Clinical genetics in transition-a comparison of genetic services in Estonia, Finland, and the Netherlands.

Genetics has traditionally enabled the reliable diagnosis of patients with rare genetic disorders, thus empowering the key role of today's clinical geneticists in providing healthcare. With the many novel technologies that have expanded the genetic toolkit, genetics is increasingly evolving beyond rare disease diagnostics. When placed in a transition context-like we do here-clinical genetics is likely to become a fully integral part of future healthcare and clinical genetic expertise will be required increasingly outside traditional clinical genetic settings. We explore transition effects on the thinking (culture), organizing (structure), and performing (practice) in clinical genetics, taking genetic healthcare in Estonia, Finland, and the Netherlands as examples. Despite clearly distinct healthcare histories, all three countries have initially implemented genetic healthcare in a rather similar fashion: as a diagnostic tool for predominantly rare congenital diseases, with clinical geneticists as the main providers. Dynamics at different levels, such as emerging technologies, biobanks and data infrastructure, and legislative frameworks, may require development of a new system attuned with the demands and (historic) context of specific countries. Here, we provide an overview of genetic service provisions in Estonia, Finland, and the Netherlands to consider the impact of historic and recent events on prospective developments in genetic healthcare.

"I would like to discuss it further with an expert": a focus group study of Finnish adults' perspectives on genetic secondary findings.

Lowered costs of genomic sequencing facilitate analyzing large segments of genetic data. Ethical debate has focused on whether and what kind of incidental or secondary findings (SFs) to report, and how to obtain valid informed consent. However, people's support needs after receiving SFs have received less attention. We explored Finnish adults' perspectives on reporting genetic SFs. In this qualitative study which included four focus group discussions (N = 23) we used four vignette letters, each reporting a genetic SF predisposing to a different disease: familial hypercholesterolemia, long QT syndrome, Lynch syndrome, and Li-Fraumeni syndrome. Transcribed focus group discussions were analyzed using inductive thematic analysis. Major themes were immediate shock, dealing with worry and heightened risk, fear of being left alone to deal with SFs, disclosing to family, and identified support needs. Despite their willingness to receive SFs, participants were concerned about being left alone to deal with them. Empathetic expert support and timely access to preventive care were seen as essential to coping with shock and worry, and disclosing SFs to family. Discussion around SFs needs to concern not only which findings to report, but also how healthcare systems need to prepare for providing timely access to preventive care and support for individuals and families.

APOE and AGT in the Finnish p.Arg133Cys CADASIL population.

BACKGROUND: CADASIL is an inherited systemic small vessel disease, the affected status of brain vessels leading to subcortical vascular dementia. The defective gene is NOTCH3 in which over 230 different pathogenic mutations have been identified. The clinical course of CADASIL is highly variable even within families. Previous studies have shown that additional genetic factors modify the phenotype. AIMS AND METHODS: Altogether, 134 Finnish CADASIL patients with p.Arg133Cys mutation were analysed for possible associations between the apolipoprotein E (APOE) genotype, angiotensinogen (AGT) p.Met268Thr polymorphism or neutral p.Ala202Ala NOTCH3 polymorphism and earlier first-ever stroke or migraine. RESULTS: We found no association between the APOE genotypes, AGT polymorphism, NOTCH3 polymorphism and earlier first-ever stroke or migraine. CONCLUSIONS: The APOE, AGT and NOTCH3 polymorphism did not modify the onset of strokes or migraine in our CADASIL sample, which is one of the largest mutationally homogenous CADASIL populations published to date. International collaboration, pooled analyses and genomewide approaches are warranted to identify the genetic factors that modify the highly variable CADASIL phenotype.

The return of unexpected research results in a biobank study and referral to health care for heritable long QT syndrome.

BACKGROUND: In this study, we examined how biobank study participants, who were found to have long QT syndrome (LQTS), a potentially life-threatening but treatable cardiac arrhythmia condition, experienced the process of disclosure of unexpected results and referral to health care. METHODS: All 27 subjects with a LQTS mutation finding were asked to complete a questionnaire. Four participants did not uptake the re-testing and 5 others did not respond to the questionnaire. We received 17 questionnaires from 6 males and 11 females, aged 46-82; 5 of them were also willing to participate in qualitative interviews. RESULTS: Of the respondents, 16/17 had experienced the process of receiving the results as positive and useful, especially if they had had symptoms. One respondent experienced the process negatively due to concerns related to informing her children. All respondents felt that genetic results should be reported back to the participants, while 2 indicated that this should occur only in the case of treatable conditions. Respondents had informed all of their children about the genetic condition, except 2 minors. CONCLUSIONS: The respondents from a population biobank study who were informed about an unexpected genetic finding evaluated this process as mainly positive. They considered that delivering genetic information about a life-threatening but actionable condition has more beneficial than adverse consequences. The feedback policy for biobanks should include how and who is informed, advise treatment or care pathways for actionable findings, and it should also include suitable options for those who do not want to know about such findings.

Genetic screening in Europe.

Genetic screening has been defined as any kind of test performed systematically for the early detection or exclusion of a genetic disease, genetic predisposition or resistance to a disease, or to determine whether a person carries a gene variant that may produce disease in his or her offspring. In comparison to 'genetic testing', the term 'genetic screening' should be reserved for the explicit and systematic application of a diagnostic genetic test across a whole population of asymptomatic people (population screening) or a subset of a population such as pregnant women (prenatal/antenatal screening) or newborn infants (neonatal screening). This survey intends to present the current (2006-2008) status of genetic screening and the organization of genetic screening programmes in selected European countries as a background for future attempts to harmonize standards and procedures of genetic screening, an explicit aim of the European Network of Excellence, EuroGentest (www.eurogentest.org). Our report builds on the first comprehensive assessment of genetic screening programmes in Germany by the European Society of Human Genetics, starting with a workshop of experts in 1999, the production of background documentation in 2000, and a final report in 2003.

Direct contact in inviting high-risk members of hereditary colon cancer families to genetic counselling and DNA testing.

BACKGROUND: Identification of hereditary predisposition to cancer has limited significance if not followed by efficient cancer prevention in the family. Probands are traditionally left to inform their relatives about the increased risk, but distant relatives may remain uninformed. An approach to contacting directly at-risk persons assumed to be unaware of their increased cancer risk was taken. With cancer prevention as the ultimate goal, the study was aimed at investigating attitudes towards and psychosocial consequences of this novel strategy. METHODS: In families with hereditary non-polyposis colorectal cancer (Lynch syndrome), 286 healthy adult relatives with a 50% risk of a predisposing mutation were contacted by letter. Of these, 112 participated in counselling and predictive testing. Baseline information and information obtained 1 month after the test for 73 respondents were compared with 299 corresponding subjects, approached via the proband (family-mediated approach in our previous study) in these families. RESULTS: After the contact letter, 51% consented to the study. Of these, 92% approved of the direct contact and 33% had tried to seek information. In 34% of the mutation carriers, neoplasia was identified in the first post-test colonoscopy. Although post-test fear of cancer increased among the mutation carriers and decreased among noncarriers, almost all participants were satisfied with their decision to participate, independently of their test results, parallel to the family-mediated approach. CONCLUSION: In this large-scale study, relatives in cancer families were actively contacted to inform them of the condition and genetic counselling. Their attitudes were encouraging, and the psychosocial consequences were similar to the family-mediated approach. Our results suggest the appropriateness of direct contact as an alternative method of contact in cases of life-threatening treatable disease.

Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia.

Epidemiological studies have consistently shown elevated rates of breast cancer among female blood relatives of patients with ataxia telangiectasia (AT), a rare autosomal recessive disease. A large proportion of the members of AT families are carriers of AT-causing gene mutations in ATM (Ataxia Telangiectasia Mutated), and it has been hypothesised that these otherwise healthy carriers are predisposed to breast cancer. This is an extended and enlarged follow-up study of cancer incidence in blood relatives of 75 patients with verified AT in 66 Nordic families. Blood relatives were identified through population registry linkages, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. The ATM mutation carrier probabilities of relatives were assigned from the combined information on location in family, consanguinity, if any, and supplementary carrier screening in some families. Among the 1445 blood relatives of AT patients, 225 cancers were observed, with 170.4 expected, yielding a standardised incidence ratio (SIR) of 1.3 (95% confidence interval (CI), 1.1-1.4). Invasive breast cancer occurred in 34 female relatives (SIR, 1.7; 95% CI, 1.2-2.4) and was diagnosed in 21 women before the age of 55 years (SIR, 2.9; 95% CI, 1.8-4.5), including seven mothers of probands (SIR, 8.1; 95% CI, 3.3-17). When the group of mothers was excluded, no clear relationship was observed between the allocated mutation carrier probability of each family member and the extent of breast cancer risk. We concluded that the increased risk for female breast cancer seen in 66 Nordic AT families appeared to be restricted to women under the age of 55 years and was due mainly to a very high risk in the group of mothers. The findings of breast cancer risk in mothers, but not other likely mutation carriers, in this and other studies raises questions about the hypothesis of a simple causal relationship with ATM heterozygosity.

Genetic testing for maturity onset diabetes of the young: uptake, attitudes and comparison with hereditary non-polyposis colorectal cancer.

AIMS/HYPOTHESIS: Mutations in hepatic nuclear factor 1alpha cause a monogenic form of diabetes, maturity onset diabetes of the young type 3 (MODY3). Our aim was (1) to assess the uptake of genetic testing for MODY3 and to determine factors affecting it, and (2) to compare attitudes to predictive genetic testing between families with MODY3 and a previously studied group at risk of hereditary non-polyposis colorectal cancer (HNPCC). METHODS: Adult members of two extended MODY3 pedigrees, either with diabetes or a 50% risk of having inherited the mutation (n=144, age 18-60 years), were invited to an educational counselling session followed by a possibility to obtain the gene test result. Data were collected through questionnaires before counselling and 1 month after the test disclosure. RESULTS: Eighty-nine out of 144 (62%) participated in counselling, and all but one wanted the test result disclosed. No significant sociodemographic differences were observed between the participants and non-participants. The counselling uptake was similar among diabetic and non-diabetic subjects. Uncertainty about the future and the risk for the children were the most common reasons to take the gene test. At follow-up, most subjects in both MODY3 (100%) and HNPCC (99%) families were satisfied with their decision to take the test and trusted the result. The majority of both diabetic and non-diabetic subjects considered that the MODY3 gene test should be offered either in childhood (50 and 37%) or as a teenager (30 and 37%). CONCLUSIONS: Genetic testing for MODY3 was well accepted among both diabetic and non-diabetic participants. The subjects found the gene test reliable and they were satisfied with their decision regarding the predictive test.

New options for prenatal diagnosis in autosomal recessive polycystic kidney disease by mutation analysis of the PKHD1 gene.

Due to the poor prognosis of severe autosomal recessive polycystic kidney disease (ARPKD), there is a strong demand for prenatal diagnosis (PD). Reliable PD testing is possible by molecular genetic analysis only. Although haplotype-based analysis is feasible in most cases, it is associated with a risk of misdiagnosis in families without pathoanatomically proven diagnosis. Linkage analysis is impossible in families where DNA of the index patient is not available. Direct mutation analysis of the recently identified polycystic kidney and hepatic disease 1 gene opens new options in families to whom a reliable PD cannot be offered on the basis of linkage analysis. We for the first time report two cases with PD based on mutation detection, illustrating the new options for PD in ARPKD.

Valproate embryopathy in three sets of siblings: further proof of hereditary susceptibility.

The fetal valproate syndrome (FVS) is characterized by distinctive facial appearance, major and minor malformations, and developmental delay. Generally, only a small proportion of prenatally exposed children are affected. The authors describe three families in whom the occurrence of FVS in all the siblings strongly suggests hereditary susceptibility to valproic acid-induced adverse outcome. The risk for recurrence in a subsequent pregnancy may be high and should be taken into account in the counseling of parents and in considering drug treatment.

Psychological consequences of predictive genetic testing for hereditary non-polyposis colorectal cancer (HNPCC): a prospective follow-up study.

Predictive genetic testing for cancer allows identification of those with the mutation (mutation positive) who should undergo cancer surveillance aiming at early detection of cancer and those without the mutation (mutation negative), whose unnecessary worry can be alleviated and who need not undergo frequent surveillance. However, there is a risk that predictive testing might have a harmful emotional impact on an individual. In the course of a predictive genetic testing protocol, we assessed general anxiety (by the State-Trait Anxiety Inventory [STAI]), fear of cancer and death, satisfaction with life and attitude to the future using a questionnaire survey in 271 individuals tested for hereditary non-polyposis colorectal cancer (HNPCC). Measurements were made before the first counseling (baseline), at the test disclosure session (STAI only) and 1 and 12 months after disclosure. Although at every measurement, the mutation-positive individuals were more afraid of cancer than those who were mutation negative, in both groups fear of cancer decreased significantly from baseline after disclosure. The mutation-positive subjects were more anxious than their counterparts immediately after the test disclosure, but the differences had disappeared at the follow-ups. In other variables, neither differences between the groups defined by mutation status nor changes with time were detected. Our findings suggest that counseling and testing relieve fear of cancer; no harmful emotional impact was detectable at the 1-year follow-up. To confirm these findings, however, the impact of testing should be studied after a longer interval. Furthermore, to evaluate the ultimate interpretation of these results, studies are needed to investigate the impact of fear of cancer on surveillance behavior among the mutation-positive subjects.

Localization of a susceptibility gene for familial nonmedullary thyroid carcinoma to chromosome 2q21.

The familial form of nonmedullary thyroid carcinoma (NMTC) is a complex genetic disorder characterized by multifocal neoplasia and a higher degree of aggressiveness than its sporadic counterpart. In a large Tasmanian pedigree (Tas1) with recurrence of papillary thyroid carcinoma (PTC), the most common form of NMTC, an extensive genomewide scan revealed a common haplotype on chromosome 2q21 in seven of the eight patients with PTC. To verify the significance of the 2q21 locus, we performed linkage analysis in an independent sample set of 80 pedigrees, yielding a multipoint heterogeneity LOD score (HLOD) of 3.07 (alpha=0.42), nonparametric linkage (NPL) 3.19, (P=.001) at marker D2S2271. Stratification based on the presence of at least one case of the follicular variant of PTC, the phenotype observed in the Tas1 family, identified 17 such pedigrees, yielding a maximal HLOD score of 4.17 (alpha=0.80) and NPL=4.99 (P=.00002) at markers AFMa272zg9 and D2S2271, respectively. These results indicate the existence of a susceptibility locus for familial NMTC on chromosome 2q21.

Hirschsprung disease, mental retardation and dysmorphic facial features in five unrelated children.

We report five patients with Hirschsprung disease, severe mental retardation and dysmorphic facial features including hypertelorism, prominent forehead and dysmorphic ears. All four boys had hypospadias. All had postnatally retarded growth. One of them had a de novo apparently balanced translocation 46,XY,t(2;11)(q22.2;q21). There are several reports on patients with Hirschsprung disease, mental retardation and various dysmorphic features. Some of them, especially those reported by Tanaka et al. [(1993) Pediatr Neurol 9:479-481], Lurie et al. [(1994) Genet Couns 5:11-14] and Mowat et al. [(1998) J Med Genet 35:617-623] closely resemble our patients suggesting that they have the same malformation syndrome.

Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease.

Hirschsprung disease (HD) has been described in association with microcephaly, mental retardation and characteristic facial features, delineating a syndrome possibly caused by mutations localized at chromosome 2q22--q23. We have analyzed a de novo translocation breakpoint at 2q22 in one patient presenting with this syndrome, and identified a gene, SIP1, which is disrupted by this chromosomal rearrangement. SIP1 encodes Smad interacting protein 1, a new member of the delta EF1/Zfh-1 family of two-handed zinc finger/homeodomain transcription factors. We determined the genomic structure and expression of the human SIP1 gene. Further analysis of four independent patients showed that SIP1 is altered by heterozygous frameshift mutations causing early truncation of the protein. SIP1, among other functions, seems to play crucial roles in normal embryonic development of neural structures and neural crest. Its deficiency, in altering function of the TGF beta/BMP/Smad-mediated signalling cascade, is consistent with some of the dysmorphic features observed in this syndrome, in particular the enteric nervous system defect that underlies HD.

Nephronophthisis and ulcerative colitis in siblings: a new association.

Nephronophthisis (NPH) is a chronic tubulointerstitial nephritis leading to terminal renal insufficiency. The disease is heterogeneous, but usually the inheritance pattern is autosomal recessive. In 80% of cases, the disease is caused by a homozygous deletion in NPHP1 gene in chromosome 2q13. Ulcerative colitis is an inflammatory bowel disease with chronic diarrhea, rectal bleeding and characteristic histological findings. Its etiology is suggested to be multifactorial, consisting of genetic susceptibility and unknown exogenous factors. We present two siblings with NPH and ulcerative colitis. As NPH in this family is not linked to 2q13, this association may represent a new, syndromic form of NPH.

Involvement of BRCA1 and BRCA2 in breast cancer in a western Finnish sub-population.

To date, two major familial breast cancer predisposition genes, BRCA1 and BRCA2, have been identified with hundreds of germ-line mutations, accounting for 5--10% of all breast cancer and 40--60% of all inherited breast cancer. Unexpectedly elevated incidence of breast cancer, especially in the older age classes, was observed in a Western Finnish region representing a relatively homogeneous population. This study was designed to test the hypothesis that there are inherited BRCA1 or BRCA2 mutations, which confer variable and/or age-dependent penetrance on carriers. Expecting a founder effect, we searched for geographical clustering of breast cancer cases and searched for associations between the affected phenotype and shared genomic segments in the BRCA1 and BRCA2 genomic regions. Our haplotype association study did not reveal any founder effects for either BRCA1 or BRCA2. However, there were two mutations prevalent in this geographical area with minor founder effects, BRCA2 T8555G and 999del5. This is one of the few geographically ascertained, population-based studies that indicate an overall frequency of BRCA1 and BRCA2 mutations at about 2--3% in all breast cancer cases. The geographical clustering of breast cancer cases was not explained by BRCA1 or BRCA2 genes.

Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries.

BACKGROUND: Epidemiologic studies of the families of patients with ataxia-telangiectasia (A-T), a recessive genetic neurologic disorder caused by mutation of the ATM gene, suggest that heterozygous carriers of an ATM mutation are at increased risk of cancer. A population-based study of cancer incidence in A-T families with unbiased selection and tracing of relatives would confirm this hypothesis. METHODS: We conducted a study in the Nordic countries of 1218 blood relatives of 56 A-T patients from 50 families. The relatives were identified from population registries, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. All statistical tests were two-sided. RESULTS: Among the 56 patients with A-T, we observed six cases of cancer (four leukemias and two non-Hodgkin's lymphomas) compared with 0.16 expected, yielding a standardized incidence ratio (SIR) of 37 (95% confidence interval [CI] = 13 to 80). Among the 1218 relatives, 150 cancers were recorded, with 126 expected (SIR = 1.19; 95% CI = 1.01 to 1.40). Invasive breast cancer occurred in 21 female relatives of A-T patients (SIR = 1.54; 95% CI = 0.95 to 2.36), including five of the 50 mothers (all of whom are obligate ATM mutation carriers) (SIR = 7.1; 95% CI = 2.3 to 17). Relatives who were less likely to be carriers of a mutant ATM allele had no increase or only a modest, statistically nonsignificant increase in the risk of breast cancer. There was no evidence of increased risk for cancer at any other site. CONCLUSIONS: We confirmed the previously recognized high risk of lymphoma and leukemia in A-T patients. Our data are also consistent with an increased risk of breast cancer among blood relatives of A-T patients. The epidemiologic findings suggest, however, that, even if ATM mutations are responsible for some breast cancer cases, ATM is a relatively weak genetic risk factor for the disease.