An exploration of knowledge, risk perceptions, and communication in a family with multiple genetic risks for Parkinson's disease.

Genomic testing increasingly challenges health care providers and patients to understand, share, and use information. The provision of polygenic risks is anticipated to complicate comprehension, communication, and risk perception further. This manuscript aims to illuminate the challenges confronting families with multiple genetic risks for Parkinson's disease. Identifying and planning for such issues may prove valuable to family members now and in the future, should neuroprotective or genotype-specific therapies become available. We present qualitative data from interviews with a multi-generational family carrying pathogenic variants in the glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) genes which are associated with an increased risk for developing Parkinson's disease (PD). The family includes two brothers (heterozygous for LRRK2 p.G2019S and homozygous for GBA1 p.N409S) and their four descendants. The brothers were concordant for GD and discordant for PD. Genetic counseling and testing were provided to four of the six participants. Two years later, semi-structured interviews were conducted with the initial participants (n = 4) and two additional first-degree relatives. Interviews were transcribed and thematically analyzed, providing the basis for this report. Illuminated topics include the perceived risk of developing PD, recall of genetic information, and family communication. With the expanding use of exome and genome sequencing, we anticipate that genetic counselors will increasingly face the challenges demonstrated by this case involving multiple genetic risks for PD, limited data to clarify risk, and the inherent variability of family communication, genetic knowledge, and risk perception. This clinical case report provides a compelling narrative demonstrating the need for additional research exploring these multifaceted topics relevant to both families facing these challenges and providers striving to assist, support and guide their journey.

The first pancreatic neuroendocrine tumor in Li-Fraumeni syndrome: a case report.

BACKGROUND: Li-Fraumeni syndrome is a cancer predisposition syndrome caused by germline TP53 tumor suppressor gene mutations, with no previous association with pancreatic neuroendocrine tumors (PNETs). Here we present the first case of PNET associated with Li-Fraumeni syndrome. CASE PRESENTATION: This is a 43-year-old female who underwent laparoscopic distal pancreatectomy at age 39 for a well-differentiated grade 2 cystic PNET. When the patient was 41 years old, her seven-year-old daughter was found to have an astrocytoma and a germline TP53 mutation. While undergoing surveillance with 68Gallium-DOTATATE positron emission tomography/computed tomography for her PNET, the patient was found to have a large choroid plexus papilloma in her right temporal lobe. She underwent genetic counseling and testing that identified a germline pathogenic variant in TP53, leading to the diagnosis of Li-Fraumeni syndrome. Her PNET had a hemizygous pathogenic TP53 mutation with loss of the wild-type alternate allele, consistent with loss of heterozygosity and the two-hit hypothesis. She was enrolled in a Li-Fraumeni syndrome protocol and continues surveillance screening with our service. CONCLUSIONS: This is the first PNET reported in association with Li-Fraumeni syndrome. Pancreatic cancer risk is elevated in this syndrome, and our case highlights the need for vigilance in screening for pancreatic neoplasms in these patients.

A novel frameshift mutation in SOX10 causes Waardenburg syndrome with peripheral demyelinating neuropathy, visual impairment and the absence of Hirschsprung disease.

Waardenburg syndrome (WS) is a group of genetic disorders associated with varying components of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and eyes. There exist four different WS subtypes, each defined by the absence or presence of additional features. One of the genes associated with WS is SOX10, a key transcription factor for the development of neural crest-derived lineages. Here we report a 12-year-old boy with a novel de novo SOX10 frameshift mutation and unique combination of clinical features including primary peripheral demyelinating neuropathy, hearing loss and visual impairment but absence of Hirschsprung disease and the typical pigmentary changes of hair or skin. This expands the spectrum of currently recognized phenotypes associated with WS and illustrates the phenotypic heterogeneity of SOX10-associated WS.

Challenging issues arising in counseling families experiencing holoprosencephaly.

The provision of information and support to families experiencing holoprosencephaly (HPE) in a loved one is unequivocally challenging, even for the most experienced clinicians. It deserves the balance of pertinent information coupled with medical guidance that forms the basis for shared decision-making; all of which is ideally contained within a supportive environment. It requires a willingness to carefully listen to the specific concerns of the parents and family allowing them to revisit challenging issues as much as needed to encourage existing road blocks to be resolved. It necessitates that professionals see each and every family as unique, without preconceived notions about what is or is not important and being prepared to accept thoughts and decisions that may not fit with the professional's own beliefs. To some, this may sound impractical, inefficient, or even impossible within the time constrained models of modern day clinical services. However, in practice, this patient-focused approach is arguably the most essential step in providing "personalized medicine" to the populations we encounter. This manuscript is intended to provide a brief review of relevant literature and case discussions to highlight issues for families learning of the diagnosis of HPE during a pregnancy, at birth, during childhood or more rarely, in adolescence.

In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics.

PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.

Muenke syndrome: An international multicenter natural history study.

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal, and calcaneal fusions, and behavioral differences. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings. Muenke syndrome constitutes the most common syndromic form of craniosynostosis, with an incidence of 1 in 30,000 births and is defined by the presence of the p.Pro250Arg mutation in FGFR3. Participants were recruited from international craniofacial surgery and genetic clinics. Affected individuals, parents, and their siblings, if available, were enrolled in the study if they had a p.Pro250Arg mutation in FGFR3. One hundred and six patients from 71 families participated in this study. In 51 informative probands, 33 cases (64.7%) were inherited. Eighty-five percent of the participants had craniosynostosis (16 of 103 did not have craniosynostosis), with 47.5% having bilateral and 28.2% with unilateral synostosis. Females and males were similarly affected with bicoronal craniosynostosis, 50% versus 44.4% (P = 0.84), respectively. Clefting was rare (1.1%). Hearing loss was identified in 70.8%, developmental delay in 66.3%, intellectual disability in 35.6%, attention deficit/hyperactivity disorder in 23.7%, and seizures in 20.2%. In patients with complete skeletal surveys (upper and lower extremity x-rays), 75% of individuals were found to have at least a single abnormal radiographical finding in addition to skull findings. This is the largest study of the natural history of Muenke syndrome, adding valuable clinical information to the care of these individuals including behavioral and cognitive impairment data, vision changes, and hearing loss.

Executive Function and Adaptive Behavior in Muenke Syndrome.

OBJECTIVE: To investigate executive function and adaptive behavior in individuals with Muenke syndrome using validated instruments with a normative population and unaffected siblings as controls. STUDY DESIGN: Participants in this cross-sectional study included individuals with Muenke syndrome (P250R mutation in FGFR3) and their mutation-negative siblings. Participants completed validated assessments of executive functioning (Behavior Rating Inventory of Executive Function [BRIEF]) and adaptive behavior skills (Adaptive Behavior Assessment System, Second Edition [ABAS-II]). RESULTS: Forty-four with a positive FGFR3 mutation, median age 9 years, range 7 months to 52 years were enrolled. In addition, 10 unaffected siblings served as controls (5 males, 5 females; median age, 13 years; range, 3-18 years). For the General Executive Composite scale of the BRIEF, 32.1% of the cohort had scores greater than +1.5 SD, signifying potential clinical significance. For the General Adaptive Composite of the ABAS-II, 28.2% of affected individuals scored in the 3rd-8th percentile of the normative population, and 56.4% were below the average category (<25th percentile). Multiple regression analysis did not identify craniosynostosis as a predictor of BRIEF (P = .70) or ABAS-II scores (P = .70). In the sibling pair analysis, affected siblings performed significantly poorer on the BRIEF General Executive Composite and the ABAS-II General Adaptive Composite. CONCLUSION: Individuals with Muenke syndrome are at an increased risk for developing adaptive and executive function behavioral changes compared with a normative population and unaffected siblings.

Pathogenic mutations in GLI2 cause a specific phenotype that is distinct from holoprosencephaly.

BACKGROUND: Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly. OBJECTIVE: To characterise the genotypic and phenotypic findings in individuals with GLI2 variants and clarify clinical findings in individuals with loss-of-function mutations. METHODS: Through the National Institutes of Health and collaborating centres, ∼400 individuals with HPE spectrum disorders, endocrine disorders or craniofacial anomalies were screened for GLI2 mutations. Results were combined with all published cases. We compared the clinical and molecular features of individuals with truncating mutations to individuals with variants of unknown significance (defined as not resulting in protein truncation, reported in normal controls and/or deemed unlikely to be pathogenic by functional prediction software). RESULTS: 112 individuals with variants in GLI2 were identified, with 43 having truncating mutations. Individuals with truncating mutations were more likely to have both pituitary anomalies and polydactyly versus those with variants of unknown significance (p<0.0001 by Fisher's exact test); only 1 of 43 had frank HPE. These individuals were more likely to have recognised penetrance (polydactyly or pituitary anomalies or both) than those without truncating mutations (p=0.0036 by Fisher's exact test). A common facial phenotype was seen in individuals (with midface hypoplasia, cleft lip/palate and hypotelorism) with truncating mutations. CONCLUSIONS: Individuals with truncating mutations in GLI2 typically present with pituitary anomalies, polydactyly and subtle facial features rather than HPE. This will be helpful in screening populations for GLI2 mutations and for counselling affected patients. TRIAL REGISTRATION: 98-HG-0249/04-HG-0093.

Exploring psychological responses to genetic testing for Lynch Syndrome within the family context.

OBJECTIVE: Genetic testing for hereditary cancer susceptibility syndromes is a family-centered process. Nonetheless, little research has explored how the family context affects psychological responses to genetic testing. We examine how personal test results and the test results of immediate and extended family members shape responses to genetic testing. METHODS: Individuals at risk of carrying a mutation associated with an inherited cancer susceptibility syndrome (Lynch syndrome) received genetic testing. Six months after receiving their results, participants reported on cancer distress, cancer worry, and depressive symptoms. RESULTS: Among mutation carriers for Lynch syndrome, the higher the proportion of carriers in their immediate family, the less cancer worry and distress they reported. In contrast, mutation carriers and non-carriers with a high proportion of carriers in their immediate family and mutation carriers with a high proportion of carriers in their extended family were at elevated risk for clinically significant levels of depressive symptoms. CONCLUSION: Personal test results alone are not highly predictive of psychological outcomes. Instead, the interaction between personal and family test results, or in some cases, family test results alone, predict key psychological outcomes. The current research has important implications for genetic counseling and intervention efforts. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Analysis of renal anomalies in VACTERL association.

BACKGROUND: VACTERL association refers to a combination of congenital anomalies that can include: vertebral anomalies, anal atresia, cardiac malformations, tracheo-esophageal fistula with esophageal atresia, renal anomalies (typically structural renal anomalies), and limb anomalies. METHODS: We conducted a description of a case series to characterize renal findings in a cohort of patients with VACTERL association. Out of the overall cohort, 48 patients (with at least three component features of VACTERL and who had abdominal ultrasound performed) met criteria for analysis. Four other patients were additionally analyzed separately, with the hypothesis that subtle renal system anomalies may occur in patients who would not otherwise meet criteria for VACTERL association. RESULTS: Thirty-three (69%) of the 48 patients had a clinical manifestation affecting the renal system. The most common renal manifestation (RM) was vesicoureteral reflux (VUR) in addition to a structural defect (present in 27%), followed by unilateral renal agenesis (24%), and then dysplastic/multicystic kidneys or duplicated collected system (18% for each). Twenty-two (88%) of the 25 patients with a structural RM had an associated anorectal malformation. Individuals with either isolated lower anatomic anomalies, or both upper and lower anatomic anomalies were not statistically more likely to have a structural renal defect than those with isolated upper anatomic anomalies (p = 0.22, p = 0.284, respectively). CONCLUSION: Given the high prevalence of isolated VUR in our cohort, we recommend a screening VCUG or other imaging modality be obtained to evaluate for VUR if initial renal ultrasound shows evidence of obstruction or renal scarring, as well as ongoing evaluation of renal health.

Analysis of cardiac anomalies in VACTERL association.

BACKGROUND: Congenital heart disease (CHD) is estimated to affect between 3 and 5% of all newborns. Extra-cardiac malformations are observed in 7 to 50% of patients with CHD. One relatively well-known association that can occur in the context of CHD is VACTERL. Controversy still remains regarding the definition of VATER association and its expansion to VACTERL, the appropriate diagnostic criteria and the overall incidence. METHODS: We conducted a description of a case series to characterize the cardiac findings present in a cohort of patients meeting the criteria for VACTERL association. RESULTS: Forty-six of 220 were eligible for inclusion into the study, 67% (31 of 46) had CHD. The most common CHD was ventricular septal defect, present in 18 of 31 patients (58%). There was no statistically significant association between CHD severity and the presence or absence of other VACTERL component features, specifically anorectal malformation (p = 0.18) or tracheo-esophageal fistula (p = 0.72). CHD presence also did not correlate with the presence of tracheo-esophageal fistula or anorectal malformation. CONCLUSION: Although this study does not, by design, provide further evidence toward the questions of whether CHD is a defining feature of VACTERL association, the frequency of CHD in our cohort does lend support to it being an important medical consideration in patients with VACTERL association. Based on our experience, we strongly recommend a screening echocardiogram to evaluate for CHD in individuals with a potential diagnosis of VACTERL association.

Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog.

BACKGROUND: Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of non-chromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. OBJECTIVE: To characterise genetic and clinical findings in individuals with SHH mutations. METHODS: Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. RESULTS: This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p<0.0001 compared to ZIC2 or SIX3). Individuals with truncating mutations were significantly more likely to have frank HPE than those with non-truncating mutations (49% vs 35%, respectively; p=0.012). While mutations were significantly more common in the N-terminus than in the C-terminus (including accounting for the relative size of the coding regions, p=0.00010), no specific genotype-phenotype correlations could be established regarding mutation location. CONCLUSIONS: SHH mutations overall result in milder disease than mutations in other common HPE related genes. HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive.

The role of religious and existential well-being in families with Lynch syndrome: prevention, family communication, and psychosocial adjustment.

This study explored the role of religious (RWB) and existential well-being (EWB) on psychosocial factors, support network characteristics, and screening practices in families with Lynch syndrome, also referred to as hereditary nonpolyposis colon cancer (HNPCC). Participants were individuals with Lynch syndrome associated cancers and their first-degree relatives at risk of inheriting an identified deleterious mutation. Analyses considered both family RWB and EWB norms and individual deviations from that norm. Analyses controlled for age, gender, cancer diagnosis, number of respondents, and network size. Higher family RWB was associated with increased depressive symptoms (p < .05) and avoidant cognitions (p < .05). Higher family EWB was related to decreased depression symptoms (p < .001). Higher family EWB was associated with fecal occult blood testing (p < .01), and family communication about genetic counselling and testing (p < .01). Analyses pointed to individual effects of EWB above and beyond family-level effects. Individuals with lower EWB than their family had lower perceived risk for colorectal cancer (p < .05), communicated disease risk information to less family members (p < .05), and were less likely to undergo recent colonoscopies (p < .05). Participants with lower EWB than their family also had higher cancer worry (p < .01) and increased depressive symptoms (p < .001). Findings indicate the importance of assessing individuals within the context of their family network and being aware of family characteristics which may impact individual adjustment to disease risk. Interventions considering family-level factors may provide efficient pathways to improving psychosocial factors, screening practices, communication about disease risk and genetic testing, and cancer prevention.

Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR.

Lenz microphthalmia is inherited in an X-linked recessive pattern and comprises microphthalmia, mental retardation, and skeletal and other anomalies. Two loci associated with this syndrome, MAA (microphthalmia with associated anomalies) and MAA2, are situated respectively at Xq27-q28 (refs. 1,2) and Xp11.4-p21.2 (ref. 3). We identified a substitution, nt 254C-->T; P85L, in BCOR (encoding BCL-6-interacting corepressor, BCOR) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus. Oculofaciocardiodental syndrome (OFCD; OMIM 300166) is inherited in an X-linked dominant pattern with presumed male lethality and comprises microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities. Given their phenotypic overlap, we proposed that OFCD and MAA2-associated Lenz microphthalmia were allelic, and we found different frameshift, deletion and nonsense mutations in BCOR in seven families affected with OFCD. Like wild-type BCOR, BCOR P85L and an OFCD-mutant form of BCOR can interact with BCL-6 and efficiently repress transcription. This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6. We cloned the zebrafish (Danio rerio) ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations of the eye, skeleton and central nervous system consistent with the human syndromes, confirming that BCOR is a key transcriptional regulator during early embryogenesis.

Personalized genomic medicine: lessons from the exome.

While genomic sequencing methods are powerful tools in the discovery of the genetic underpinnings of human disease, incidentally-revealed novel genomic risk factors may be equally important, both scientifically, and as relates to direct patient care. We performed whole-exome sequencing on a child with VACTERL association who suffered severe post-surgical neonatal pulmonary hypertension, and identified a potential novel genetic risk factor for this complication: a heterozygous mutation in CPSI. Newborn screening results from this patient's monozygotic twin provided evidence that this mutation, in combination with an environmental trigger (in this case, surgery), may have resulted in pulmonary artery hypertension due to inadequate nitric oxide production. Identification of this genetic risk factor allows for targeted medical preventative measures in this patient as well as relatives with the same mutation, and illustrates the power of incidental medical information unearthed by whole-exome sequencing.

A broad range of ophthalmologic anomalies is part of the holoprosencephaly spectrum.

Holoprosencephaly (HPE) is the most common disorder of the developing forebrain in humans, and is characterized by failed or incomplete cleavage of the cerebral hemispheres and deep brain structures. HPE includes wide phenotypic variability, with a continuum of both brain and craniofacial anomalies. While "classic" eye findings, including the spectrum of midline anomalies ranging from cyclopia to hypotelorism, as well as chorioretinal coloboma and microphthalmia, have been frequently described in patients with HPE, other subtle eye anomalies may also occur. In our study we prospectively analyzed a small cohort of 10 patients in whom we identified mutations in SHH, SIX3, ZIC2, or FGF8, the latter of which is a very recently described HPE-associated gene. We found that 9 of 10 patients had at least two ophthalmologic anomalies, including refractive errors, microcornea, microphthalmia, blepharoptosis, exotropia, and uveal coloboma. These findings contribute to the understanding of the phenotypic variability of the HPE spectrum, and highlight findings in one medically important but often incompletely investigated system.

De novo deletion of chromosome 20q13.33 in a patient with tracheo-esophageal fistula, cardiac defects and genitourinary anomalies implicates GTPBP5 as a candidate gene.

BACKGROUND: Tracheo-esophageal fistula (TEF) with/or without esophageal atresia (EA) is a common congenital malformation that is often accompanied by other anomalies. The causes of this condition are thought to be heterogeneous but are overall not well understood. CASE REPORT: We identified a patient with a TEF/EA, as well as cardiac and genitourinary anomalies, who was found to have a 0.7 Mb de novo deletion of chromosome 20q13.33. One gene within the deleted interval, GTPBP5, is of particular interest as a candidate gene. CONCLUSIONS: GTPBP5 bears further study as a cause of TEF/EA accompanied by other malformations.

Understanding patterns of health communication in families at risk for hereditary nonpolyposis colorectal cancer: examining the effect of conclusive versus indeterminate genetic test results.

In families meeting criteria for hereditary nonpolyposis colorectal cancer (HNPCC), genetic testing may or may not identify a mutation. Communication about genetic testing and risk in families with identified HNPCC mutations is associated with individual and relational factors. Similar communication patterns would be expected in families with similar clinical and pathological characteristics, but without an identified HNPCC mutation; however, previous studies have not included such families. Social network analysis was used to compare communication networks and associated individual and relational factors in families with and without identified HNPCC mutations. Respondents from families without identified mutations communicated about genetic counseling and testing and risk for HNPCC with a significantly smaller proportion of network members, compared to respondents from mutation-positive families. Members of families without identified mutations were also more likely to share thoughts about risk for HNPCC with network members whose advice they take, compared to members of families with known mutations. These findings extend our knowledge of communication in families at risk of HNPCC to include the many families in which a causative mutation has not yet been identified. Differences in the breadth of communication about genetics and risk for HNPCC, and the possibility that members of families without identified mutations may seek advice from those with whom they communicate about risk, provide new avenues for future research. Understanding existing communication patterns could help improve education and counseling processes, and facilitate the development of interventions designed to assist in family discussions of risk.

Generation after generation: exploring the psychological impact of providing genetic services through a cascading approach.

PURPOSE: The provision of genetic services often occurs in a cascading fashion within families experiencing inherited diseases. This study examines whether previous family experiences with genetic services influences levels of psychological well-being of family members receiving services later. METHODS: Two hundred ninety-seven persons from 38 families with Lynch syndrome completed questionnaires before receiving genetic services. Baseline levels of test-related distress, depressive symptoms, and cancer worries were assessed in relationship to the (1) amount of time elapsed since services were provided to the index case and (2) generation of the family member relative to the index case. RESULTS: Family members in the same generation as the index case experienced significant increases in test-related distress (P = 0.003) and cancer worry (P = 0.001) with increasing time between receipt of genetic test results by the index case and provision of services to family members. Change in the number of depressive symptoms was not significant (P = 0.17). CONCLUSION: The provision of genetic services through a cascading approach significantly increases distress and worry among family members within the same generation as the index case who receive services at increasingly distant time intervals. Additional research is needed to explore social influences after the introduction of genetic services.

Explanations of risk in families without identified mutations for hereditary nonpolyposis colorectal cancer.

PURPOSE: Genetic testing for hereditary forms of cancer does not always identify a causative mutation. Little is known about personal or family response to these indeterminate results when a hereditary form of cancer is suspected. This study explored thoughts about and responses to risk for hereditary nonpolyposis colorectal cancer (HNPCC) when a family member has received indeterminate genetic test results. DESIGN: In this qualitative study, data were gathered from index cases who received indeterminate genetic test results through a longitudinal study offering genetic counseling and testing for HNPCC. First-degree relatives of these indeterminate index cases were also invited to participate in the qualitative interview. METHODS: Semistructured telephone interviews were conducted with index cases and their at-risk first-degree relatives. Data were analyzed using the within- and across-case method. FINDINGS: The across-case analysis led to the development of the Awareness and Surveillance Trajectory, which describes individual interpretations of and responses to risk, based on personal and family history. Explanations of risk addressed the meaning of cancer in the family and provided context for individual interpretations. They were identified using within-case analysis and organized into a typology: innate, exceptional, idiosyncratic, and undeveloped explanations. CONCLUSIONS: Members of families without identified HNPCC mutations vary in their explanations for, interpretations of, and responses to indeterminate genetic test results. CLINICAL RELEVANCE: Explanations of family risk and interpretations of individual risk offer healthcare providers valuable information. In combination with the Awareness and Surveillance Trajectory, assessment of these beliefs can facilitate development of individualized recommendations and strategies for possible preventive actions.