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L Sandkuijl

Publications and source records attributed to L Sandkuijl.

9 recordsLinked to original sources
PubMed2000

Interchromosomal repeat array interactions between chromosomes 4 and 10: a model for subtelomeric plasticity.

Chromosomal rearrangements occur more frequently in subtelomeric domains than in other regions of the genome and are often associated with human pathology. To further elucidate the plasticity of subtelomeric domains, we examined the 3.3 kb D4Z4 repeat array on chromosome 4 and its homologue on chromosome 10 in 208 Dutch blood donors by pulsed field gel electrophoresis. These subtelomeric repeats are known to rearrange and partial deletions of this polymorphic array on chromosome 4 are associated with facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant myopathy. Our results show that mitotic rearrangements occur frequently as 3% of individuals display somatic mosaicism for a repeat expansion or contraction explaining the high variability of subtelomeric repeat array sizes. Translocated 4-type repeat arrays on chromosome 10 and the reverse configuration of 10-type repeat arrays on chromosome 4 are observed in 21% of individuals. The translocated repeat arrays on chromosome 4 tend to be more heterogeneous than 4-type repeats on chromosome 10. The repeat length on chromosome 4 is on average larger than on chromosome 10. But on both chromosomes we observe a multi-modal repeat length distribution with equidistant peaks at intervals of 65 kb, possibly reflecting a higher-order chromatin structure. Interestingly, in as many as six random blood donors (3%) we identified FSHD-sized 4-type repeat arrays. Assuming that these individuals are clinically unaffected, these results imply an incomplete penetrance in the upper range of FSHD alleles. Overall, the observed dynamic characteristics of these homologous domains may serve as a model for subtelomeric plasticity.

Chromosomes, Human, Pair 10↗
PubMed2000

De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is caused by deletion of most copies of the 3.3-kb subtelomeric D4Z4 repeat array on chromosome 4q. The molecular mechanisms behind the deletion and the high proportion of new mutations have remained elusive. We surveyed 35 de novo FSHD families and found somatic mosaicism in 40% of cases, in either the patient or an asymptomatic parent. Mosaic males were typically affected; mosaic females were more often the unaffected parent of a nonmosaic de novo patient. A genotypic-severity score, composed of the residual repeat size and the degree of somatic mosaicism, yields a consistent relationship with severity and age at onset of disease. Mosaic females had a higher proportion of somatic mosaicism than did mosaic males. The repeat deletion is significantly enhanced by supernumerary homologous repeat arrays. In 10% of normal chromosomes, 4-type repeat arrays are present on chromosome 10. In mosaic individuals, 4-type repeats on chromosome 10 are almost five times more frequent. The reverse configuration, also 10% in normal chromosomes, was not found, indicating that mutations may arise from transchromosomal interaction, to which the increase in 4-type repeat clusters is a predisposing factor. The somatic mosaicism suggests a mainly mitotic origin; mitotic interchromosomal gene conversion or translocation between fully homologous 4-type repeat arrays may be a major mechanism for FSHD mutations.

Age of Onset↗
PubMed1999

A new dosage test for subtelomeric 4;10 translocations improves conventional diagnosis of facioscapulohumeral muscular dystrophy (FSHD).

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the size reduction of a polymorphic repeat array on 4q35. Probe p13E-11 recognises this chromosomal rearrangement and is generally used for diagnosis. However, diagnosis of FSHD is complicated by three factors. First, the probe cross hybridises to a highly homologous repeat array locus on chromosome 10q26. Second, although a BlnI polymorphism allows discrimination between the repeat units on chromosomes 4 and 10 and greatly facilitates FSHD diagnosis, the occurrence of translocations between chromosomes 4 and 10 further complicates accurate FSHD diagnosis. Third, the recent identification of deletions of p13E-11 in both control and FSHD populations is an additional complicating factor. Although pulsed field gel electrophoresis is very useful and sometimes necessary to detect these rearrangements, this technique is not operational in most FSHD diagnostic laboratories. Moreover, repeat arrays >200 kb are often difficult to detect and can falsely suggest a deletion of p13E-11. Therefore, we have developed an easy and reliable Southern blotting method to identify exchanges between 4 type and 10 type repeat arrays and deletions of p13E-11. This BglII-BlnI dosage test addresses all the above mentioned complicating factors and can be carried out in addition to the standard Southern blot analysis for FSHD diagnosis as performed in most laboratories. It will enhance the specificity and sensitivity of conventional FSHD diagnosis to the values obtained by PFGE based diagnosis of FSHD. Moreover, this study delimits the FSHD candidate gene region by mapping the 4;10 translocation breakpoint proximal to the polymorphic BlnI site in the first repeat unit.

Blotting, Southern↗
PubMed1994

An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21.

Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does not show association to specific HLA haplotypes. Unravelling the APECED locus will identify a novel gene outside the HLA loci influencing the outcome of autoimmune diseases. We have assigned the disease locus to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Linkage disequilibrium studies have significantly increased the informativeness of the analyses and helped to locate the critical DNA region for the APECED locus to just 500 kilobases, a much more precise definition than linkage analyses alone could achieve.

Chromosome Mapping↗
PubMed1991

A multipedigree linkage study of X-linked deafness: linkage to Xq13-q21 and evidence for genetic heterogeneity.

A locus for X-linked nonsyndromic deafness has previously been allocated to the Xq13-q21 region based on linkage studies in two separate pedigrees. This has been substantiated by the observation of deafness as a clinical feature of male patients with cytogenetically detectable deletions across this region. The question of a second locus for deafness in this chromosomal region has been raised by the audiologically distinct nature of the deafness in some of the deleted patients compared to that observed in those patients upon whom the linkage data are based. We have performed detailed clinical evaluation and linkage studies on seven pedigrees with nonsyndromic X-linked deafness and conclude that there is evidence for at least two loci for this form of deafness, including one in the Xq13-q21 region. We have observed different radiological features among the pedigrees which map to Xq13-q21, suggesting that even among these pedigrees the deafness is due to different pathological processes. Given these findings, we suggest that the classification of nonsyndromic X-linked deafness based solely on audiological criteria may need to be reviewed.

Chromosome Mapping↗
PubMed1991

Covariate-dependent age-at-onset distributions for Huntington disease.

A combined logistic regression and life-table analysis is presented on age-at-onset data for Huntington disease. Covariates included in the analysis were sex of the at-risk individual, parental age at onset, and sex of transmitting parent. Parental age at onset and parental sex were found to be significant covariates for age at onset in the offspring, and the appropriate logistic regression functions are calculated by maximum likelihood methods. These regression functions permit a more precise evaluation of carrier risks and likelihoods than hitherto was possible by simple computational means. We further introduce a novel method to account for sibship correlations in the significance assessment, using log-likelihood differences between different models.

Adolescent↗
PubMedDate not supplied

Linkage analysis under locus heterogeneity: behaviour of the A-test in complex analyses.

The admixture test (A-test) is a popular method for the analysis of linkage data when locus heterogeneity is suspected. It can be applied on pairwise linkage data, multipoint data and even for the simultaneous analysis of data from multiple dispersed candidate regions. However, very little is known about the conditions for the use of the method under these divergent circumstances. By performing analytical evaluations, we demonstrate that the A-test is inconsistent if there is a relationship between the phenotype and the probability of being linked. Biased estimates of the recombination fraction (theta) and the proportion of linked families (alpha) may occur if the actual frequency of linked families is not identical among small and large families. We conclude that the A-test should be used with caution if the phenotype and the probability of developing the phenotype at a certain age cannot be shown to be equal for family members of linked and unlinked families. If dissimilarities in family size cannot be ruled out, the extent of bias should be considered and size specific alpha-values should be used in risk calculations.

Bias↗
PubMedDate not supplied

Linkage of DFNB1 to non-syndromic neurosensory autosomal-recessive deafness in Mediterranean families.

Recent studies show a susceptibility locus (DFNB1) responsible for non-syndromic neurosensory autosomal-recessive deafness (NSRD) mapping to the pericentromeric region of chromosome 13q. In order to better understand the frequency with which DFNB1 is the gene for deafness in our patient population and the role of DFNB1 in Caucasians, we performed a genetic linkage study with four microsatellite markers linked to DFNB1 in a total of 48 independent Mediterranean families, of which 30 and 18 were of Italian and Spanish descent, respectively. A maximum two-point lod score of 7.28 was found with marker D13S115 at a recombination frequency of theta 0.1. Significant lod scores were also obtained for D13S143, D13S292 and D13S175. Genetic heterogeneity was confirmed using the HOMOG program which indicated absence of linkage to DFNB1 in approximately 21% of the sample. This study clearly demonstrates that DFNB1 plays an important role in 79% of Mediterranean families with NSRD. Furthermore, results from multipoint analysis predict that the DFNB1 gene maps between markers D13S175 and D13S115 which are separated by approximately 14.2 cM.

Chromosome Mapping↗