Genetic heterogeneity in autosomal dominant pattern dystrophy of the retina

PURPOSE: Mutations in the retinal degeneration slow (RDS)/peripherin gene have been shown to be associated with pattern dystrophy of the retina (PDR) and other retinal dystrophies. The aim of our study was to confirm or exclude the RDS locus and the rhodopsin (RHO) locus as the disease causing locus in a large Swiss family affected with pattern dystrophy of the retina. MATERIALS AND METHODS: A Swiss family with 14 members across 3 generations affected with PDR was examined. Eleven living family members were investigated using 6 markers surrounding the RDS and RHO loci. RESULTS: Linkage to two possible candidate genes, the RDS gene on chromosome 6p and the rhodopsin gene on chromosome 3q, could be excluded. CONCLUSIONS: The family provides evidence for genetic heterogeneity of PDR and is in agreement with heterogeneity in other retinal dystrophies. Further investigations are in progress to map the gene causing PDR in this family

Genomewide homozygosity mapping and molecular analysis of a candidate gene located on 22q13 (fibulin-1) in a previously undescribed vitreoretinal dystrophy

OBJECTIVES To localize the gene that causes an autosomal recessively inherited vitreoretinal dystrophy that has not been described, to our knowledge, and to analyze a candidate gene mapped to 22q13 (fibulin-1 [FBLN1]). METHODS Homozygosity mapping with 500 microsatellite markers spread over the whole genome (mean distance, 7.2 centimorgans [cM]) and mutation analysis of the complete coding region of FBLN1. RESULTS Homozygosity for all analyzed markers was found in the 4 affected siblings in a region on chromosome 22 encompassing 12 cM from D22S444 (centromeric) to D22S1170 (telomeric). Lod scores were between 0.017 and 2.36 (theta = 0). A mutation analysis of the complete coding region of FBLN1, which encodes interacting extracellular matrix proteins, revealed 4 previously undescribed single nucleotide polymorphisms. CONCLUSIONS A genomewide homozygosity mapping analysis supported the hypothesis that the gene responsible for a unique vitreoretinal dystrophy is located on chromosome 22q13. No obviously pathogenic mutation was found in the candidate gene, FBLN1

Erbliche Schwerhörigkeit: neue Möglichkeiten der Diagnostik

Mutations in many different genes can result in hearing loss. Using different molecular genetic methods, the disease-causing gene mutations can often be identified or at least localised to defined regions of the genome. These new diagnostic possibilities result from the localisation and identification of a number of hearing-loss genes in the last five years. Diagnostic investigations should always be accompanied by a genetic counselling of the family. In addition, the isolation thus far of 11 genes mutated in autosomal dominant inherited hearing loss, as well as of 6 genes mutated in autosomal recessive inherited hearing loss, has contributed to a better understanding of the molecular pathology of hearing loss in general. However, we are only beginning to see the whole picture, as an estimated 50 to 80 hearing loss genes remain to be discovered

Psychiatric symptoms and CAG expansion in Huntington's disease

The mutation responsible for Huntington's disease (HD) is an elongated CAG repeat in the coding region of the IT15 gene. A PCR-based test with high sensitivity and accuracy is now available to identify asymptomatic gene carriers and patients. An inverse correlation between CAG copy number and age at disease onset has been found in a large number of affected individuals. The influence of the CAG repeat expansion on other phenotypic manifestations, especially specific psychiatric symptoms has not been studied intensively. In order to elucidate this situation we investigated the relation between CAG copy number and distinct psychiatric phenotypes found in 79 HD-patients. None of the four differentiated categories (personality change, psychosis, depression, and nonspecific alterations) showed significant differences in respect to size of the CAG expansion. In addition, no influence of individual sex on psychiatric presentation could be found. On the other hand in patients with personality changes maternal transmission was significantly more frequent compared with all other groups. Therefore we suggest that clinical severity of psychiatric features in HD is not directly dependent on the size of the dynamic mutation involved. The complex pathogenetic mechanisms leading to psychiatric alterations are still unknown and thus genotyping does not provide information about expected psychiatric symptoms in HD gene carriers

Angeborene Innenohrschwerhörigkeit durch Mutationen im Connexin-26-Gen

Hearing loss is a frequent disease with an estimated incidence of 1:1000 in children. Hereditary hearing loss is characterised by enormous genetic heterogeneity, which makes diagnosis difficult. Approximately 50% of the Caucasian patients with autosomal recessive inherited hearing loss carry mutations in the connexin- 26 gene on chromosome 13. Standard screening procedures such as SSCP (single strand conformation polymorphism) analysis, DHPLC (denaturing high performance liquid chromatography) and subsequent sequencing are used to investigate this gene. A genetic test is thus available which can be offered to probands in genetic counselling. We investigated 11 patients with hearing loss and found sequence aberrations in 7 patients, which is causative for the hearing loss in at least 5 patients. The first application of DHPLC in Switzerland is also documented

Direct genetic diagnosis in Huntington's chorea

Huntington's disease is a late manifesting autosomal dominant neurodegenerative disorder. It is characterized by motor disturbance, loss of cognitive functions and psychiatric manifestations. Recently, the disease causing mutation, an unstable DNA sequence in the coding region of the Huntington gene on chromosome 4p, has been identified. A trinucleotide (CAG) repeat is expanded over the normal range and can easily be detected by standard laboratory methods. Accurate genetic testing can now be offered in clinically questionable cases and to subjects at risk for Huntington's disease. Furthermore, there seems to be a correlation between the size of the expanded CAG repeat and the age of onset in affected individuals. We have investigated more than 130 individuals from different affected families and illustrate the advantages and the clinical application of the new method

Codons 837 and 838 in the Retinal Guanylate Cyclase Gene on Chromosome 17p: Hot Spots for Mutations in Autosomal Dominant Cone-Rod Dystrophy?

Cone-rod dystrophies (CRDs) represent a clinically and genetically heterogeneous group of chorioretinal dystrophies characterized by gradual loss of visual acuity, central visual field defects, and photophobia. We investigated a Swiss family with autosomal dominant CRD (adCRD). Members of 3 generations showed reduced visual acuity and abnormalities on electroretinograms compatible with CRD. Blood was taken from 5 affected and 4 unaffected family members, as well as from 2 children at risk

A novel complex mutation event in the peripherin/rds gene in a family with retinal pattern dystrophy

Purpose: To report a complex mutation in the peripherin/RDS gene found in a family in whom retinal pattern dystrophy is segregating as an autosomal dominant trait. Methods: Clinical data were collected from family members of a large Swiss family affected by autosomal dominant retinal pattern dystrophy. Single strand conformation polymorphism (SSCP) analysis of the candidate gene peripherin/RDS and subsequent sequencing of the first exon were performed. Results: Pattern dystrophy of the retina was suspected in 18 family members aged 30 years or older. Assuming a homogeneous phenotype, the candidate locus peripherin/RDS was investigated. SSCP analysis of the first exon of the peripherin/RDS gene showed an aberrant pattern in 18 affected individuals. Direct sequencing of polymerase chain reaction products detected a complex mutation, del265-268GCCA ins AGGGCC, leading to a stop codon at amino acid position 99. Conclusion: To our knowledge, we report the first complex mutation in the peripherin/RDS gene as the cause of a mild macular phenotype, supporting the importance of molecular diagnosis in genetic counseling.</p

Mcleod syndrome: A novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings

The McLeod syndrome is an X-linked disorder caused by mutations of the XK gene encoding the XK protein. The syndrome is characterized by absent Kx erythrocyte antigen, weak expression of Kell blood group system antigens, and acanthocytosis. In some allelic variants, elevated creatine kinase, myopathy, neurogenic muscle atrophy, and progressive chorea are found. We describe a family with a novel point mutation in the XK gene consisting of a C to T base transition at nucleotide position 977, introducing a stop codon. Among seven affected males, five manifested with psychiatric disorders such as depression, bipolar disorder, or personality disorder, but only two presented with chorea. Positron emission tomography and magnetic resonance volumetry revealed reduced striatal 2-fluoro-2-deoxy-glucose (FDG) uptake and diminished volumes of the caudate nucleus and putamen that correlated with disease duration. In contrast, none of 12 female mutation carriers showed psychiatric or movement disorders. However, a semidominant effect of the mutation was suggested by erythrocyte and blood group mosaicism and reduced striatal FDG uptake without structural abnormalities. Therefore, patients with psychiatric signs or symptoms segregating in an X-linked trait should be examined for acanthocytosis and Kell/Kx blood group serology