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Biomedical subjects

M Nordenskjöld

Publications and source records attributed to M Nordenskjöld.

At least 19 recordsLinked to original sources
PubMed2006

Assignment of the gene locus for severe congenital neutropenia to chromosome 1q22 in the original Kostmann family from Northern Sweden.

Autosomal recessive severe congenital neutropenia (SCN) or Kostmann syndrome is characterised by reduced neutrophil counts and subsequent recurrent bacterial infections. The disease was originally described in a large consanguineous pedigree from Northern Sweden. A genome-wide autozygosity scan was initiated on samples from four individuals in the original pedigree using high density single nucleotide polymorphism (SNP) genotyping arrays in order to map the disease locus. Thirty candidate regions were identified and the ascertainment of samples from two additional patients confirmed a single haplotype with significant association to the disorder (p<0.01) on chromosome 1q22. One affected individual from the original Kostmann pedigree was confirmed as a phenocopy. The minimal haplotype shared by affected individuals spans a candidate region of 1.2 Mb, containing several potential candidate genes.

Chromosome Mapping↗
PubMed2006

Genome-wide linkage analysis of allergic rhinoconjunctivitis in a Swedish population.

BACKGROUND: Allergic rhinoconjunctivitis is a common complex disorder characterized by itching and irritation in the nose, bouts of sneezing, watery rhinorrhoea, nasal congestion and itchy eyes with tears and swelling. Like other atopic disorders such as allergic asthma and atopic dermatitis, the development involves complex interactions of genes and environmental factors. OBJECTIVE: The purpose of this study was to identify susceptibility loci for allergic rhinoconjunctivitis. METHODS: We conducted a genome-wide linkage analysis using a non-parametric, affected-relative-pair method. The 250 families used were collected originally for an atopic dermatitis linkage study. RESULTS: Three regions showed favour in evidence of linkage to allergic rhinoconjunctivitis: 3q13 (D3S1278: logarithm of odds ratio (LOD)=1.64, P<0.003), 4q34-35 (D4S1652: LOD=1.49, P<0.005) and 18q12 (D18S535: LOD=1.94, P<0.002). In addition, four regions showed weaker evidence in favour of linkage: 6p22-24 (D6S1959: LOD=1.39, P<0.006), 9p11-q12 (D9S1118: LOD=1.15, P<0.02), 9q33.2-34.3 (D9S915: LOD=1.29, P<0.01) and 17q11.2 (D17S1294: LOD=1.13, P<0.02). In single-point analysis, one locus on chromosome 3 close to marker D3S1278 reaches the suggestive level (LOD=2.28, P<6 x 10(-4)) while one on chromosome 17 close to marker D17S921 almost reaches this level (LOD=2.17, P<8 x 10(-4), Table 3). CONCLUSION: Our results support the linkage to allergic rhinoconjunctivitis on 3q13, 6p23-p24 and 9q34.3 shown in previous investigations.

Chromosomes, Human, Pair 17↗
PubMed2006

Spectrum and clinical implications of syntaxin 11 gene mutations in familial haemophagocytic lymphohistiocytosis: association with disease-free remissions and haematopoietic malignancies.

OBJECTIVE: To determine the frequency and spectrum of mutations in the gene encoding syntaxin 11 (STX11) in familial haemophagocytic lymphohistiocytosis (FHL), a rare autosomal recessive disorder of immune dysregulation characterised by a defect in natural killer cell function. METHODS: Mutational analysis of STX11 by direct sequencing was done in 28 FHL families that did not harbour perforin mutations, previously identified in some FHL patients. A detailed investigation of clinical features of these patients was also undertaken. RESULTS: Two different STX11 mutations were identified, one nonsense mutation and one deletion, affecting six of 34 children in four of 28 unrelated PRF1 negative families. Both mutations have been reported before. Three patients experienced long periods (> or = 1 year) in remission without specific treatment, which is very uncommon in this disease. Despite the milder phenotype, some children with STX11 mutations developed severe psychomotor retardation. Two of the six patients harbouring STX11 gene defects developed myelodysplastic syndrome (MDS) or acute myelogenous leukaemia (AML). CONCLUSIONS: STX11 gene mutations were found in 14% of the PRF1 negative FHL families included in the present cohort. These results suggest that STX11 gene mutations may be associated with secondary malignancies (MDS/AML), and that there is segregation of specific clinical features in FHL patients with an underlying genotype.

Acute Disease↗
PubMed2005

Children and adults with acute lymphoblastic leukaemia have similar gene expression profiles.

OBJECTIVES: To compare the gene expression pattern in children and adults with acute lymphoblastic leukaemia (ALL) in order to improve our understanding of the difference in disease biology and prognosis. METHODS: The gene expression profiles in diagnostic samples from 29 children and 15 adults with ALL were analysed using the oligonucleotide chip Hu95ver2a, produced by Affymetrix. RESULTS: Unsupervised hierarchical cluster analysis revealed that, in spite of differences in outcome, patients clustered irrespective of age, first by T-cell or B-precursor immunophenotype, and second by cytogenetic changes within the B-precursor group. The expression pattern analysis allowed the reclassification of some samples into the proper cytogenetic group. We also showed that separate clustering of samples with the BCR/ABL translocation could be explained by different breakpoint regions in the BCR. No significant difference in gene expression was observed between samples with and without CDKN2A deletion within the B-precursor group. Analysis of different age groups revealed a similarity in expression profiles when infants with the MLL translocation and adults over 40 yr of age were compared irrespective of karyotype. CONCLUSIONS: In spite of the difference in clinical outcome, the gene expression pattern in children and adults with ALL is very similar and is primarily dependent on immunophenotype and cytogenetic aberrations. However, when age groups are compared, the expression patterns of infants and adults over 40 show a remarkable similarity.

Adult↗
PubMed2005

Detection of chromosomal imbalances in children with idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH).

Chromosomal aberrations are a common cause of multiple anomaly syndromes that include growth and developmental delay and dysmorphism. Novel high resolution, whole genome technologies, such as array based comparative genomic hybridisation (array-CGH), improve the detection rate of submicroscopic chromosomal abnormalities allowing re-investigation of cases where conventional cytogenetic techniques, Spectral karyotyping (SKY), and FISH failed to detect abnormalities. We performed a high resolution genome-wide screening for submicroscopic chromosomal rearrangements using array-CGH on 41 children with idiopathic mental retardation (MR) and dysmorphic features. The commercially available microarray from Spectral Genomics contained 2600 BAC clones spaced at approximately 1 Mb intervals across the genome. Standard chromosome analysis (>450 bands per haploid genome) revealed no chromosomal rearrangements. In addition, multi-subtelomeric FISH screening in 30 cases and SKY in 11 patients did not detect any abnormality. Using array-CGH we detected chromosomal imbalances in four patients (9.8%) ranging in size from 2 to 14 Mb. Large scale copy number variations were frequently observed. Array-CGH has become an important tool for the detection of chromosome aberrations and has the potential to identify genes involved in developmental delay and dysmorphism. Moreover, the detection of genomic imbalances of clinical significance will increase knowledge of the human genome by performing genotype-phenotype correlation.

Adolescent↗
PubMed2002

Susceptibility loci for atopic dermatitis on chromosomes 3, 13, 15, 17 and 18 in a Swedish population.

Atopic dermatitis is a hereditary, pruritic, inflammatory and chronic skin disease that typically presents in early childhood and may continue or recur later. The etiology of atopic dermatitis is unknown, but several lines of evidence indicate that it is a multifactorial disorder caused by the combined influence of genetic and environmental factors, even though the relative contributions of genes and environment are not known. To identify important loci that contribute to the development of atopic dermatitis, we conducted a genome-wide linkage analysis with 367 microsatellite markers, using a non-parametric affected relative-pair method in 109 pedigrees. Three qualitative phenotypes and one semi-quantitative phenotype were studied. For the phenotype atopic dermatitis, linkage to chromosome region 3p24-22 was found. For another phenotype, atopic dermatitis combined with raised allergen-specific IgE levels, a suggestive linkage was found to chromosome region 18q21. For the semi-quantitative phenotype severity score of atopic dermatitis, suggestive linkage was found to chromosome regions 3q14, 13q14, 15q14-15 and 17q21. Identifying chromosome regions linked to susceptibility genes for atopic dermatitis provides a platform from which the search for atopic dermatitis genes can proceed.

Chromosome Mapping↗
PubMed2002

Analysis of association and linkage for the interleukin-4 and interleukin-4 receptor b;alpha; regions in Swedish atopic dermatitis families.

BACKGROUND: Atopic dermatitis (AD) is caused by genetic and environmental factors that interact to determine disease susceptibility and severity. Several lines of evidence suggest that the IL-4 gene and the IL-4-receptor alpha (IL-4Ralpha) gene are involved in the development of atopic diseases. OBJECTIVE: The objective of this study was to evaluate the possible involvement of the chromosomal regions 5q31 and 16p12, which include the genes coding for the IL-4 and the IL-4Ralpha in AD. METHODS: We conducted linkage analysis and association studies using the microsatellite markers D16S298 and D16S403 and a single nucleotide polymorphism in the promoter region of the IL-4 gene (- 590C/T) in 406 Swedish families with at least two siblings affected with AD, in total 1514 individuals. RESULTS AND CONCLUSION: We report linkage (P < 0.005) to the - 590C/T polymorphism in the promoter of the IL-4 gene for the semiquantitative trait severity score of AD. Neither linkage nor association was found to the IL-4Ralpha chromosomal region.

Chromosome Mapping↗
PubMed2002

Single cell CGH analysis reveals a high degree of mosaicism in human embryos from patients with balanced structural chromosome aberrations.

We have performed comparative genomic hybridization (CGH) analysis of single blastomeres from human preimplantation embryos of patients undergoing preimplantation genetic diagnosis (PGD) for inherited structural chromosome aberrations and from embryos of IVF couples without known chromosomal aberrations. The aim was to verify the PGD results for the specific translocation, reveal the overall genetic balance in each cell and visualize the degree of mosaicism regarding all the chromosomes within the embryo. We successfully analysed 94 blastomeres from 28 human embryos generated from 13 couples. The single cell CGH could verify most of the unbalanced translocations detected by PGD. Some of the embryos exhibited a mosaic pattern regarding the chromosomes involved in the translocation, and different segregation could be seen within an embryo. In addition to the translocations, we found a high degree of numerical aberrations including monosomies, trisomies and duplications or deletions of parts of chromosomes. All of the embryos (100%) were mosaic, containing more than one chromosomally uniform cell line, or even chaotic with a different chromosomal content in each blastomere.

Blastocyst↗
PubMed2002

Clinical and genetic studies of Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant cancer syndrome characterised by benign skin tumours, renal tumours, and spontaneous pneumothorax. The gene has been mapped to chromosome 17p11.2 and recently identified, expressing a novel protein called folliculin. We report the clinical and genetic studies of four sporadic BHD cases and four families with a total of 23 affected subjects. Haplotype analysis of these families using BHD linked markers showed they did not share the same affected alleles, excluding common ancestry. Mutation analysis of the BHD gene identified two germline mutations on exon 11 (c.1733insC and c.1733delC) in three of four families as well as two of four sporadic cases. A novel somatic mutation, c.1732delTCinsAC, was detected in a BHD related chromophobe renal carcinoma. Our results confirmed the (C)8 tract in exon 11 as a mutational hot spot in BHD and should always be considered for future genetic testing. Our observation also indicated that the second hit (of Knudson's two hit theory) in some BHD related tumours is in the form of somatic mutation rather than LOH. In a large French family in which eight affected subjects carry the c.1733delC mutation, a phenocopy who has multiple episodes of spontaneous pneumothorax was identified. A total of five mutation carriers (aged between 37 to 66) did not have any evidence of BHD features, suggesting either reduced penetrance or late age of onset of the disease. In addition, six out of eight affected subjects who have positive germline mutation have confirmed neoplastic colonic polyps, indicating that colorectal neoplasia is an associated feature of BHD in some families. Our studies have observed several interesting genetic features in BHD: (1) the poly (C) tract in exon 11 as a mutational hot spot; (2) the existence of phenocopy; (3) reduced penetrance or late age of onset of disease; (4) association with colorectal neoplasia in some families; and (5) somatic mutation instead of LOH as the second hit in BHD tumours.

Adult↗
PubMed2001

Analysis of short stature homeobox-containing gene ( SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity.

Dyschondrosteosis (DCO; also called Léri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.

Blotting, Southern↗
PubMed2001

Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2.

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant neoplasia syndrome characterized mainly by benign skin tumors, and to a lesser extent, renal tumors and spontaneous pneumothorax. To map the BHD locus, we performed a genome-wide linkage analysis using polymorphic microsatellite markers on a large Swedish BHD family. Evidence of linkage was identified on chromosome 17p12-q11.2, with a maximum LOD score of 3.58 for marker D17S1852. Further haplotype analysis defined a approximately 35 cM candidate interval between the two flanking markers, D17S1791 and D17S798. This information will facilitate the identification of the BHD gene, leading to the understanding of its underlying molecular etiology.

Carcinoma, Renal Cell↗
PubMed2001

[Hereditary thyroid cancer can be cured by prophylactic surgery].

Multiple endocrine neoplasia type 2 (MEN 2) is a rare syndrome in which the consequences for the patient and family members are considerable. Mutation analysis of the RET proto-oncogene is crucial for decision-making regarding each patient. Today, carriers of MEN 2 mutations should be offered prophylactic thyroidectomy with the potential to eliminate the risk for potentially lethal medullary thyroid carcinoma (MTC). Here, we present the first Swedish experience of such operations performed mainly on the basis of genetic analysis. Twenty patients underwent total thyroidectomy at a mean age of 13.5 (6-43) years. In all cases, either manifest MTC (n = 11) or C-cell hyperplasia was found. So far, no patient has any sign of recurrence or developmental insufficiency at 1-5 years follow-up. As the medical and ethical problems in this group of patients are substantial, and as the operations are performed in otherwise healthy children, they should be treated at centers with adequate multidisciplinary expertise and competence.

Adolescent↗
PubMed2001

Spectrum of perforin gene mutations in familial hemophagocytic lymphohistiocytosis.

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, approximately 30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%-40% of the FHL cases and the FHL 1 locus on chromosome 9 for approximately 10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes.

Amino Acid Substitution↗
PubMed2001

Clinical outcome of treatment cycles using preimplantation genetic diagnosis for structural chromosomal abnormalities.

OBJECTIVES: To explore oocyte recovery, embryo quality, the number of transferable embryos and pregnancy rate after preimplantation genetic diagnosis (PGD) in patients with structural chromosomal aberrations. METHODS: PGD was performed in seven couples with Robertsonian translocations (Rob), eight couples with reciprocal translocations (Rec), two couples with inversions and one couple with a deletion. A total of 43 treatment cycles were carried out. RESULTS: A total of 14.2 oocytes per cycle were retrieved. Fertilisation and cleavage rates were 63% and 58%, respectively. Of the biopsied embryos 20% were transferable. Comparison of the Rob and Rec group revealed no significant differences in number of oocytes, fertilisation or cleavage rates. The number of transferable embryos after biopsy was significantly higher in the Rob group than in the Rec group. When embryo transfer (ET) was performed the pregnancy rate did not differ between the Rob and the Rec groups. Twenty-eight embryo transfers (one or two embryos) were carried out leading to eight clinical pregnancies (29% per ET): two twins, four singletons, one miscarriage and one ectopic pregnancy. All the children are carriers of balanced chromosomal aberrations. CONCLUSION: An acceptable pregnancy rate can be achieved among couples with structural chromosomal abnormalities.

Adult↗
PubMed2001

Linkage and association to candidate regions in Swedish atopic dermatitis families.

We have studied, in 406 families with at least two siblings affected with atopic dermatitis (in total 1514 individuals) from the Swedish population, linkage and association to five chromosomal regions (2q35, 5q31-33, 6p21, 11q13 and 14q11) previously implicated in atopic diseases. The region on 14q11 gave evidence for linkage to atopic dermatitis (NPL-score: 2.36, P<0.009). In the 11q13 region, there was a clear association to an intragenic marker in the beta-subunit of the high-affinity IgE receptor for raised allergen-specific serum IgE levels (P<0.009). When a quantitative variable for the severity of atopic dermatitis was studied, evidence was found in favour of linkage to the 5q31-33 region, with the highest Z-score (2.06) close to the marker D5S458 (P<0.005).

Age of Onset↗