Heather Zierhut

A Dominant Mutation in Human RAD51 Reveals Its Function in DNA Interstrand Crosslink Repair Independent of Homologous Recombination.

Repair of DNA interstrand crosslinks requires action of multiple DNA repair pathways, including homologous recombination. Here, we report a de novo heterozygous T131P mutation in RAD51/FANCR, the key recombinase essential for homologous recombination, in a patient with Fanconi anemia-like phenotype. In vitro, RAD51-T131P displays DNA-independent ATPase activity, no DNA pairing capacity, and a co-dominant-negative effect on RAD51 recombinase function. However, the patient cells are homologous recombination proficient due to the low ratio of mutant to wild-type RAD51 in cells. Instead, patient cells are sensitive to crosslinking agents and display hyperphosphorylation of Replication Protein A due to increased activity of DNA2 and WRN at the DNA interstrand crosslinks. Thus, proper RAD51 function is important during DNA interstrand crosslink repair outside of homologous recombination. Our study provides a molecular basis for how RAD51 and its associated factors may operate in a homologous recombination-independent manner to maintain genomic integrity.

Alternative donor hematopoietic cell transplantation for Fanconi anemia

Historically, alternative donor hematopoietic cell transplantation (HCT) for Fanconi anemia (FA) patients resulted in excessive morbidity and mortality. To improve outcomes, we made sequential changes to the HCT conditioning regimen. A total of 130 FA patients (median age, 9.0 years; range, 1-48) underwent alternative donor HCT at the University of Minnesota between 1995 and 2012. All patients received cyclophosphamide (CY), single fraction total body irradiation (TBI), and antithymocyte globulin (ATG) with or without fludarabine (FLU), followed by T-cell-depleted bone marrow or unmanipulated umbilical cord blood transplantation. The addition of FLU enhanced engraftment 3-fold. The incidence of grades 2-4 acute and chronic graft-versus-host disease was 20% and 10%, respectively. Severe toxicity was highest in patients >10 years of age or those with a history of opportunistic infections or transfusions before HCT. Mortality was lowest in patients without a history of opportunistic infection or transfusions and who received conditioning with TBI 300 cGy, CY, FLU, and ATG. These patients had a probability of survival of 94% at 5 years. Alternative donor HCT is now associated with excellent survival for patients without prior opportunistic infections or transfusions and should be considered for all FA patients after the onset of marrow failure. These studies were registered at http://www.clinicaltrials.gov as NCT00005898, NCT00167206, and NCT00352976.

Haematopoietic cell transplantation for acute leukaemia and advanced myelodysplastic syndrome in Fanconi anaemia

Acute leukaemia or advanced myelodysplastic syndrome (MDS ≥ 5% blasts) in Fanconi anaemia (FA) patients is associated with a poor prognosis. We report 21 FA patients with acute leukaemia or advanced MDS who underwent haematopoietic cell transplantation (HCT) at the University of Minnesota between 1988 and 2011. Six patients had biallelic BRCA2 mutations. Eight patients received pre‐transplant cytoreduction, with 3 achieving complete remission. HCT donor source included human leucocyte antigen‐matched sibling (n = 2) or alternative donors (n = 19). Neutrophil engraftment was 95% for the entire cohort, and the incidence of acute graft‐versus‐host disease was 19%. 5‐year overall survival (OS) was 33%, with a relapse rate of 24%, with similar OS in patients with biallelic BRCA2 mutations. Our study supports the use of HCT in the treatment of FA patients with acute leukaemia or advanced MDS, however, the role of chemotherapy prior to HCT remains unclear for this population. FA patients with biallelic BRCA2 are unique and may benefit from higher dose chemotherapy relative to other complementation groups.

Defining Our Clinical Practice: The Identification of Genetic Counseling Outcomes Utilizing the Reciprocal Engagement Model

The need for evidence-based medicine, including comparative effectiveness studies and patient-centered outcomes research, has become a major healthcare focus. To date, a comprehensive list of genetic counseling outcomes, as espoused by genetic counselors, has not been established and thus, identification of outcomes unique to genetic counseling services has become a priority for the National Society of Genetic Counselors (NSGC). The purpose of this study was to take a critical first step at identifying a more comprehensive list of genetic counseling outcomes. This paper describes the results of a focus group study using the Reciprocal-Engagement Model (REM) as a framework to characterize patient-centered outcomes of genetic counseling clinical practice. Five focus groups were conducted with 27 peer nominated participants who were clinical genetic counselors, genetic counseling program directors, and/or outcomes researchers in genetic counseling. Members of each focus group were asked to identify genetic counseling outcomes for four to five of the 17 goals of the REM. A theory-driven, thematic analysis of focus group data yielded 194 genetic counseling outcomes across the 17 goals. Participants noted some concerns about how genetic counseling outcomes will be measured and evaluated given varying stakeholders and the long-term nature of genetic concerns. The present results provide a list of outcomes for use in future genetic counseling outcomes research and for empirically-supported clinical interventions.

A Rapid Systematic Review of Outcomes Studies in Genetic Counseling

As healthcare reimbursement is increasingly tied to value-of-service, it is critical for the genetic counselor (GC) profession to demonstrate the value added by GCs through outcomes research. We conducted a rapid systematic literature review to identify outcomes of genetic counseling. Web of Science (including PubMed) and CINAHL databases were systematically searched to identify articles meeting the following criteria: 1) measures were assessed before and after genetic counseling (pre-post design) or comparisons were made between a GC group vs. a non-GC group (comparative cohort design); 2) genetic counseling outcomes could be assessed independently of genetic testing outcomes, and 3) genetic counseling was conducted by masters-level genetic counselors, or non-physician providers. Twenty-three papers met the inclusion criteria. The majority of studies were in the cancer genetic setting and the most commonly measured outcomes included knowledge, anxiety or distress, satisfaction, perceived risk, genetic testing (intentions or receipt), health behaviors, and decisional conflict. Results suggest that genetic counseling can lead to increased knowledge, perceived personal control, positive health behaviors, and improved risk perception accuracy as well as decreases in anxiety, cancer-related worry, and decisional conflict. However, further studies are needed to evaluate a wider array of outcomes in more diverse genetic counseling settings.

Waiting for the next Shoe to Drop: The Experience of Parents of Children with Fanconi Anemia

Fanconi Anemia (FA) is a rare genetic disease that generally affects children and results in bone marrow failure requiring blood or marrow transplantation for survival. A unique feature of the condition is the long, often many years, waiting period between genetic diagnosis and treatment. This qualitative study looked at the lived experience of parents confronting their child’s diagnosis of FA. We aimed to describe factors which parents found helpful or detrimental during the waiting time period and to recommend strategies to support families who will have these experiences in the future. Categories that emerged were: parents’ emotional responses, thoughts about FA (which occurred daily for most parents), sources of stress, mechanisms of coping, family dynamics and responses that were supportive and non-supportive. We found that most parents experience stress, uncertainty, and active surveillance throughout the course of the illness. Healthcare professionals, and especially physicians, were agents of both the most and least supportive experiences of parents. Parents described family centered team care as helpful throughout the illness and health professional education as a priority need.

How Inclusion of Genetic Counselors on the Research Team Can Benefit Translational Science

Genetic counselors could help recruit study participants and bring a more clinical focus to translational studies. Translational research in medicine is necessarily a team-based endeavor, and, indeed, translational research teams often include researchers from many different disciplines. We outline some of the practical challenges that are particularly salient to translational research, both for scientists and study participants, and propose that genetic counselors—a group of specialty-trained health care professionals who are as yet only infrequently recruited to collaborate in translational research teams—could contribute a unique perspective and skill set that would be invaluable in the effective navigation of these challenges. We propose that collaboration with genetic counselors could not only benefit individual translational research teams but also potentially help shift the research agenda for translational medicine.

Association of rib anomalies and childhood cancers

Background:Congenital anomalies have been found more often in children with cancer than in those without. Rib abnormalities (RAs) have been associated with childhood cancer; however, studies have differed in the type of RAs and cancers implicated.Methods:Rib abnormalities were assessed predominantly by X-ray in a hospital-based case–control study.Results:There was a significant difference in the number of cases vs controls with RAs after controlling for age and sex, specifically for acute myelogenous leukaemia, renal tumours, and hepatoblastoma.Conclusion:The results of this study support previous reports that there is an association of rib anomalies with childhood cancer.

Family history of cancer and non-malignant diseases and risk of childhood acute lymphoblastic leukemia: A Children's Oncology Group Study

BACKGROUND Studies of family history of cancer and non-malignant diseases in childhood acute lymphoblastic leukemia (ALL) show inconsistent findings. Most studies show no increased risk with family history of cancer. Non-malignant diseases such as allergic diseases, autoimmune diseases, birth defects and thyroid diseases have been reported to be associated with ALL. METHODS We conducted a case-control study of family history of cancer and selected non-malignant conditions (allergic diseases, autoimmune diseases, birth defects, and thyroid diseases). ALL cases were obtained from Childrens Cancer Group institutions from January 1989 to June 1993. Controls were recruited via random digit dialing. Family history for first degree relatives and grandparents of ALL cases and controls was collected by structured telephone questionnaires. Conditional logistical regression was used to calculate odds ratios adjusting for potential confounders. RESULTS We found a borderline association of ALL and having a family member with a history of cancer in cases (n=1842) compared to controls (n=1986) (OR=0.98, 95%CI=0.93, 1.00) and an inverse association for esophageal cancer based on small numbers. Family history of food and drug allergies demonstrated a modestly reduced risk (OR=0.83, 95%CI=0.73, 0.95) as did family history of rheumatoid arthritis (OR=0.79, 95%CI=0.65, 0.96). There were no associations with family history of any autoimmune diseases, immunodeficiencies, birth defects, thyroid diseases and risk of childhood ALL. CONCLUSIONS These results show no association of overall family history of cancer with childhood ALL, while providing additional evidence for an inverse association with family history of allergic disease. Two potentially new associations of ALL with family history of esophageal cancer and rheumatoid arthritis require confirmation in other studies and validation with medical records.

Next generation sequencing in endocrine practice

With the completion of the Human Genome Project and advances in genomic sequencing technologies, the use of clinical molecular diagnostics has grown tremendously over the last decade. Next-generation sequencing (NGS) has overcome many of the practical roadblocks that had slowed the adoption of molecular testing for routine clinical diagnosis. In endocrinology, targeted NGS now complements biochemical testing and imaging studies. The goal of this review is to provide clinicians with a guide to the application of NGS to genetic testing for endocrine conditions, by compiling a list of established gene mutations detectable by NGS, and highlighting key phenotypic features of these disorders. As we outline in this review, the clinical utility of NGS-based molecular testing for endocrine disorders is very high. Identifying an exact genetic etiology improves understanding of the disease, provides clear explanation to families about the cause, and guides decisions about screening, prevention and/or treatment. To illustrate this approach, a case of hypophosphatasia with a pathogenic mutation in the ALPL gene detected by NGS is presented.