Reflections of parents of children with 22q11.2 Deletion Syndrome on the experience of receiving psychiatric genetic counseling: 'Awareness to Act'.

Individuals with 22q11.2 deletion syndrome (22qDS) have a 25%-41% risk for a psychotic disorder. Although early intervention for psychiatric conditions leads to the best long-term outcomes, healthcare providers often provide inadequate information about these issues and psychiatric services are underused by this population. We conducted semi-structured interviews with parents of children with 22qDS a month after they received psychiatric genetic counseling (pGC), to evaluate outcomes and perceived value of pGC with respect to parents' needs. Using grounded theory, we generated a theoretical framework of the process of building parental awareness of psychiatric risks associated with 22qDS and protective and management strategies for mental health (MH). Parents described how after their child's diagnosis with 22qDS, a variety of barriers stalled their building awareness of psychiatric risk and protective/management strategies: dealing with the immediate symptoms of 22qDS; child's young age; parental fear and stigma; and missing MH guidance. These barriers led them to carry the burden of worrying over missing emerging psychiatric symptoms and the stress over advocating for their child's MH. Parents indicated pGC was beneficial in that led them to achieve an 'awareness to act,' feeling confident in being alert and equipped to protect and/or manage their child's MH.

Length of Uninterrupted CAG, Independent of Polyglutamine Size, Results in Increased Somatic Instability, Hastening Onset of Huntington Disease.

Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT [reference: (CAG)n-CAA-CAG], since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region [(CAG)n-CAG-CAG]. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36-39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.

Patient perspectives on the process and outcomes of psychiatric genetic counseling: An "Empowering Encounter".

Genetic counseling (GC) for individuals with mental illness (MI) has been shown to improve patient outcomes, such as increased empowerment and self-efficacy. However, we do not understand how the process of GC results in these improvements or what aspects of the process are critical. In this qualitative study, we explored the process and outcome of psychiatric GC from the patient's perspective. Ten Canadian adults with a diagnosed MI were interviewed prior to, and 1 month following, psychiatric GC. Interview transcripts were analyzed using Grounded Theory methodology and generated a theoretical framework that describes the process and outcomes of psychiatric GC from the patient's perspective. Participants described the counseling process to be an "empowering encounter" and identified specific attributes of the process and characteristics of the counselor that contributed to their empowerment. Participants gained a new perspective on the cause and management of their MI, which seemed to facilitate a deeper acceptance of their condition. Consequently, participants reported being empowered and feeling less shame, blame, and guilt; which reportedly made them more able to manage their MI and protect their mental health; and more open to talking about their condition with family and friends. This study provides a better understanding of how the process of GC influences patient outcomes and highlights features of the process that maximize patient benefit.

The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population.

Huntington disease (HD) is the most common monogenic neurodegenerative disorder in populations of European ancestry, but occurs at lower prevalence in populations of East Asian or black African descent. New mutations for HD result from CAG repeat expansions of intermediate alleles (IAs), usually of paternal origin. The differing prevalence of HD may be related to the rate of new mutations in a population, but no comparative estimates of IA frequency or the HD new mutation rate are available. In this study, we characterize IA frequency and the CAG repeat distribution in fifteen populations of diverse ethnic origin. We estimate the HD new mutation rate in a series of populations using molecular IA expansion rates. The frequency of IAs was highest in Hispanic Americans and Northern Europeans, and lowest in black Africans and East Asians. The prevalence of HD correlated with the frequency of IAs by population and with the proportion of IAs found on the HD-associated A1 haplotype. The HD new mutation rate was estimated to be highest in populations with the highest frequency of IAs. In European ancestry populations, one in 5,372 individuals from the general population and 7.1% of individuals with an expanded CAG repeat in the HD range are estimated to have a molecular new mutation. Our data suggest that the new mutation rate for HD varies substantially between populations, and that IA frequency and haplotype are closely linked to observed epidemiological differences in the prevalence of HD across major ancestry groups in different countries.

Women's experiences of participating in a prospective, longitudinal postpartum depression study: insights for perinatal mental health researchers.

Barriers to recruitment for research on mental illness include participant distrust of researchers and social stigma. Though these issues may be acutely important in perinatal mental health research, they remain unexplored in this context. In order to inform strategies to more fully engage women in perinatal mental health research, we explored the motivations and experiences of women with a history of major depressive disorder who participated in a prospective longitudinal research study on postpartum depression (PPD). Sixteen women with a history of depression who had either completed or recently made a decision about participation in a longitudinal research study about PPD were interviewed by telephone. Qualitative, semi-structured interviews explored participants' decision-making about, and experiences of, participation. Interviews were audio-recorded, transcribed, and qualitatively analyzed using elements of grounded theory methodology. Follow-up interviews were conducted with four participants to refine and clarify preliminary results. Foundational elements necessary for women to consider participating in PPD research included personal acceptance of illness and trust in the research team/institution. Other main motivators included perceived personal relevance, anticipated benefits (including access to support/resources, learning opportunities, and improved self-worth), altruism, and accessible study procedures. Our data suggest that participating in perinatal mental health research may help women make meaning of their mental illness experience and is perceived as providing support. The findings-particularly around the importance of participant-researcher rapport and accessibility of study design-may inform strategies that improve participation rates, decrease attrition, and maximize participant benefits in perinatal mental health research.

Obsessive-Compulsive Disorder: The Process of Parental Adaptation and Implications for Genetic Counseling.

Obsessive-compulsive disorder (OCD) has primarily pediatric onset and well-documented unique impacts on family functioning. Limited research has assessed the understanding that parents of children with OCD have of the etiology of the condition, and there are no data regarding potential applications of genetic counseling for this population. We recruited 13 parents of 13 children diagnosed with OCD from the OCD Registry at British Columbia Children's Hospital, and conducted qualitative semi-structured telephone interviews to explore participants' experiences with their child's OCD, causal attributions of OCD, and perceptions of two genetic counseling vignettes. Interviews were audio-recorded, transcribed, and analyzed using elements of grounded theory qualitative methodology. Analysis revealed key components and contextual elements of the process through which parents adapt to their child's OCD. This adaptation process involved conceptualizing the meaning of OCD, navigating its impact on family dynamics, and developing effective illness management strategies. Adaptation took place against a backdrop of stigmatization and was shaped by participants' family history of mental illness and their child's specific manifestations of OCD. Parents perceived genetic counseling, as described in the vignettes, as being empowering, alleviating guilt and blame, and positively impacting treatment orientation. These data provide insight into the process of parental adaptation to pediatric OCD, and suggest that genetic counseling services for families affected by OCD may help facilitate adaptation to this illness.

A new mutation for Huntington disease following maternal transmission of an intermediate allele.

New mutations for Huntington disease (HD) originate from CAG repeat expansion of intermediate alleles (27-35 CAG). Expansions of such alleles into the pathological range (≥ 36 CAG) have been exclusively observed in paternal transmission. We report the occurrence of a new mutation that defies the paternal expansion bias normally observed in HD. A maternal intermediate allele with 33 CAG repeats expanded in transmission to 48 CAG repeats causing a de novo case of HD in the family. Retrospectively, the mother presented with cognitive decline, but HD was never considered in the differential diagnosis. She was diagnosed with dementia and testing for HD was only performed after her daughter had been diagnosed. This observation of an intermediate allele expanding into the full penetrance HD range after maternal transmission has important implications for genetic counselling of females with intermediate repeats.

Conceptualizing genetic counseling as psychotherapy in the era of genomic medicine.

Discussions about genetic contributions to medical illness have become increasingly commonplace. Physicians and other health-care providers in all quarters of medicine, from oncology to psychiatry, routinely field questions about the genetic basis of the medical conditions they treat. Communication about genetic testing and risk also enter into these conversations, as knowledge about genetics is increasingly expected of all medical specialists. Attendant to this evolving medical landscape is some uncertainty regarding the future of the genetic counseling profession, with the potential for both increases and decreases in demand for genetic counselors being possible outcomes. This emerging uncertainty provides the opportunity to explicitly conceptualize the potentially distinct value and contributions of the genetic counselor over and above education about genetics and risk that may be provided by other health professionals. In this paper we suggest conceptualizing genetic counseling as a highly circumscribed form of psychotherapy in which effective communication of genetic information is a central therapeutic goal. While such an approach is by no means new--in 1979 Seymour Kessler explicitly described genetic counseling as a "kind of psychotherapeutic encounter," an "interaction with a psychotherapeutic potential"--we expand on his view, and provide research evidence in support of our position. We review available evidence from process and outcome studies showing that genetic counseling is a therapeutic encounter that cannot be reduced to one where the counselor performs a simple "conduit for information" function, without losing effectiveness. We then discuss potential barriers that may have impeded greater uptake of a psychotherapeutic model of practice, and close by discussing implications for practice.

High frequency of intermediate alleles on Huntington disease-associated haplotypes in British Columbia's general population.

Intermediate alleles (27-35 CAG, IAs) for Huntington disease (HD) usually do not confer the disease phenotype but are prone to CAG repeat instability. Consequently, offspring are at-risk of inheriting an expanded allele in the HD range (≥36 CAG). IAs that expand into a new mutation have been hypothesized to be more susceptible to instability compared to IAs identified on the non-HD side of a family from the general population. Frequency estimates for IAs are limited and have largely been determined using clinical samples of HD or related disorders, which may result in an ascertainment bias. This study aimed to establish the frequency of IAs in a sample of a British Columbia's (B.C.) general population with no known association to HD and examine the haplotype of new mutation and general population IAs. CAG sizing was performed on 1,600 DNA samples from B.C.'s general population. Haplotypes were determined using 22 tagging SNPs across the HTT gene. 5.8% of individuals were found to have an IA, of which 60% were on HD-associated haplotypes. There was no difference in the haplotype distribution of new mutation and general population IAs. These findings suggest that IAs are relatively frequent in the general population and are often found on haplotypes associated with expanded CAG lengths. There is likely no difference in the propensity of new mutation and general population IAs to expand into the disease range given that they are both found on disease-associated haplotypes. These findings have important implications for clinical practice.

CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease.

INTRODUCTION: New mutations for Huntington disease (HD) occur due to CAG repeat instability of intermediate alleles (IA). IAs have between 27 and 35 CAG repeats, a range just below the disease threshold of 36 repeats. While they usually do not confer the HD phenotype, IAs are prone to paternal germline CAG repeat instability. Consequently, they may expand into the HD range upon transmission to the next generation, producing a new mutation. Quantified risk estimates for IA repeat instability are extremely limited but needed to inform clinical practice. METHODS: Using small-pool PCR of sperm DNA from Caucasian men, we examined the frequency and magnitude of CAG repeat instability across the entire range of intermediate CAG sizes. The CAG size-specific risk estimates generated are based on the largest sample size ever examined, including 30 IAs and 18 198 sperm. RESULTS: Our findings demonstrate a significant risk of new mutations. While all intermediate CAG sizes demonstrated repeat expansion into the HD range, alleles with 34 and 35 CAG repeats were associated with the highest risk of a new mutation (2.4% and 21.0%, respectively). IAs with ≥33 CAG repeats showed a dramatic increase in the frequency of instability and a switch towards a preponderance of repeat expansions over contractions. CONCLUSIONS: These data provide novel insights into the origins of new mutations for HD. The CAG size-specific risk estimates inform clinical practice and provide accurate risk information for persons who receive an IA predictive test result.

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes.

Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript.

When they hear what we say: ethical challenges in presenting research findings to the Huntington disease community.

Sharing findings with the Huntington disease (HD) community and other genetic disease communities is challenging because of the sensitivity involved in effectively communicating findings to participants. We describe our experiences of presenting multi-disciplinary research findings to the HD community, and discuss the need to: (1) balance potential benefits and harms for participants, researchers, and others; (2) demonstrate respect for participants' needs, expectations, and priorities; and (3) ensure transparency and respect for autonomy.

CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup.

Huntington disease (HD) is an autosomal-dominant disorder that results from >or=36 CAG repeats in the HD gene (HTT). Approximately 10% of patients inherit a chromosome that underwent CAG expansion from an unaffected parent with <36 CAG repeats. This study is a comprehensive analysis of genetic diversity in HTT and reveals that HD patients of European origin (n = 65) have a significant enrichment (95%) of a specific set of 22 tagging single nucleotide polymorphisms (SNPs) that constitute a single haplogroup. The disease association of many SNPs is much stronger than any previously reported polymorphism and was confirmed in a replication cohort (n = 203). Importantly, the same haplogroup is also significantly enriched (83%) in individuals with 27-35 CAG repeats (intermediate alleles, n = 66), who are unaffected by the disease, but have increased CAG tract sizes relative to the general population (n = 116). These data support a stepwise model for CAG expansion into the affected range (>or=36 CAG) and identifies specific haplogroup variants in the general population associated with this instability. The specific variants at risk for CAG expansion are not present in the general population in China, Japan, and Nigeria where the prevalence of HD is much lower. The current data argue that cis-elements have a major predisposing influence on CAG instability in HTT. The strong association between specific SNP alleles and CAG expansion also provides an opportunity of personalized therapeutics in HD where the clinical development of only a small number of allele-specific targets may be sufficient to treat up to 88% of the HD patient population.