Exploring genetic counselors' experiences with non-paternity in clinical settings.

Non-paternity (NP) is a challenging dilemma faced by genetics providers and there is little consensus on whether this finding should be disclosed. Discussions in the literature are highly theoretical, with limited research regarding how disclosure decisions are enacted in practice. We explored genetic counselors' (GCs) clinical experiences with NP to understand if, how, and why this finding is communicated. Our semi-structured interviews with genetic counselors in the United States and Canada were analyzed using reflexive thematic analysis to analyze data inductively, describe themes, and present a meaningful interpretation of the data. Eighteen participants who responded to list-serv messages were interviewed. Our framework describes five salient themes: (1) GC-lab relationship: the GCs awareness of laboratory processes such as quality control metrics that can uncover NP findings and the way in which a finding of NP was disclosed by the laboratory had an impact on disclosure decisions. This triggered a decision-making trajectory that involved (2) consultation, (3) ethical reasoning, and (4) practical constraints. GCs frequently consulted other professionals during decision-making. These conversations impacted disclosure decisions with some consultations carrying greater weight than others. GCs weighed moral concepts of patient autonomy, medical relevance, and preventing harm to rationalize decisions. Access to patients and documentation requirements often dictated how disclosure occurred. Finally, once a decision had been made and enacted, GCs used the experience to reconsider their approach to (5) consenting in future cases, with some GCs altering their pre-test counseling to always include a discussion of NP. Although NP scenarios are frequently unique in context, our findings demonstrate several common decision-making factors GCs harness to navigate the identification of NP through clinical genetic testing.

FANCA c.3624C>T (p.Ser1208=) is a hypomorphic splice variant associated with delayed onset of Fanconi anemia.

ABSTRACT: Fanconi anemia (FA) is a hereditary, DNA repair deficiency disorder caused by pathogenic variants in any 1 of 22 known genes (FANCA-FANCW). Variants in FANCA account for nearly two-thirds of all patients with FA. Clinical presentation of FA can be heterogeneous and include congenital abnormalities, progressive bone marrow failure, and predisposition to cancer. Here, we describe a relatively mild disease manifestation among 6 individuals diagnosed with FA, each compound heterozygous for 1 established pathogenic FANCA variant and 1 FANCA exon 36 variant, c.3624C>T. These individuals had delayed onset of hematological abnormalities, increased survival, reduced incidence of cancer, and improved fertility. Although predicted to encode a synonymous change (p.Ser1208=), the c.3624C>T variant causes a splicing error resulting in a FANCA transcript missing the last 4 base pairs of exon 36. Deep sequencing and quantitative reverse transcription polymerase chain reaction analysis revealed that 6% to 10% of the FANCA transcripts included the canonical splice product, which generated wild-type FANCA protein. Consistently, functional analysis of cell lines from the studied individuals revealed presence of residual FANCD2 ubiquitination and FANCD2 foci formation, better cell survival, and decreased late S/G2 accumulation in response to DNA interstrand cross-linking agent, indicating presence of residual activity of the FA repair pathway. Thus, the c.3624C>T variant is a hypomorphic allele, which contributes to delayed manifestation of FA disease phenotypes in individuals with at least 1 c.3624C>T allele.

Parental request for familial carrier testing in early childhood: The genetic counseling perspective.

Professional guidelines generally caution against carrier testing in minors, though prior research indicates parents request and providers sometimes facilitate testing for unaffected siblings of a child affected by a genetic disorder. We investigated the perspectives of genetic counselors in North America regarding carrier testing prior to adolescence. Practicing genetic counselors (n = 177) responded to an electronic survey assessing their willingness to facilitate testing in four hypothetical scenarios and their evaluation of parental motivations. Participants did not find parental arguments for testing persuasive, and most were unwilling to facilitate carrier testing in children. A significant interaction effect indicated the presence of nonactionable carrier-associated health risks in adulthood made participants significantly less hesitant when the mode of inheritance was X-linked. Participants considered parental motivations that center the child's interests as significantly more persuasive. This study suggests genetic counselors are resistant to carrier testing for familial disorders in young children and tend to align with current guidelines, yet they recognize nuance in various cases. Further investigation into this topic is warranted to support genetic counselors facing these requests as the ethics of pediatric carrier testing continues to be debated.

A case series of adrenoleukodystrophy in children conceived through in vitro fertilization with an egg donor.

Objective: To report 3 cases of adrenoleukodystrophy (ALD) in children conceived by in vitro fertilization (IVF) and egg donation. Design: A case report. Patients: Patients aged 4-5 years old, evaluated by the University of Minnesota Leukodystrophy Center, who were diagnosed with ALD after being conceived by IVF with oocytes provided by the same donor. Interventions: One patient received a hematopoietic stem cell transplant from a human leukocyte antigen-matched donor, and 1 patient received autologous lentiviral corrected hematopoietic cells. The disease state in 1 patient was unfortunately too advanced for effective treatment to be administered. Main Outcome Measures: Progression of disease after diagnosis or treatment was observed by cerebral magnetic resonance imaging and monitoring the development or advancement of any cognitive, adaptive, and motor deficits. Results: Patients who received a transplant for ALD successfully experienced little to no disease progression at least 6 months to 1 year after treatment. Conclusions: These 3 cases of transmission of ALD through oocyte donation and IVF highlight the potential need to implement more comprehensive genetic screening of gamete donors to prevent the transfer of rare but severe genetic diseases through IVF. Further, these cases highlight limitations in carrier screening guidelines that limit reportable variants to pathogenic and likely pathogenic variants.

"It's Just Flourishing Hope Everywhere": The Experiences of Incarcerated Men Sharing Their Stories.

Of the 2.2 million people incarcerated throughout the United States, 93% are men. The current phenomenological study adds to the existing body of qualitative research on the lived experiences of men who are incarcerated and supports storytelling as a therapeutic technique. Four essential themes were revealed through an analysis of participant interviews: (1) substance use, (2) anticipation of storytelling, (3) the act of storytelling, and (4) reflections on storytelling. Understanding these experiences can assist in the development of storytelling-based interventions and community programing that is mutually beneficial to both the teller and the listener.

Genomic signature of Fanconi anaemia DNA repair pathway deficiency in cancer.

Fanconi anaemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink repair resulting in chromosome breakage1-3. The FA repair pathway protects against endogenous and exogenous carcinogenic aldehydes4-7. Individuals with FA are hundreds to thousands fold more likely to develop head and neck (HNSCC), oesophageal and anogenital squamous cell carcinomas8 (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or infection with human papillomavirus9 (HPV). Here, by sequencing genomes and exomes of FA SCCs, we demonstrate that the primary genomic signature of FA repair deficiency is the presence of high numbers of structural variants. Structural variants are enriched for small deletions, unbalanced translocations and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not in the context of HPV infection, and lead to somatic copy-number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte-intrinsic inflammatory signalling, which would contribute to the aggressive nature of FA SCCs. We propose that the genomic instability in sporadic HPV-negative HNSCC may arise as a result of the FA repair pathway being overwhelmed by DNA interstrand crosslink damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA-crosslinking damage.

Genetic counseling student demographics: an empirical comparison of two cohorts.

Genetic counseling student characteristics may be evolving with the expansion and diversification of the genetic counseling field. We compared characteristics and previously accrued experiences of genetic counseling students enrolled in the 2018-2019 academic year with genetic counseling students surveyed by Lega et al. (Journal of Genetic Counseling, 14, 395; 2005). Four-hundred thirty students completed a survey (60% response rate) assessing demographics, select application experiences, encouragement and discouragement to apply to genetic counseling programs, and career certainty and motivations. Data analyses comprised descriptive statistics, content analysis of open-ended responses, and t tests and chi-square tests to compare responses to variables also assessed by Lega et al. Similarities between the two cohorts included most students being female, White/Caucasian, and biology majors; they reported a similar amount and type of support and discouragement; and they had strong career certainty. Salient group differences included the current cohort having a larger proportion of males (8% versus 3%; p=.007), greater percentage of parent(s) with a high socioeconomic status (SES; 31% versus 17%; p=.005), a lower first application cycle acceptance rate (71% versus 80%; p<.001), and they were more strongly influenced to pursue genetic counseling by future income (p<.001), desire to help others (p=.002), the profession's prestige (p<.001), and programs' 2-year duration (p<.001). Students applied to an average of six programs during their first application cycle and paid, on average, $1,648 for all application and interview expenses in their acceptance year. A vast majority (99%) had advocacy experiences (most commonly crisis intervention) and shadowing opportunities (94%), and 26% worked as genetic counseling assistants prior to their acceptance. Most students were interested primarily in cancer genetics at the time of survey completion. The genetic counseling field should continue efforts to improve racial and gender diversity and identify ways to increase program accessibility/affordability for individuals at all SES levels.

An exploration of novice genetic counselors' transitional challenges: Commencement is just the beginning.

Although transitional challenges exist in many professions, no research has explicitly investigated challenges novice genetic counselors encounter as they enter the workforce. This qualitative study explored challenges genetic counselors face when transitioning from student to practicing counselor and their strategies for managing them. Fifteen novice genetic counselors (~1-2 years post-degree experience), recruited via the National Society of Genetic Counselors, participated in semi-structured phone interviews. Interview questions explored professional and personal challenges faced in their first 6 months, how challenges changed over time, strategies they used to manage these challenges, and resources they thought would have been helpful to have from the beginning. Inductive analysis of interview data yielded themes including: interpersonal challenges with colleagues (e.g. handling differences of opinion); intrapersonal challenges (e.g. lacking confidence, not feeling ready to 'go solo'); patient care challenges (e.g. being viewed as young/inexperienced); and logistical challenges (e.g. billing). Personal challenges included moving to a new location, preparing for boards, establishing a work-life balance, and factors associated with one's significant others. Strategies to address challenges included seeking support and guidance from experienced genetic counselors and peers, using peer supervision groups, and involvement in community activities. Participants recommended connecting with recent graduates through national and local programs to facilitate the transition from student to genetic counselor. Results suggest the 'transition years' pose a variety of professional and personal challenges. Support and guidance are key to evolving from student to practicing counselor. Creating venues to help novice counselors make connections with colleagues and other recent graduates may be beneficial.

The Power of Storytelling: The Experiences of Incarcerated Women Sharing Their Stories.

Women are the fastest growing prison population in the United States. Women who are incarcerated are characterized by significant mental health needs and intense societal stigma. Despite such vulnerabilities, little is known about their experiences or the pathways that lead them toward recovery and rehabilitation. This qualitative research explores the lived experiences of incarcerated women sharing their stories with high school students and their teachers as part of a community outreach project entitled "Stories of Change." Six women were interviewed about what it was like to participate in the project. The data were coded and analyzed using phenomenological techniques, and the results were interpreted through a social constructionist framework. Five themes were revealed through an analysis of the interviews: (a) making a contribution, (b) connecting with others, (c) difficulty of telling their story, (d) identifying personal growth, and (e) moving forward. Storytelling is a powerful experience with lasting effects on the teller. This research explores the phenomenon of storytelling within a context of incarceration and stigma. These findings point toward the importance of providing programming to women within the criminal justice system that allows for meaningful interaction with normative individuals and opportunities for storytelling.

Comparable Outcomes after HLA-Matched Sibling and Alternative Donor Hematopoietic Cell Transplantation for Children with Fanconi Anemia and Severe Aplastic Anemia.

Fanconi anemia (FA)-associated severe aplastic anemia (SAA) requires allogeneic hematopoietic cell transplantation (HCT) for cure. With the evolution of conditioning regimens over time, outcomes of alternative donor HCT (AD-HCT) have improved dramatically. We compared outcomes of HLA-matched sibling donor HCT (MSD-HCT; n = 17) and AD-HCT (n = 57) performed for FA-associated SAA at a single institution between 2001 and 2016. Overall survival at 5 years was 94% for MSD-HCT versus 86% for AD-HCT, neutrophil engraftment was 100% versus 95%, platelet recovery was 100% versus 89%, grade II-IV acute graft-versus-host disease (GVHD) was 6% versus 12%, grade III-IV acute GVHD was 6% versus 4%, and chronic GVHD was 0 versus 7%, with no statistically significant differences by type of transplant. The use of UCB was associated with decreased rates of neutrophil recovery in AD-HCT and platelet recovery in both MSD-HCT and AD-HCT. A trend toward a higher serious infection density before day +100 post-HCT was observed in AD-HCT compared with MSD-HCT (P = .02). These data demonstrate that AD-HCT should be considered at the same time as MSD-HCT for patients with FA-associated SAA.

Phenotypic variability in patients with Fanconi anemia and biallelic FANCF mutations.

Fanconi anemia is a heterogeneous genetic disorder that is characterized by progressive bone marrow failure, congenital anomalies, and markedly increased risk for malignancies. Mutations in the FANCF (FA-F) gene represent approximately 2% of affected patients. Currently, information on the phenotypic findings of patients with Fanconi anemia from biallelic mutations in FANCF is limited. Here, we report three patients who illustrate the clinical variability within the FA-F group. This analysis suggests a more severe phenotype for those with the common c.484_485delCT mutation. © 2016 Wiley Periodicals, Inc.

Estradiol, SHBG and leptin interplay with food craving and intake across the menstrual cycle.

OBJECTIVE: To understand the association between ovarian hormones, non-acute satiety hormones and craving calorie dense foods in the luteal phase. METHODS: 17 premenopausal women, mean age 23.2 y, mean BMI 22.4kg/m(2) with regular menstrual cycles were studied during late follicular (FP) and luteal phases (LP). Estradiol, progesterone, DHEAS, SHBG, insulin and leptin, were measured in fasting samples. The validated Food Craving Inventory was used to record the types of foods volunteers habitually ate - rich in fat, carbohydrate or sweet taste, as well as craved during the LP of their menstrual cycle. RESULTS: Estradiol was inversely associated with leptin in FP (r=-0.62, p=0.01). Leptin was inversely associated with habitual intake of sweet foods, in both phases (FP: r=-0.64, p=0.01; LP: r=-0.63, p=0.01). SHBG in LP was positively associated with craving sweet and carbohydrate rich foods. Hierarchical cluster analysis revealed two groups of women, one with high estradiol, high estradiol/leptin ratio, high sweet and carbohydrate cravings (p<0.05); the other group had lower estradiol, lower estradiol/leptin ratio, and reported less craving. CONCLUSIONS: The estradiol-leptin axis may be a determinant of luteal phase craving and habitual food intake in menstruating women. CLINICAL TRIAL REGISTRATION NUMBER: NCT01407692.

Paternal or Maternal Uniparental Disomy of Chromosome 16 Resulting in Homozygosity of a Mutant Allele Causes Fanconi Anemia.

Fanconi anemia (FA) is a rare inherited disorder caused by pathogenic variants in one of 19 FANC genes. FA patients display congenital abnormalities, and develop bone marrow failure, and cancer susceptibility. We identified homozygous mutations in four FA patients and, in each case, only one parent carried the obligate mutant allele. FANCA and FANCP/SLX4 genes, both located on chromosome 16, were the affected recessive FA genes in three and one family respectively. Genotyping with short tandem repeat markers and SNP arrays revealed uniparental disomy (UPD) of the entire mutation-carrying chromosome 16 in all four patients. One FANCA patient had paternal UPD, whereas FA in the other three patients resulted from maternal UPD. These are the first reported cases of UPD as a cause of FA. UPD indicates a reduced risk of having another child with FA in the family and has implications in prenatal diagnosis.

Genetic Counselors' Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels.

The development of hereditary cancer genetic testing panels has altered genetic counseling practice. Mutations within certain genes on cancer panels pose not only a cancer risk, but also a reproductive risk for autosomal recessive conditions such as Fanconi anemia, constitutional mismatch repair deficiency syndrome, and ataxia telangiectasia. This study aimed to determine if genetic counselors discuss reproductive risks for autosomal recessive conditions associated with genes included on cancer panels, and if so, under what circumstances these risks are discussed. An on-line survey was emailed through the NSGC list-serv. The survey assessed 189 cancer genetic counselors' experiences discussing reproductive risks with patients at risk to carry a mutation or variant of uncertain significance (VUS) in a gene associated with both an autosomal dominant cancer risk and an autosomal recessive syndrome. Over half (n = 82, 55 %) reported having discussed reproductive risks; the remainder (n = 66, 45 %) had not. Genetic counselors who reported discussing reproductive risks primarily did so when patients had a positive result and were of reproductive age. Reasons for not discussing these risks included when a patient had completed childbearing or when a VUS was identified. Most counselors discussed reproductive risk after obtaining results and not during the informed consent process. There is inconsistency as to if and when the discussion of reproductive risks is taking place. The wide variation in responses suggests a need to develop professional guidelines for when and how discussions of reproductive risk for autosomal recessive conditions identified through cancer panels should occur with patients.

De novo truncating variants in the AHDC1 gene encoding the AT-hook DNA-binding motif-containing protein 1 are associated with intellectual disability and developmental delay.

Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.

Genetic counseling for Fanconi anemia: crosslinking disciplines.

Fanconi anemia (FA) is the most common of the inherited bone marrow failure syndromes with an incidence of approximately 1/100,000 to 1/200,000 live births. FA is a genetically complex and phenotypically heterogeneous condition involving birth defects, bone marrow failure, and cancer predisposition. This rare disease became well known in the genetic counseling community in 2002, when it was identified that biallelic mutations in BRCA2 can cause FA. Knowledge gained from the growing association between FA and breast cancer pathways has brought even more light to the complex genetic issues that arise when counseling families affected by this disease. Genetic counseling issues surrounding a diagnosis of FA affect many different disciplines. This review will serve as a way to cross-link the various topics important to genetic counselors that arise throughout the life of a patient with FA. Issues covered will include: an overview of FA, phenotypic presentation, management and treatment, the genetics and inheritance of FA, cytogenetic and molecular testing options, and the risks to family members of an individual with FA.