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.

Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen.

Autosomal recessive polycystic kidney disease (ARPKD) is one of the major hereditary nephropathies in children predominantly presenting in early childhood. The clinical picture is variable but there is a fatal outcome in many cases. We have performed linkage analysis in 16 ARPKD families and localized the ARPKD gene to chromosomal region 6p21-cen with no evidence for genetic heterogeneity among different clinical phenotypes. Linkage was confirmed using six adjacent microsatellite markers and the highest lod score of 7.42 was obtained with D6S272 at theta = 0.00. Our findings should lead to more accurate forms of prenatal diagnosis than those currently available using ultrasound.

A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10.

Hirschsprung disease (HSCR) is a frequent congenital disorder (1 in 5,000 newborns) of unknown origin characterized by the absence of parasympathetic intrinsic ganglion cells of the hindgut. Taking advantage of a proximal deletion of chromosome 10q (del 10q11.2-q21.2) in a patient with total colonic aganglionosis, and of a high-density genetic map of microsatellite DNA markers, we performed genetic linkage analysis in 15 non-syndromic long-segment and short-segment HSCR families. Multipoint linkage analysis indicated that the most likely location for a HSCR locus is between loci D10S208 and D10S196, suggesting that a dominant gene for HSCR maps to 10q11.2, a region to which other neural crest defects have been mapped.

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.

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.

"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.

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.

Population-based molecular detection of hereditary nonpolyposis colorectal cancer.

PURPOSE: Cancer morbidity and mortality can be dramatically reduced by colonoscopic screening of individuals with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, creating a need to identify HNPCC. We studied how HNPCC identification should be carried out on a large scale in a sensitive and efficient manner. PATIENTS AND METHODS: Colorectal cancer specimens from consecutive newly diagnosed patients were studied for microsatellite instability (MSI). Germline mutations in the MLH1 and MSH2 genes were searched for in MSI(+) individuals. RESULTS: Among 535 colorectal cancer patients, 66 (12%) were MSI(+). Among these, 18 (3.4% of the total) had disease-causing germline mutations in MLH1 or MSH2. Among these 18 patients, five were less than 50 years old, seven had a previous or synchronous colorectal or endometrial cancer, and 15 had at least one first-degree relative with colorectal or endometrial cancer. Notably, 17 (94%) of 18 patients had at least one of these three features, which were present in 22% of all 535 patients. Combining these data with a previous study of 509 patients, mutation-positive HNPCC accounts for 28 (2.7%) of 1,044 cases of colorectal cancer, predicting a greater than one in 740 incidence of mutation-positive individuals in this population. CONCLUSION: Large-scale molecular screening for HNPCC can be done by the described two-stage procedure of MSI determination followed by mutation analysis. Efficiency can be greatly improved by using three high-risk features to select 22% of all patients for MSI analysis, whereby only 6% need to have mutation analysis. Sensitivity is only slightly impaired by this procedure.

Spectrum of COL4A5 mutations in Finnish Alport syndrome patients.

Alport syndrome (AS) is a hereditary kidney disorder, mainly caused by mutations in the X-chromosomal gene (COL4A5) encoding the type IV collagen a5 chain. In this study, detection of COL4A5 mutations was performed in 17 Finnish Alport syndrome families. Regions around the 51 previously known exons, as well as the two recently characterized exons 41A and 41B in COL4A5, were PCR-amplified from the patient DNA. Direct sequencing of the amplified products was performed and mutations were found in 12 families. None of the mutations involved exons 41A or 41B. Three of the mutations were potential splicing mutations, two of which were studied at the mRNA level. Seven of the mutations were single base substitutions, and two were deletions. In five families, no mutations were found.

Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.

The Ataxia Telangiectasia Mutation (ATM) gene is mutated in the rare recessive syndrome Ataxia Telangiectasia (AT), which is characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. In this study, 41 AT families from Denmark, Finland, Norway, and Sweden were screened for ATM mutations. The protein truncation test (PTT), fragment length and heteroduplex analyses of large (0.8-1.2 kb) cDNA fragments were used. In total, 67 of 82 (82%) of the disease-causing alleles were characterized. Thirty-seven unique mutations were detected of which 25 have not previously been reported. The mutations had five different consequences for the ATM transcript: mutations affecting splicing (43%); frameshift mutations (32%); nonsense mutations (16%); small in-frame deletions (5%); and one double substitution (3%). In 28 of the probands mutations were found in both alleles, in 11 of the probands only one mutated allele was detected, and no mutations were detected in two Finnish probands. One-third of the probands (13) were homozygous, whereas the majority of the probands (26) were compound heterozygote with at least one identified allele. Ten alleles were found more than once; one Norwegian founder mutation constituted 57% of the Norwegian alleles. Several sequence variants were identified, none of them likely to be disease-causing. Some of them even involved partial skipping of exons, leading to subsequent truncation of the ATM protein.

Nephronophthisis in Finland: epidemiology and comparison of genetically classified subgroups.

Nephronophthisis--medullary cystic kidney disease is a progressive chronic tubulointerstitial nephritis leading to terminal renal failure. About two thirds of the patients with familial juvenile nephronophthisis, an autosomal recessive disease, have a homozygous deletion at the gene locus on 2q13. Through a nationwide search, 59 patients were ascertained in Finland. The incidence was 1:61,800 live births when calculated over a 20-year period. Of the patients, 17 came from four families showing dominant inheritance and 37 patients from 28 apparently recessive families when classified by family history, clinical features or presence of a deletion on 2q13. Two were considered as new dominant mutations; three sporadic patients could not be classified. The most significant difference between the patients with deletions, patients without deletions but having recessive family history, and patients belonging to families with dominant inheritance was the age at first symptoms, at the start of dialysis and at transplantation. These facts will be of help in determining the mode of inheritance of a sporadic patient without a deletion.

Tibial muscular dystrophy. Late adult-onset distal myopathy in 66 Finnish patients.

OBJECTIVE: To clarify the classification of two previously reported groups of patients with anterior tibial distal dystrophy, to find additional patients with the disease, and to describe the clinical features of this disease. DESIGN: National survey of the records of patients with neuromuscular diseases in Finland. Findings of selected patients were compared with those of previously reported cases. PATIENTS: Thirty-six previously described patients and 30 additional patients from the current survey, with 41 symptomatic patients and 25 subjectively asymptomatic affected relatives. RESULTS: There were 66 patients with late adult-onset tibial muscular dystrophy. Symptoms appear after the age of 35 years with reduced ankle dorsiflexion, and progress is slow without marked disability. Facial muscles, upper extremities, and proximal muscles are usually spared. Muscle biopsy results reveal nonspecific dystrophic changes in clinically affected muscles, and frequently severe adipose replacement in the anterior tibial muscles occurs. Asymptomatic muscles have mild myopathic changes only. Vacuolar degeneration is detected in a minority of patients. Electromyography shows profound myopathic changes in the anterior tibial muscle, but extensor brevis muscles are well preserved. Computed tomography or magnetic resonance imaging of muscles discloses marked involvement of tibial extensor muscles and focal patches of fatty degeneration in various asymptomatic muscles. Pedigree data suggest autosomal dominant inheritance. CONCLUSIONS: Tibial muscular dystrophy might represent a new form of distal myopathy and it is rather common, at least in Finland.

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.

Bone dysplasia, midface hypoplasia, and deafness: three new patients and review of the literature.

We report on 3 unrelated patients with a syndrome of sensorineural deafness (3/3), midface hypoplasia (3/3), disproportionate shortness with short limbs (3/3), cleft palate or bifid uvula (3/3), and lack of high myopia (3/3). This brings the number of reported patients with this condition to 11. Different names such as oto-spondylo-megaepiphyseal dysplasia (OSMED) or the Insley-Astley syndrome have been used. We propose the name "syndrome of bone dysplasia, midface hypoplasia, and deafness" which lists the 3 main manifestations of the condition.

RAPADILINO syndrome with radial and patellar aplasia/hypoplasia as main manifestations.

A new malformation syndrome is described in a pair of sibs and 3 sporadic patients. The characteristic manifestations are radial aplasia or hypoplasia, absence of thumbs, absent or hypoplastic patellae, dislocations of joints, unusual face, cleft or highly arched palate, diarrhea in infancy, small stature, and normal intelligence. Recessive inheritance seems the most plausible cause. The acronym RAPADILINO syndrome is proposed.

Congenital scalp defects with distal limb anomalies (Adams-Oliver syndrome): report of ten cases and review of the literature.

We describe one family with 5 affected persons in 4 generations, another family with 2 affected brothers and 3 sporadic cases of the rare syndrome of congenital scalp defects with distal limb deficiency. The manifestations of this syndrome are highly variable. Review of the literature showed 11 families and 19 sporadic cases. In most families the disorder clearly follows an autosomal dominant pattern of inheritance, but in some families with reduced penetrance. Important differential diagnoses are the syndrome of scalp defect and postaxial polydactyly, the syndrome of scalp defect and split-hand defect, amniotic band sequence, and epidermolysis bullosa dystrophica type Bart.

Familial congenital diaphragmatic defects: aspects of etiology, prenatal diagnosis, and treatment.

We present 14 familial cases from five Finnish families affected with a life-threatening congenital diaphragmatic defect (CDD) and review data on 53 previously published familial cases. CDD occurred in three sibs and their half brother's son, and probably in all four offspring of parents consanguineous as both first and second cousins. In the remaining three Finnish families and in the vast majority of the previously reported familial cases, only two sibs were affected. Two thirds of those affected were males both in the Finnish and the overall series. Pedigree data, delayed fusion of the diaphragm as the primary pathogenetic mechanism, varying anatomical structure of the defective hemidiaphragm, association with other congenital anomalies, and data on animal experiments are more in accordance with multifactorial determination than with recessive inheritance. This does not exclude other genetic causes in some familial cases. The recurrence risk for sibs after one affected sib is about 2%. As the prognosis, especially in familial cases of CDD has remained grave, the development of fetal surgical treatment is desirable. This emphasizes the future role of prenatal diagnosis by ultrasound.

Complete maternal isodisomy of chromosome 8 in an individual with an early-onset ileal carcinoid tumor.

Uniparental disomy (UPD) is a condition in which diploid individuals possess a chromosome pair from a single parent. In some instances, UPD causes an abnormal phenotype due to imprinting effects, reduction to homozygosity at recessive disease loci, or trisomy mosaicism. Here we report the first account of an individual with apparently nonmosaic complete maternal isodisomy of chromosome 8. This individual was identified during routine genotyping in a genomewide search for type 2 diabetes susceptibility genes, although he does not have diabetes. He is of normal appearance, stature, and intelligence, but there is an unusual history of early onset ileal carcinoid. The discovery of other maternal UPD 8 cases will be necessary to define whether this condition causes a distinct phenotype.

Polycystic kidney disease. Morphological diagnosis of recessive and dominant polycystic kidney disease in infancy and childhood.

Histological findings in 75 children with polycystic kidney disease were analysed. The patients had been divided into recessive (RPKD), dominant (DPKD), and sporadic cases on the basis of family investigations. The histological findings in the patients with RPKD and DPKD were compared with each other in order to define criteria for classification of the sporadic patients. The kidneys of the neonatally-deceased patients with RPKD (26 patients) and DPKD (4 patients) were macroscopically very similar. On histological investigation, all patients with RPKD (32 patients) showed cysts derived from the collecting ducts. In DPKD, the cyst epithelium was more variable, and the presence of glomerular cysts served as a useful histological marker of this disorder. In RPKD there was diffuse biliary dysgenesis, in contrast to the normal liver in the neonatally-deceased DPKD patients. However, one DPKD patient who survived also had biliary dysgenesis. Using the observed differences between RPKD and DPKD as criteria, all sporadic patients with satisfactory histological material could be classified as RPKD. We conclude that the differential diagnosis between RPKD and DPKD can be based on kidney and liver histology.