Natural history studies We operate several clinical research protocols to assess the range of severity, spectrum of malformations, and natural history of pleiotropic developmental anomalies. We use clinical evaluations that include history and physical examination, imaging studies including radiography, ultrasound, and tomography, as well as EEG, pulmonary function testing, etc. to characterize functional and structural anomalies. In selected cases we also perform surgical treatments if they offer clinical benefit and can advance our understanding of the disease under study. Some of the disorders that we are currently studying include non-syndromic polydactyly, Proteus syndrome, fibroadipose overgrowth syndrome, a progeriod syndrome, and Lenz microphthalmia syndrome. A recent focus has been to understand the relationship of Proteus syndrome to deep vein thrombosis and pulmonary embolism. To address this we are performing a systematic evaluation of both vascular and plasma mediators of coagulation in these patients. Genotype-Phenotype studies A key objective of genetic research is to understand not only what genes are associated with what phenotypes, but to understand in detail how specific variants are correlated with specific manifestations and the severity and complications of these disorders. These studies take a great deal of time and effort to attract sufficient patients. We are currently focusing on fibroadipose overgrowth disorders and are developing a cohort of >100 patients with detailed clinical analysis coupled to mutation detection from biopsied specimens. The challenge here is greater than it is for germline (inherited) disorders because in addition to gene, variant, and genetic background, one must take into account the mosaicism level in the patient, which is clearly an important variable. We have published interim results on the first 32 such patients, the largest in the world. Therapeutic Studies The identification of the molecular etiology for Proteus syndrome and fibroadipose overgrowth and CLOVES syndrome provide an exciting new opportunity to develop therapeutic approaches to these devastating disorders. We have undertaken efforts to develop data for valid therapeutic endpoints for therapy of overgrowth disorders. We are working on two primary approaches - the first is an MRI volumetric approach in collaboration with NIH Clinical Center imaging. The second approach is a quantitative surface measurement technique. We have established a productive collaborative agreement with a pharmaceutical companies to repurpose an oncology drug for these trials. We have performed significant in vitro work (see companion Z01 on molecular studies) and have designed a phase 0 dose finding trial for this drug which has received preliminary IRB approval and we have been assigned an IND by the FDA. We have also cofounded an international consortium to test therapeutic agents in PIK3CA related overgrowth disorders with the University of Cambridge and Lyon University. This trial was launched in the summer of 2015 Behavioral studies We have also undertaken studies to explore the behavioral aspects of these disorders. Adaptation to these conditions is a key component of quality of life for patients. To that end, we have completed interview studies to evaluate self-perception and adaptation in patients with Bardet-Biedl syndrome. This manuscript is now ready for submission. We have also developed a qualitative interview study for patients with these disorders who receive genomic testing results to gauge their interest and reactions to this testing, a key attribute that clinicians will need to consider when undertaking such analyses, whether clinical or research sequencing. Transcripts from these interviews have been coded and analyzed and will be analyzed this fall. In addition, Dr. Biesecker is a co-founder and co-director of the Elements of Morphology dysmorphology standards working group. This group is working to standardize malformation descriptions to increase the utility of clinical descriptions and journal reports. Our next project will be an expanded set of limb morphology terms to follow on our prior set of limb terms.

Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Human Genome Research
Department
Type
DUNS #
City
State
Country
Zip Code
Tavtigian, Sean V; Greenblatt, Marc S; Harrison, Steven M et al. (2018) Modeling the ACMG/AMP variant classification guidelines as a Bayesian classification framework. Genet Med 20:1054-1060
Biesecker, Leslie G (2018) Myths and Misdiagnoses of Proteus Syndrome. Asian J Anesthesiol 56:41-41
Biesecker, Barbara Bowles; Biesecker, Leslie Glenn (2018) 50 Years Ago in The Journal of Pediatrics: The Rationale for Genetic Counseling. J Pediatr 193:33
Biesecker, Leslie G (2018) Mosaic disorders and the Taxonomy of Human Disease. Genet Med 20:800-801
Al-Olabi, Lara; Polubothu, Satyamaanasa; Dowsett, Katherine et al. (2018) Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. J Clin Invest 128:1496-1508
Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A et al. (2018) Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants. Genet Med 20:1175-1185
Nathan, Neera R; Patel, Rachna; Crenshaw, Molly M et al. (2018) Pathogenetic insights from quantification of the cerebriform connective tissue nevus in Proteus syndrome. J Am Acad Dermatol 78:725-732
Crenshaw, Molly M; Goerlich, Cara G; Ivey, Lauren E et al. (2018) Orthopaedic Management of Leg-length Discrepancy in Proteus Syndrome: A Case Series. J Pediatr Orthop 38:e138-e144
Bush, Lynn W; Beck, Anita E; Biesecker, Leslie G et al. (2018) Professional responsibilities regarding the provision, publication, and dissemination of patient phenotypes in the context of clinical genetic and genomic testing: points to consider-a statement of the American College of Medical Genetics and Genomics (AC Genet Med 20:169-171
Sapp, Julie C; Hu, Lian; Zhao, Jean et al. (2017) Quantifying survival in patients with Proteus syndrome. Genet Med 19:1376-1379

Showing the most recent 10 out of 40 publications