45,X/46,XY mosaicism: Clinical manifestations and long term follow-up.

45,X/46,XY chromosomal mosaicism presents a range of clinical manifestations, including phenotypes from Turner syndrome through genital abnormalities to apparently unaffected phenotypic males; however, the full clinical spectrum has not yet been fully delineated since prior studies on the clinical phenotype and associated risk of gonadal tumors included small cohorts and limited follow-up. To better describe the clinical manifestations and long-term outcome of patients with 45,X/46,XY mosaicism. We conducted a retrospective chart review of patients with 45,X/46,XY from three health centers (Hospital for Sick Children and Mount Sinai Hospital in Canada, and University of Pittsburgh Medical Center in United States). Of 100 patients with 45,X/46,XY karyotype, 47 were raised as females and 53 as males. Females were significantly shorter than males (p = 0.04) and height Z-score was significantly decreased with age for both genders (p = 0.02). Growth hormone (GH) treatment did not result in a significant height increase compared to the untreated group (p = 0.5). All females required puberty induction in contrast to majority of males. Five females were diagnosed with gonadal tumors, while no males were affected. Around 58% of patients exhibited at least one Turner syndrome stigmata. This study expands the clinical spectrum, long-term outcomes, and associated tumor risk in a large cohort of patients with 45,X/46,XY mosaicism. Additionally, it highlights our experience with GH therapy and prophylactic gonadectomy.

Finding the sweet spot: a qualitative study exploring patients' acceptability of chatbots in genetic service delivery.

Chatbots, web-based artificial intelligence tools that simulate human conversation, are increasingly in use to support many areas of genomic medicine. However, patient preferences towards using chatbots across the range of clinical settings are unknown. We conducted a qualitative study with individuals who underwent genetic testing for themselves or their child. Participants were asked about their preferences for using a chatbot within the genetic testing journey. Thematic analysis employing interpretive description was used. We interviewed 30 participants (67% female, 50% 50 + years). Participants considered chatbots to be inefficient for very simple tasks (e.g., answering FAQs) or very complex tasks (e.g., explaining results). Chatbots were acceptable for moderately complex tasks where participants perceived a favorable return on their investment of time and energy. In addition to achieving this "sweet spot," participants anticipated that their comfort with chatbots would increase if the chatbot was used as a complement to but not a replacement for usual care. Participants wanted a "safety net" (i.e., access to a clinician) for needs not addressed by the chatbot. This study provides timely insights into patients' comfort with and perceived limitations of chatbots for genomic medicine and can inform their implementation in practice.

The Clinician-reported Genetic testing Utility InDEx (C-GUIDE): Preliminary evidence of validity and reliability.

PURPOSE: Demonstrating the clinical utility of genetic testing is fundamental to clinical adoption and reimbursement, but standardized definitions and measurement strategies for this construct do not exist. The Clinician-reported Genetic testing Utility InDEx (C-GUIDE) offers a novel measure to fill this gap. This study assessed its validity and inter-rater reliability. METHODS: Genetics professionals completed C-GUIDE after disclosure of test results to patients. Construct validity was assessed using regression analysis to measure associations between C-GUIDE and global item scores as well as potentially explanatory variables. Inter-rater reliability was assessed by administering a vignette-based survey to genetics professionals and calculating Krippendorff's α. RESULTS: On average, a 1-point increase in the global item score was associated with an increase of 3.0 in the C-GUIDE score (P < .001). Compared with diagnostic results, partially/potentially diagnostic and nondiagnostic results were associated with a reduction in C-GUIDE score of 9.5 (P < .001) and 10.2 (P < .001), respectively. Across 19 vignettes, Krippendorff's α was 0.68 (95% CI: 0.63-0.72). CONCLUSION: C-GUIDE showed acceptable validity and inter-rater reliability. Although further evaluation is required, C-GUIDE version 1.2 can be useful as a standardized approach to assess the clinical utility of genetic testing.

Clinically and biologically relevant subgroups of Wilms tumour defined by genomic and epigenomic analyses.

BACKGROUND: Although cure rates for Wilms tumours (WT) are high, many patients receive therapy with attendant long-term complications. Our goal was to stratify WT using genome-wide analyses to identify candidate molecular features for patients who would benefit from a reduction in therapy. METHODS: We generated DNA methylation and exome sequencing data on WT-kidney pairs (n = 57) and unpaired tumours (n = 27) collected either at our centre or by the Children's Oncology Group. Samples were divided into a discovery set (n = 32) and validation set (n = 52). RESULTS: Analysis of DNA methylation revealed two subgroups of WT with distinct features. Subgroup A has a similar DNA methylation profile to mature kidney, while Subgroup B has genome-wide dysregulation of DNA methylation. The rate of non-synonymous missense mutations and segmental chromosomal aberrations was higher in Subgroup B tumours, suggesting that this group has genome instability related to its epigenetic state. Subgroup A had a higher proportion of cases of bilateral disease. Tumours with high-risk histology or from patients who relapsed were only found in Subgroup B. CONCLUSION: We have identified subgroup-specific molecular events that could inform future work supporting more targeted therapeutic approaches and patient stratification. We propose a novel developmental tumour model based on these findings.

The role of digital tools in the delivery of genomic medicine: enhancing patient-centered care.

PURPOSE: Alternative models of genetic counseling are needed to meet the rising demand for genomic sequencing. Digital tools have been proposed as a method to augment traditional counseling and reduce burden on professionals; however, their role in delivery of genetic counseling is not established. This study explored the role of the Genomics ADvISER, a digital decision aid, in delivery of genomic counseling. METHODS: We performed secondary analysis of 52 pretest genetic counseling sessions that were conducted over the course of a randomized controlled trial evaluating the effectiveness of the Genomics ADvISER. As part of the trial, participants were randomized to receive standard counseling or use the tool and then speak with a counselor. A qualitative interpretive description approach using thematic analysis and constant comparison was used for analysis. RESULTS: In the delivery of genomic counseling, the Genomics ADvISER contributed to enhancing counseling by (1) promoting informed dialogue, (2) facilitating preference-sensitive deliberation, and (3) deepening personalization of decisions, all of which represent fundamental principles of patient-centered care: providing clear high-quality information, respecting patients' values, preferences, and expressed needs, and providing emotional support. CONCLUSION: This study demonstrates that our digital tool contributed to enhancing patient-centered care in the delivery of genomic counseling.

Prenatally diagnosed omphaloceles: Report of 92 cases and association with Beckwith-Wiedemann syndrome.

OBJECTIVE: Describe the prevalence, perinatal and long-term outcomes of Beckwith-Wiedemann syndrome (BWS) among prenatally detected omphaloceles. METHODS: All prenatally diagnosed omphaloceles from 2010 to 2015 within a single tertiary care centre were identified. An echocardiogram and detailed fetal ultrasound were performed, and amniocentesis was offered with karyotype/microarray analysis and BWS molecular testing. Perinatal, neonatal, and long-term outcomes were retrieved for BWS cases. RESULTS: Among 92 omphaloceles, 62 had additional anomalies. Abnormal karyotypes were identified in 23/62 (37%) non-isolated and 2/30 (7%) isolated cases. One BWS case (5%) was identified among non-isolated omphaloceles and six BWS cases (37.5%) were identified among isolated omphaloceles after exclusion of aneuploidy. Among 19 BWS cases, 21% were conceived by ART. All omphaloceles underwent primary closure. Prenatally, macrosomia and polyhydramnios were seen in 42%. Macroglossia and nephromegaly were more commonly detected postnatally. Preterm birth occurred in 10/19 (53%) cases and cesarean deliveries were performed in 7/19 (40%) cases. Overall mortality was 20% (4/19). Embryonal tumors were diagnosed in 2/16 (12.5%) children, and neurodevelopmental outcomes were normal in 9/12 (75%) survivors. CONCLUSIONS: After excluding aneuploidy, BWS was identified in 37.5% and 5% of isolated and non-isolated omphaloceles, respectively. Omphaloceles were small-moderate size with good long-term surgical and neurodevelopmental outcomes when isolated.

"A change in perspective": Exploring the experiences of adolescents with hereditary tumor predisposition.

BACKGROUND: Hereditary tumor predisposition syndromes (HTPSs) are being recognized more frequently in the etiology of pediatric cancer. Previous research indicates that disclosure of tumor susceptibility is a significant event in adolescents' lives. Insight into adolescents' adjustment to knowledge of their syndromes can guide healthcare delivery, particularly genetic counseling. This study explored the experiences of adolescents with hereditary tumor predisposition and their perceptions of living at risk. METHODS: Seven adolescents, ages 14 to 17, representing six different childhood-onset HTPSs, were purposively sampled and interviewed using a study-specific semistructured interview guide. We explored the disclosure process, support systems, and the perceived benefits and harms of knowledge of hereditary tumor susceptibility. Interview transcripts were analyzed via interpretive description. RESULTS: Three major themes emerged from the data: (1) The benefits of knowledge outweigh the harms; (2) context surrounding genetic testing must be recognized; and (3) self-concept is influenced but not defined by tumor risk. CONCLUSIONS: We conclude that adolescents recognize the challenges associated with awareness of tumor predisposition but may also identify positive aspects in their experiences, reflecting a changed life perspective. Results of this exploratory study suggest strategies that can guide pretest and posttest genetic counseling of adolescents for HTPSs, facilitating the adaptive incorporation of genetic information into an adolescent's self-concept.

Prenatal and preconception genetic counseling for consanguinity: Consanguineous couples' expectations, experiences, and perspectives.

Consanguinity, the union between two individuals who are related as second cousins or closer, is a long-standing and respected tradition in many communities. Although there are social and economic benefits of consanguineous unions, offspring are at increased risk of having an inherited genetic condition or congenital anomaly. Genetic counseling services for consanguinity are available to couples at many centers. However, little is known about patient expectations of and experiences with genetic counseling for this indication, or their perspectives on genetic screening relevant to family planning, such as expanded carrier screening (ECS). This exploratory qualitative study involved interviews with 13 individuals who had recently received preconception or prenatal genetic counseling for consanguinity at a single center. We sought to gain insight into their expectations for the genetic counseling session, experiences discussing family history and reproductive risks with the genetic counselor, and views on ECS. Interview transcripts were analyzed using an interpretive descriptive approach. Data analysis revealed three main themes: (a) anticipation balances apprehension before the appointment; (b) genetic counseling reduces anxiety and empowers; and (c) the need for wider information dissemination about consanguinity-related risks and genetic services. Our findings support the personal utility of genetic counseling for consanguinity and demonstrate the need for increased visibility and access to genetics information, counseling, and testing relevant to this patient population.

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.

BACKGROUND: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers. METHODS: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant. RESULTS: Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set (n = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in BRCA1 or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants - associated with cancer, cardiac or neurodegenerative phenotypes - remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual. INTERPRETATION: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care.

Informed Decision-Making in the Context of Prenatal Chromosomal Microarray.

The introduction of chromosomal microarray (CMA) into the prenatal setting has involved considerable deliberation due to the wide range of possible outcomes (e.g., copy number variants of uncertain clinical significance). Such issues are typically discussed in pre-test counseling for pregnant women to support informed decision-making regarding prenatal testing options. This research study aimed to assess the level of informed decision-making with respect to prenatal CMA and the factor(s) influencing decision-making to accept CMA for the selected prenatal testing procedure (i.e., chorionic villus sampling or amniocentesis). We employed a questionnaire that was adapted from a three-dimensional measure previously used to assess informed decision-making with respect to prenatal screening for Down syndrome and neural tube defects. This measure classifies an informed decision as one that is knowledgeable, value-consistent, and deliberated. Our questionnaire also included an optional open-ended question, soliciting factors that may have influenced the participants' decision to accept prenatal CMA; these responses were analyzed qualitatively. Data analysis on 106 participants indicated that 49% made an informed decision (i.e., meeting all three criteria of knowledgeable, deliberated, and value-consistent). Analysis of 59 responses to the open-ended question showed that "the more information the better" emerged as the dominant factor influencing both informed and uninformed participants' decisions to accept prenatal CMA. Despite learning about the key issues in pre-test genetic counseling, our study classified a significant portion of women as making uninformed decisions due to insufficient knowledge, lack of deliberation, value-inconsistency, or a combination of these three measures. Future efforts should focus on developing educational approaches and counseling strategies to effectively increase the rate of informed decision-making among women offered prenatal CMA.

Recommendations for the integration of genomics into clinical practice.

The introduction of diagnostic clinical genome and exome sequencing (CGES) is changing the scope of practice for clinical geneticists. Many large institutions are making a significant investment in infrastructure and technology, allowing clinicians to access CGES, especially as health-care coverage begins to extend to clinically indicated genomic sequencing-based tests. Translating and realizing the comprehensive clinical benefits of genomic medicine remain a key challenge for the current and future care of patients. With the increasing application of CGES, it is necessary for geneticists and other health-care providers to understand its benefits and limitations in order to interpret the clinical relevance of genomic variants identified in the context of health and disease. New, collaborative working relationships with specialists across diverse disciplines (e.g., clinicians, laboratorians, bioinformaticians) will undoubtedly be key attributes of the future practice of clinical genetics and may serve as an example for other specialties in medicine. These new skills and relationships will also inform the development of the future model of clinical genetics training curricula. To address the evolving role of the clinical geneticist in the rapidly changing climate of genomic medicine, two Clinical Genetics Think Tank meetings were held that brought together physicians, laboratorians, scientists, genetic counselors, trainees, and patients with experience in clinical genetics, genetic diagnostics, and genetics education. This article provides recommendations that will guide the integration of genomics into clinical practice.Genet Med 18 11, 1075-1084.

Genomic imbalance in the centromeric 11p15 imprinting center in three families: Further evidence of a role for IC2 as a cause of Russell-Silver syndrome.

Russell-Silver syndrome is a heterogeneous disorder characterized by intrauterine growth retardation, postnatal growth deficiency, characteristic facial appearance, and other variable features. Genetic and epigenetic alterations are identified in about 60% of individuals with Russell-Silver syndrome. Most frequently, Russell-Silver syndrome is caused by altered gene expression on chromosome 11p15 due to loss of methylation at the telomeric imprinting center. To date there have been a handful of isolated clinical reports implicating the centromeric imprinting center 2 in the etiology of Russell-Silver syndrome. Here we report three new families with genomic imbalances, involving imprinting center 2 resulting in gain of methylation at this center and a Russell-Silver syndrome phenotype, including two families with a maternally inherited microduplication and the first pediatric patient with a paternally derived microdeletion. The findings in our families provide additional evidence of a role for imprinting center 2 in the etiology of Russell-Silver syndrome and suggest that imprinting center 2 imprinting abnormalities may be a more common cause of Russell-Silver syndrome than previously recognized. Furthermore, our findings together with previous clinical reports of genomic imbalances involving imprinting center 2 serve to underscore the complexity of the epigenetic regulation of the 11p15 region making it challenging to predict phenotype on the basis of genotype alone. © 2016 Wiley Periodicals, Inc.

Congenital limb deficiencies with vascular etiology: Possible association with maternal thrombophilia.

Congenital limb deficiency defects (LDDs) are etiologically heterogeneous. Acquired causes include amniotic bands, teratogens exposure, and chorionic villus sampling before 10 weeks' gestation and intrinsic causes include single-gene disorders and chromosome abnormalities. However, a substantial number of cases, especially terminal transverse deficiency defects, occur without an obvious cause and are ascribed to vascular disruption events. Some studies have found an association between maternal thrombophilia and congenital LDDs. We investigated this association through a review of all prenatally identified LDDs at a major tertiary care center in Toronto, Canada over a 12-year period. Our results showed a higher prevalence of thrombophilias among women with a pregnancy affected with an LDD when compared to the general population [χ2 (3) = 54.63, P < 0.01]. Our research was strengthened by the inclusion of affected pregnancies regardless of outcome, and strict criteria to avoid including LDDs with a non-vascular etiology. Most LDDs were identified during the routine 18-20 week anatomy ultrasound, but some were discovered as early as 13 weeks' gestation. We found an excess of left-sided defects among terminal transverse but not longitudinal deficiencies; additionally, all diagnoses of maternal thrombophilia occurred in the terminal transverse group. Our results support thrombophilia screening in all women with a prenatally diagnosed fetal LDD as well as careful evaluation of the fetal extremities during prenatal ultrasounds in women with a known thrombophilia. © 2016 Wiley Periodicals, Inc.

Experience with genetic counseling: the adolescent perspective.

Adolescence is a complex period of development that involves creating a sense of identity, autonomy, relationships and values. This stage of adjustment can be complicated by having a genetic condition. Genetic counseling can play an important role in providing information and support to this patient population; however, resources and guidelines are currently limited. In order to appropriately establish genetic counseling approaches and resource development, we investigated the experiences and perspectives of adolescents with a genetic condition with respect to their genetic counseling interactions. Using a qualitative exploratory approach, eleven semi-structured interviews were conducted with adolescents diagnosed with a genetic condition who received genetic counseling between the ages of 12 and 18 years at The Hospital for Sick Children. Transcripts were analyzed thematically using qualitative content analysis, from which three major interrelated themes emerged: 1) understanding the genetic counselor's role; 2) increasing perceived personal control; and 3) adolescent-specific factors influencing adaptation to one's condition. Additionally, a list of suggested tools and strategies for genetic counseling practice were elucidated. Our findings can contribute to the development of an adolescent-focused framework to enhance emerging genetic counseling approaches for this patient population, and can also facilitate the transition process from pediatric to adult care within patient and family-centered contexts.

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.

The Relationship Between Burnout and Occupational Stress in Genetic Counselors.

Burnout represents a critical disruption in an individual's relationship with work, resulting in a state of exhaustion in which one's occupational value and capacity to perform are questioned. Burnout can negatively affect an individual's personal life, as well as employers in terms of decreased work quality, patient/client satisfaction, and employee retention. Occupational stress is a known contributor to burnout and occurs as a result of employment requirements and factors intrinsic to the work environment. Empirical research examining genetic counselor-specific burnout is limited; however, existing data suggests that genetic counselors are at increased risk for burnout. To investigate the relationship between occupational stress and burnout in genetic counselors, we administered an online survey to members of three genetic counselor professional organizations. Validated measures included the Maslach Burnout Inventory-General Survey (an instrument measuring burnout on three subscales: exhaustion, cynicism, and professional efficacy) and the Occupational Stress Inventory-Revised (an instrument measuring occupational stress on 14 subscales). Of the 353 respondents, more than 40 % had either considered leaving or left their job role due to burnout. Multiple regression analysis yielded significant predictors for burnout risk. The identified sets of predictors account for approximately 59 % of the variance in exhaustion, 58 % of the variance in cynicism, and 43 % of the variance in professional efficacy. Our data confirm that a significant number of genetic counselors experience burnout and that burnout is correlated with specific aspects of occupational stress. Based on these findings, practice and research recommendations are presented.

High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS), an overgrowth and tumor predisposition syndrome is clinically heterogeneous. Its variable presentation makes molecular diagnosis particularly important for appropriate counseling of patients with respect to embyronal tumor risk and recurrence risk. BWS is characterized by macrosomia, omphalocele, and macroglossia. Additional clinical features can include hemihyperplasia, embryonal tumors, umbilical hernia, and ear anomalies. BWS is etiologically heterogeneous arising from dysregulation of one or both of the chromosome 11p15.5 imprinting centers (IC) and/or imprinted growth regulatory genes on chromosome 11p15.5. Most BWS cases are sporadic and result from loss of maternal methylation at imprinting center 2 (IC2), gain of maternal methylation at imprinting center 1 (IC1) or paternal uniparental disomy (UPD). Heritable forms of BWS (15 %) have been attributed mainly to mutations in the growth suppressor gene CDKN1C, but have also infrequently been identified in patients with copy number variations (CNVs) in the chromosome 11p15.5 region. Four hundred and thirty-four unrelated BWS patients referred to the molecular diagnostic laboratory were tested by methylation-specific multiplex ligation-dependent probe amplification. Molecular alterations were detected in 167 patients, where 103 (62 %) showed loss of methylation at IC2, 23 (14 %) had gain of methylation at IC1, and 41 (25 %) showed changes at both ICs usually associated with paternal UPD. In each of the three groups, we identified patients in whom the abnormalities in the chromosome 11p15.5 region were due to CNVs. Surprisingly, 14 patients (9 %) demonstrated either deletions or duplications of the BWS critical region that were confirmed using comparative genomic hybridization array analysis. The majority of these CNVs were associated with a methylation change at IC1. Our results suggest that CNVs in the 11p15.5 region contribute significantly to the etiology of BWS. We highlight the importance of performing deletion/duplication testing in addition to methylation analysis in the molecular investigation of BWS to improve our understanding of the molecular basis of this disorder, and to provide accurate genetic counseling.

Risk estimates for complex disorders: comparing personal genome testing and family history.

PURPOSE: Personal genome testing allows the identification of single-nucleotide polymorphisms associated with an increased risk for common complex disorders. An area of concern in the use of personal genome testing is how risk estimates generated differ from traditional measures of risk (e.g., family history analysis). We sought to analyze the concordance of risk estimates generated by family history analysis and by personal genome testing. METHODS: Risk categorizations for 20 complex conditions included in Navigenics personal genome testing were compared with risk categorization estimates derived from family history assessment using the kappa (κ) statistic. RESULTS: The only conditions showing slight agreement between risk assessment methods were Alzheimer disease (κ = 0.131), breast cancer (κ = 0.154), and deep vein thrombosis (κ = 0.201) in females, and colon cancer (κ = 0.124) in males. Eighty-six individuals (11.4%) were found to have additional genetic risks not assessed by personal genome testing after family and medical history assessment, including 38 individuals with family histories suggestive of hereditary cancer syndromes. CONCLUSION: Discordance between personal genome testing and family history risk estimates suggests that these methods may provide independent information that could be used in a complementary manner. Results also support that eliciting family history adds value to overall risk assessment for individuals undergoing personal genome testing.

Molecular findings in Beckwith-Wiedemann syndrome.

Our understanding of Beckwith-Wiedemann syndrome (BWS) has recently been enhanced by advances in its molecular characterization. These advances have further delineated intricate (epi)genetic regulation of the imprinted gene cluster on chromosome 11p15.5 and the role of these genes in normal growth and development. Studies of the molecular changes associated with the BWS phenotype have been instrumental in elucidating critical molecular elements in this imprinted region. This review will provide updated information on the multiple new regulatory elements that have been recently found to contribute to in cis or in trans control of imprinted gene expression in the chromosome 11p15.5 region and the clinical expression of the BWS phenotype.