. If you have any questions, please do not hesitate to contact us.
EVENT: Cancer Then & Now – November 10, 2015
GPS’ Jon Heusel is one of the presenters at this fantastic event about the future of cancer care.
When: Tuesday, November 10, 6-8pm
Where: Drury Inn & Suites Arnold, 3800 State Route 141, Arnold, MO 63010
RSVP: Register for this free event by calling 314-747-7222 or 800-600-3606.
This event is sponsored by the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.
