Research of Krista J. Qualmann, MS, CGC
Krista J. Qualmann, MS, CGC, works in collaboration with the laboratory of Dong H. Kim, M.D., to improve the understanding of the genetic basis for neurological disease, with a specific focus on intracranial aneurysms and primary brain tumors.
One goal of our team is to determine the genetic basis of intracranial aneurysms, abnormal dilations or ‘bulges’ of intracranial blood vessels. Intracranial aneurysm rupture is the most common cause of spontaneous subarachnoid hemorrhage, which often leads to severe disability or death. Ten to twenty percent of intracranial aneurysm patients have a positive family history for aneurysms or aneurysmal rupture and there is up to a five-fold increased risk of aneurysm incidence among first-degree relatives compared to the general population. The identification of genetic determinants may provide not only a deeper understanding of aneurysm pathobiology, but also facilitate the development of diagnostic tools for identifying individuals at increased risk for aneurysm formation or rupture.
In pursuit of this goal, we have had several noteworthy successes. We recently discovered how a specific mutation in the THSD1 gene contributes to the pathophysiology of intracranial aneurysms. By examining a well-characterized and clearly defined cohort of patients and families affected by this type of aneurysm, we have identified the first genetic cause in a single large family, then extended this finding to other unrelated patients and families. To do so, we enrolled more than 100 affected families and clinically characterized more than 500 IA (intracranial aneurysm) probands. By performing whole exome sequencing on a large family, we were able to reveal a segregating nonsense THSD1 mutation. Additional THSD1 mutations were then noted in 8 unrelated probands, both familial and sporadic. Following the identification of THSD1 mutations in our intracranial aneurysm cohort, the Dong H. Kim Laboratory performed additional in vitro and in vivo studies and continue to characterize the overall function of THSD1, a protein that has been poorly characterized to date.
We continue to enroll new intracranial aneurysm patients and their families for the identification of additional genes implicated in intracranial aneurysm pathogenesis. Future studies include both targeted sequencing of notable THSD1 interactors and whole exome sequencing to identify novel genes in our patient cohort.
Primary Brain Tumors
Another goal of Ms. Qualmann’s research efforts is to better characterize the natural history of primary brain tumors in individuals with hereditary cancer/tumor predisposition syndromes. In contrast to secondary brain tumors, which result from the metastasis of tumors that originate elsewhere in the body, primary brain tumors begin de novo in the brain. Primary brain tumors are well-known features of several known syndromes and have been increasingly associated with additional inherited germline mutations as phenotypic spectrums expand and new genes are discovered. Many of the well-characterized syndromes are also associated with additional cancer pathologies, prompting genetic screening in individuals with characteristic personal and/or family histories. The identification of a syndromic diagnosis leads to additional screening recommendations and enables preventative measures for patients and other family members.
Gliomas are associated with hereditary cancer/tumor predisposition syndromes in select patients. However, clinical guidelines to determine if certain patient factors (i.e., age of onset, the presence of specific molecular features, etc.) should prompt a genetic evaluation in the absence of family history are sparse. Further characterization of syndromic patients who present with gliomas or other primary brain tumors are necessary to better identify these individuals from their sporadic counterparts.
Approximately 5-10% of patients with glioma also have a family history of the disease with no other syndromic features, a group subsequently classified as familial glioma. Similarly, familial meningiomatosis is a clinical diagnosis given to individuals with a personal history of multiple meningiomas and/or families with multiple relatives affected by meningioma with otherwise no other disease-inducing environmental exposure. Candidate genes have been proposed for both conditions that may account for a proportion of reported cases, but additional disease-associated genes are yet to be identified. In an effort bridge this gap in knowledge, we are currently collecting cohorts of patients who meet the criteria for a clinical diagnosis of familial glioma or familial meningiomatosis, as well as others who have a personal history of multiple brain tumors, multifocal disease, or a positive family history of other brain tumor types for whole exome sequence analysis.
Research Participant Recruitment
We work in collaboration with the Neurosciences Research Repository (NRR) to prospectively enroll patients and their family members. Patient consent to participation allows the NRR to gather clinically recorded admission data and longitudinal data for up to an additional 15 years after discharge. Our fundamental approach is to treat each patient as a research subject, and incorporate the collection of data as part of routine patient care. In addition, discarded samples such as blood, cerebrospinal fluid and tissue (e.g. tumors) can be collected and stored. Thus, this large biobank effectively couples bio-samples with clinical data.
1. Santiago-Sim T, Fang X, Hennessy M, Nalbach S, DePalma S, Lee MS, Greenway S, McDonough B, Hergenroeder G, Patek K, Colosimo S, Qualmann KJ, Hagan JP, Milewicz D, MacRae C, Dymecki S, Seidman C, Seidman JG. Kim DH. Mutations in THSD1 as a Cause of Intracranial Aneurysm. (forthcoming). 2016.
2. Qualmann KJ, Spaeth CG, Myers MF, Horn PS, Holland K, Mangano FT, Greiner HM. Pediatric epilepsy surgery: The prognostic value of central nervous system comorbidities in patients and their families. (forthcoming). 2016.
3. Nguyen JM, Qualmann KJ, Okashah R, Reilly A, Alexeyev M, Campbell D. 5p Deletions: Current Knowledge and Future Directions. Am J Med Genet C Semin Med Genet. 2015;169(3):224-238.
4. Lutgen V, Resch J, Qualmann K, Raddatz NJ, Panhans C, Olander EM, Kong L, Choi S, Mantsch JR, Baker DA. Behavioral assessment of acute inhibition of system xc- in rats. Psychopharmacology. 2014;1-11.
5. Lutgen V, Qualmann K, Resch J, Kong L, Choi S, Baker DA. Reduction in phencyclidine induced sensorimotor gating deficits in the rat following increased system xc- activity in the medial prefrontal cortex. Psychopharmacology. 2013;226(3):531-540.
1. Qualmann, KJ, Morales M, Liu A, Hergenroeder GW, Kim DH. Familial intracranial aneurysm: The prevalence and screening recommendations of one institution. Poster, NSGC Annual Education Conference, September 2016.
2. Qualmann KJ, Kim DH, Bhattacharjee M, Papasozomenos S, Zhu J. Suggestion of TP53 germline genetic testing based on results from next generation sequencing of tumor specimen: A case report. Electronic poster, Society for Neuro-Oncology Annual Scientific Meeting, November 2015.
3. Qualmann KJ, Tandon N, Kim DH, Shepard SR, Bhattacharjee M, Papasozomenos S, Blanco AI, Zhu J. Characterization of primary gliomas in individuals with Li-Fraumeni syndrome: A case series. Poster, Society for Neuro-Oncology Annual Scientific Meeting, November 2015.
4. Qualmann KJ, Greiner HM, Myers MF, Horn PS, Spaeth CG. Family history of epilepsy and central nervous system comorbidities as a prognostic indicator for resective surgery outcomes among pediatric epilepsy patients. Platform presentation, NSGC Annual Education Conference, October 2014.