Expanding the genotypic spectrum of Perrault syndrome.

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D-bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease-causing genes remain unidentified. We have expanded the spectrum of disease-causing variants associated with Perrault syndrome.

Familial adenomatous polyposis: mental health, psychosocial functioning and reactions to genetic risk in adolescents.

Familial adenomatous polyposis (FAP) in a parent requires diagnostic follow-up and treatment from adolescence in possible gene carriers in order to prevent cancer development. A nationwide sample (n = 22) of adolescent FAP offspring including 85% of eligible individuals aged 11-20 years and their parents were interviewed with regard to adolescent mental health, psychosocial functioning, knowledge about FAP and genetic risk, and experiences with testing and surgery. Thirty-six percent of the FAP offspring fulfilled criteria for a psychiatric diagnosis. For adolescents older than 15 years, this was increased relative to a comparison group with Hirschprung's disease and a general population sample. Neither genetic testing nor FAP diagnosis in adolescent FAP-offspring differentiated significantly between those who fulfilled the criteria and those who did not for psychiatric diagnosis, while a global score of chronic family difficulties did. This may imply that experiencing parental illness more than inheriting FAP is a perceived stressor for adolescent FAP offspring.

High prevalence of Leptospira spp. in sewer rats (Rattus norvegicus).

Earlier studies on the ecology of leptospirosis in temperate regions focused mainly on free-ranging rats in rural areas. Here we report on the occurrence of Leptospira spp. in Rattus norvegicus living in sewers in a suburban area in Copenhagen, Denmark. In 2006-2007, about 30 rats were captured in sewers at each of six different locations. Rat kidneys were screened by PCR for pathogenic Leptospira spp. In one location no infected rats were found, whereas the prevalence in the remaining five locations ranged between 48% and 89%. Micro-agglutination tests showed that serogroup Pomona, Sejroe, and Icterohaemorrhagiae were the most common. Infection was related to age with the highest prevalence observed for adult rats but there was no difference in infection rate between sexes, suggesting primarily environmental transmission. Since most reported rat problems in urban areas are related to sewer rats, the surprisingly high level of infection calls for an increased public health concern.

Correlation between prenatal ultrasound and autopsy findings: A study of second-trimester abortions.

OBJECTIVE: To evaluate discrepancies between sonographic and autopsy findings following termination of pregnancy (TOP) in the second trimester. METHODS: This retrospective report is based on 288 consecutive second-trimester abortions carried out because of fetal malformations diagnosed by ultrasound examination at a tertiary referral center. The correlation between the results from the ultrasound and autopsy examinations was evaluated. RESULTS: Autopsy was performed in 274 cases. In 160 of the 274 pregnancies (58.4%) there was full agreement between the two examination methods. Findings detected by autopsy (in addition to those leading to termination) were not observed by ultrasonography in 86 (31.4%) of the pregnancies; of the 64 malformations that occurred, 30 (46.9%) were judged as 'detectable'. In 27 (9.9%) pregnancies, observations made by ultrasound (in addition to those leading to termination) were not confirmed at autopsy. In one pregnancy, postmortem radiology examination-but not autopsy-confirmed the ultrasound observations. No pregnancies were terminated because of false positive ultrasound observations. The correlation between ultrasound and autopsy findings was evaluated by three investigators; the inter-rater agreement was high (kappa = 0.85). CONCLUSION: Discrepancies between ultrasound and autopsy findings were observed in about 40% of the pregnancies. These discrepancies confirm the need for autopsy following TOP.

The impact of an early truncating founder ATM mutation on immunoglobulins, specific antibodies and lymphocyte populations in ataxia-telangiectasia patients and their parents.

Eleven Norwegian patients (aged 2-33 years, seven males and four females) with Ataxia-telangiectasia (A-T) and their parents were investigated. Five of the patients were homozygous for the same ATM mutation, 3245delATCinsTGAT, a Norwegian founder mutation. They had the lowest IgG2 levels; mean (95% confidence interval) 0.23 (0.05-0.41) g/l versus 0.91 (0.58-1.26) g/l in the other patients (P = 0.002). Among the 11 A-T patients, six had IgG2 deficiency, six had IgA deficiency (three in combination with IgG2 deficiency) and seven had low/undetectable IgE values. All patients had very low levels of antibodies to Streptococcus pneumoniae 0.9 (0.4-1.4) U/ml, while normal levels were found in their parents 11.1 (8.7-13.4) U/ml (P < 0.001). A positive linear relationship between pneumococcal antibodies and IgG2 (r = 0.85, P = 0.001) was found in the patients. Six of 11 had diphtheria antibodies and 7 of 11 tetanus antibodies after childhood vaccinations, while 4 of 7 Hemophilus influenzae type b (Hib) vaccinated patients had protective antibodies. Ten patients had low B cell (CD19+) counts, while six had low T cell (CD3+) counts. Of the T cell subpopulations, 11 had low CD4+ cell counts, six had reduced CD8+ cell counts, and four had an increased portion of double negative (CD3+/CD4-/CD8-) gamma delta T cells. Of the 22 parents (aged 23-64 years) 12 were heterozygous for the ATM founder mutation. Abnormalities in immunoglobulin levels and/or lymphocyte subpopulations were also observed in these carriers, with no correlation to a special ATM genotype.

[Aagenaes syndrome--lymphedema and intrahepatic cholestasis]. / Aagenaes' syndrom--lymfødem og intrahepatisk gallestase.

The combination of neonatal intrahepatic cholestasis and lymphoedema in feet and legs is a specific syndrome named after the Norwegian paediatrician Øystein Aagenaes, who described the syndrome in 1968. The condition is autosomal recessively inherited and the gene is located to 15q, but not yet identified. The condition is particularly frequent in the southern most part of Norway and the gene frequency is estimated to be about 3%. The development of small lymphoid vessels is probably deficient around the small biliary tracts and in general. Aagenaes' syndrome is found in patients from other parts of Europe and the US, but more than half of the cases are of Norwegian origin.

High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder whose hallmark is bilateral vestibular schwannoma. It displays a pronounced clinical heterogeneity with mild to severe forms. The NF2 tumor suppressor (merlin/schwannomin) has been cloned and extensively analyzed for mutations in patients with different clinical variants of the disease. Correlation between the type of the NF2 gene mutation and the patient phenotype has been suggested to exist. However, several independent studies have shown that a fraction of NF2 patients with various phenotypes have constitutional deletions that partly or entirely remove one copy of the NF2 gene. The purpose of this study was to examine a 7 Mb interval in the vicinity of the NF2 gene in a large series of NF2 patients in order to determine the frequency and extent of deletions. A total of 116 NF2 patients were analyzed using high-resolution array-comparative genomic hybridization (CGH) on an array covering at least 90% of this region of 22q around the NF2 locus. Deletions, which remove one copy of the entire gene or are predicted to truncate the schwannomin protein, were detected in 8 severe, 10 moderate and 6 mild patients. This result does not support the correlation between the type of mutation affecting the NF2 gene and the disease phenotype. This work also demonstrates the general usefulness of the array-CGH methodology for rapid and comprehensive detection of small (down to 40 kb) heterozygous and/or homozygous deletions occurring in constitutional or tumor-derived DNA.

[Genetic analysis in familial adenomatous polyposis]. / Genetiske analyser ved familiaer adenomatøs polypose.

BACKGROUND: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder caused by germline mutations in the APC gene. FAP is characterised by a variable, but normally large number of colorectal adenomas and variations in extracolonic manifestations. These variations are associated with specific mutations of the APC gene. MATERIAL AND METHODS: Representatives from 70 Norwegian families are under molecular investigation. Analyses have so far been concentrated on the part of the APC gene associated with classic FAP. RESULTS: Germline mutations causing FAP have been identified in 36 of the 70 families examined. All mutations identified are confined to the first half of the gene and correlate to classic FAP. INTERPRETATION: Because of the mutation heterogeneity in FAP, the size of the APC gene and variations in phenotype, it is a laborious task to identify the causative mutations. Better approaches to the analysis of the whole APC have now been established and will result in a higher degree of mutation detection independent of phenotype. Family history and phenotype-genotype correlations are still important guidelines for efficient molecular genetic analysis of the APC gene. Genetic surveillance, personal and socio-economic benefits from presymptomatic and predictive testing of members of FAP families are discussed.

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.

[Need of better knowledge of genetic tests among Norwegian physicians]. / Stort behov for kunnskap om gentester blant norske leger.

BACKGROUND: New predictive genetic tests are introduced in clinical work, and this means new tasks for the physician. MATERIAL AND METHODS: Every sixth member of the Norwegian Medical Association practising as a general practitioner, neurologist or psychiatrist (N = 732), were asked to answer a mailed, anonymous questionnaire about their attitudes to the new tasks. RESULTS: We obtained 451 (62%) answers. There were no significant differences between the various groups in the profession. So far, 54% had no patient in their practice who had taken a predictive genetic test. About two-thirds answered that the geneticist should inform about what is known about the consequences after a test result has been given. The general practitioner wants to do the follow-up. 97% of physicians think that the test result could lead to increased distress in various ways for the tested person or his/her family. Half of the physicians would advise taking a prenatal test if one of the parents had a known risk of an inherited disease and the foetus was at risk. Only 22% are in favour of abortion if the foetus has the gene in question. INTERPRETATION: The physicians (93%) do not think they have sufficient knowledge about predictive genetic tests to handle the information procedure on their own. They want courses in medical genetics, concise and relevant information from geneticists, and the possibility of consulting with specialists.

[Psychosocial consequences of presymptomatic genetic testing. A retrospective study of testing for Huntington disease]. / Psykososiale konsekvenser av presymptomatisk gentest. Etterundersøkelse ved Huntingtons sykdom.

We studied the psychological impact and psychosocial consequences of direct presymptomatic testing for Huntington's disease in Norway. We interviewed 30 out of a total of 43 persons at risk for Huntington's disease who had been tested one to three years earlier, and had been through the test program, and 19 of their spouses. We also included 16 persons at risk who had decided not to take the test. 22 persons were non-carriers, and seven carriers. One had decided not to know the answer so far. 13 out of 30 answered that the risk of getting Huntington's disease had influenced choices they had made in their lives, but quite a few did not know that they were at risk before they had grown up. Six couples out of 21 had divorced after the test; only three said it happened because of the test result. The main problem for many of the persons who now know they are non-carriers is that siblings already are sick or know they will get the disease. 15 persons (50%) experienced the need for some kind of psychiatric treatment during the pre-test period, during the test procedure, or after the test. Eight persons said they had wanted a closer follow-up after the test; most of them had got a negative answer. In this study most of those at risk had adapted reasonably well to the test results. Only seven persons out of 30 were found to be carriers in our study. We therefore have reason to believe that among the 13 tested persons who declined to be involved in the study, the majority had been identified as carriers. Our findings may lend support to a hypothesis suggesting two kinds of response to being identified as carrier. According to studies of post-traumatic stress disorders, one group adjusts reasonably well. The other group responds by avoiding follow-up contact with professional teams, which suggests more psychosocial pain and distress.

Identical mutation in 55% of the ATM alleles in 11 Norwegian AT families: evidence for a founder effect.

The ATM gene is responsible for the autosomal recessive disorder Ataxia-Telangiectasia (AT). Many different mutations, located all across the gene, have been reported with a predominance of truncating mutations. By using PTT (protein truncation test) a mutation was found in one Norwegian AT family. Sequencing revealed that the mutation affected nucleotides 3245-3247, codon 1082, and changed the sequence from ATC to TGAT, inducing a stop codon downstream at codon 1095 and leading to early truncation of the ATM protein. Perpendicular DGGE (denaturing gradient gel electrophoresis) was used to screen 10 additional families for this mutation. The 3245 delATC insTGAT mutation was found in 12 of 22 proband alleles: five patients were homozygotes and two heterozygotes. Haplotype analyses were performed using eight microsatellite markers, within and flanking the ATM gene. All carriers of the mutation described were found to have a common haplotype of the five closest CA-repeat microsatellite markers. Genealogical investigations of the families identified a common ancestor for three of the families. The common ancestor was a woman born in 1684 in the area from which these families originate. The prevalence of this mutation in Norwegian patients now allows a major subset of AT heterozygotes to be identified, both in the general population and in breast cancer patients, so that their cancer risk can be evaluated.

[Collagen analysis in fibroblasts in osteogenesis imperfecta. Clinical benefits]. / Kollagenundersøkelse i fibroblaster ved osteogenesis imperfecta. Klinisk nytte.

We performed collagen analysis in 38 patients with osteogenesis imperfecta. In order to assess the clinical benefit of the analysis, all cases were studied retrospectively. Five patients were children with lethal osteogenesis imperfecta, in whom the diagnosis was confirmed after termination of pregnancy. In the remaining 33 patients, collagen analysis was performed because of clinical suspicion of osteogenesis imperfecta. Child abuse was suspected in seven patients. We found good correlation between the results of collagen analysis and the final diagnoses, which were based on clinical information and observation over time. In this study we also tested a set of diagnostic criteria which seem to be useful in clinical practice. The collagen analysis was of decisive diagnostic value in half (16/33) of the patients, but also in the remaining patients the clinical diagnosis was strengthened. We obtained only one false negative result. Our study indicates that in selected patients where diagnosis is difficult, collagen analysis can be an important tool in establishing the diagnosis osteogenesis imperfecta.

[Neurofibromatosis type I in Norway. A clinical prevalence study based on a small project]. / Neurofibromatose type 1 in Norge. En klinisk prevalensunderslkelse basert på arbeid i et smågruppeprosjekt.

Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder that mainly affects the skin, the nervous system and the skeleton. An incidence of 1:4,000 gives approximately 1,100 patients in Norway. At Frambu we concluded a model project for three years to achieve better care from the medical, psychosocial and educational aspects. We also included a prevalence study of symptoms and complications in 129 patients. We found a complication rate remarkably like that found in previous prevalence studies, despite the fact that many of our patients were ascertained to be relatives of affected children, and were undiagnosed until the child was examined. Our project showed that, because neurofibromatosis is a multifaceted disorder, a team approach involving health-workers and teachers is needed for better care of affected children.