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A K Gedeon

Publications and source records attributed to A K Gedeon.

At least 37 records · Page 2Linked to original sources
PubMed1993

Direct molecular diagnosis of myotonic dystrophy.

Myotonic dystrophy (DM) arises from an unstable trinucleotide (CTGn) repeat sequence within the DM locus at 19q13.3. Twenty-three myotonic dystrophy families containing 205 persons with no symptoms, minimal manifestations, classic DM or congenital DM were investigated to validate the application of the pM10M6 probe to direct molecular diagnosis. Affected family members had been diagnosed clinically and the unaffected family members had been assigned carrier probabilities close to either zero or 100%, using closely linked flanking markers. Southern analysis identified all 89 DM gene carriers as having expansions of the unstable element. PstI detected all small expansions of the repeat sequence as easily seen discrete bands; but large expansions were usually seen as diffuse smears, sometimes difficult to distinguish from lane background. EcoRI concentrated these diffuse smears, associated with somatic instability, into discrete bands which were easy to detect; but it did not resolve the smaller expansions present in 9 (10%) of the DM carriers. It is essential that PstI and EcoRI gels are run in parallel to detect all DM gene carriers. The extent of expansion of CTG correlated with age of onset and disease severity. Biopsies of various fetal tissues from two terminated pregnancies confirmed the diagnosis obtained by CVS and revealed no heterogeneity between tissues at this developmental stage. Further expansion occurred during the culture of CVS cells, indicating that direct prenatal diagnosis needs to be carried out on CVS tissue rather than on cultured cells. The intergenerational change of the repeat sequence from DM parent to DM offspring showed a significant parental sex difference for those parents with large expansions. Contraction of the unstable element was observed in the three males carrying the largest expansions and could explain why congenital DM is exclusively of maternal origin.

Female↗
PubMed1993

Genotype-phenotype relationships in fragile X syndrome: a family study.

Relationships between the measures of intellectual and physical status in the fragile X syndrome and the size of amplification of the fragile X-specific fragment, equivalent to the number of CCG repeats within the FMR1 locus, were studied by a maximum-likelihood scoring technique for analysis of pedigree data. This allows for estimation of random effects (genetic and environmental variance) concurrently with other (fixed) effects in a quantitative trait. FMR1 expression is usually shut down in males penetrant for the fragile X syndrome who have hypermethylated CCG amplifications of > or = 0.6 kb. The assumption of the step versus curvilinear function representing this relationship was tested by the likelihood-ratio criterion. The maximum-likelihood parameters were based on the most appropriate model for each measure. The results were indicative of the presence of a curvilinear relationship between the amplification size and the two intellectual scores, the Peabody Picture Vocabulary Test and Block Design Test, measuring verbal and spatial abilities, respectively. Reasons for the unexpected curvilinear regression between the amplification size and intellectual scores were explained further by methylation analysis of fragile X males with amplifications of 0.6 < delta < or = 1.2 kb who appeared to be responsible for the curvilinearity of the relationship. Four of these showed unmethylated status of the amplified bands in lymphocytes, which were presumably transcriptionally active. Removal of the aberrant individuals led to the anticipated step function between amplification and intellectual scores. For the combined anthropometric score, as well as for several single physical measures, the step function was the most appropriate model regardless of the inclusion or omission of the aberrant individuals in the pedigree sample.

Adolescent↗
PubMed1993

Refined genetic localization for central core disease.

Central core disease (CCO) is an autosomal dominant myopathy clinically distinct from malignant hyperthermia (MHS). In a large kindred in which the gene for CCO is segregating, two-point linkage analysis gave a maximum lod score, between the central core disease locus (CCO) and the ryanodine receptor locus (RYR1), of 11.8, with no recombination. Mutation within RYR1 is responsible for MHS, and RYR1 is also a candidate locus for CCO. A combination of physical mapping using a radiation-induced human-hamster hybrid panel and of multipoint linkage analysis using the Centre d'Etude du Polymorphisme Humain families established the marker order and sex-average map distances (in centimorgans) on the background map as D19S75-(5.2)-D19S9-(3.4)-D19S191-(2.2)-RYR1-(1.7)-D19S190-(1.6)-D19S47-(2.0)- CYP2B. Recombination was observed between CCO and the markers flanking RYR1. These linkage data are consistent with the hypothesis that CCO and RYR1 are allelic. The most likely position for CCO is near RYR1, with a multipoint lod score of 11.4, in 19q13.1 between D19S191 and D19S190, within the same interval as MHS (RYR1).

Alleles↗
PubMed1992

Fragile X syndrome without CCG amplification has an FMR1 deletion.

We describe a patient with typical clinical features of the fragile X syndrome, but without cytogenetic expression of the fragile X or an amplified CCG trinucleotide repeat fragment. The patient has a previously uncharacterized submicroscopic deletion encompassing the CCG repeat, the entire FMR1 gene and about 2.5 megabases of flanking sequences. This finding confirms that the fragile X phenotype can exist, without amplification of the CCG repeat or cytogenetic expression of the fragile X, and that fragile X syndrome is a genetically homogeneous disorder involving FMR1. We also found random X-inactivation in the mother of the patient who was shown to be a carrier of this deletion.

Adult↗
PubMed1992

X-linked lymphoproliferative disease: prenatal detection of an unaffected histocompatible male.

Chorionic Villous Biopsy (CVS) for diagnosis of XLP was undertaken at 10 weeks gestation in an obligate carrier. The fetus was found to be male by cytogenetic analysis. XLP (Xq25-q26) is closely linked to the RFLP markers DXS10, DXS37 and DXS42, but only DXS10 (distal to XLP) was informative for prenatal diagnosis in this family. RFLP analysis using this marker gave a 7% risk that the fetus was affected, based on the known recombination frequency between DXS10 and XLP. Further investigation was then undertaken to obtain a rapid and more accurate diagnosis using the three highly polymorphic PCR based markers. These were the AC repeat markers DXS424 (XL5A) and DXS425 (XL90A3) and the tetramer repeat marker within HPRT. DX425 is approximately 10 cM proximal to DXS10 and HPRT but is not known with certainty to map proximal or distal to XLP. DXS424 is proximal to DXS10 and HPRT and was inferred to be proximal to XLP on the basis of map distance from HPRT estimated by linkage analysis of data from CEPH pedigrees. This was confirmed by a recombinant in the XLP family between DXS424 and DXS425, placing DXS424 proximal to XLP. Diagnosis by linkage using DXS424 and DXS425, at least one of which is proximal to XLP, and distal markers DXS10 and HPRT, increased the accuracy of diagnosis using flanking marker analysis to greater than 99% that the fetus was unaffected. HLA DR typing of the CVS showed that the fetus was DR identical to a male sibling with XLP. HLA compatibility was confirmed at delivery by full HLA typing and MLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Child, Preschool↗
PubMed1992

Experience with direct molecular diagnosis of fragile X.

The utility of the pfxa3 probe for direct molecular diagnosis of the fragile X (FRAXA) has been established. This probe detects amplification of an unstable DNA element consisting of variable length CCG repeats. The size of the amplified fragment is correlated with phenotype and was determined using PstI digested DNA in family members. In 35 families with the fragile X, there was correspondence in 183 cases between the presence of an amplified unstable element and the presence of the fragile X chromosome independently determined by cytogenetics, position in the pedigree, or linked DNA markers flanking the fragile X. There was also correspondence in 124 cases between the presence of the normal 1.0 kb PstI fragment and absence of the fragile X chromosome independently determined by linked flanking markers. Six additional families considered to be isolated cases of 'fragile X' had been diagnosed before recognition of FRAXD. The pfxa3 probe confirmed the cytogenetic diagnosis in three families, the other three being rediagnosed as non-fragile X. A further two families had consistent expression of a different folate sensitive fragile site, FRAXE, close to FRAXA but not associated with fragile X syndrome and not detectable with the pfxa3 probe. Subsequent referrals were received from additional family members or from members of new families for whom carrier status had not been predetermined by linked markers. Direct pfxa3 diagnosis for the 135 females within these 222 additional cases was confirmed by dosage analysis with the control probe pS8.(ABSTRACT TRUNCATED AT 250 WORDS)

Artifacts↗
PubMed1991

Addition of MT, D16S10, D16S4, and D16S91 to the linkage map within 16q12.1-q22.1.

A 10-point genetic linkage map of the region 16q12.1 to 16q22.1 has been constructed using the CEPH reference families. Four loci, MT, D16S10, D16S91, and D16S4, not previously localized on a multipoint linkage map, were incorporated on the map presented here. The order of loci was cen-D16S39-MT, D16S65-D16S10-FRA16B-D16S38, D16S4, D16S91, D16S46-D16S47-HP-qter. The interval between D16S10 and 4D16S38 is 3.1 cM in males and 2.3 cM in females, and contains FRA16B. The cloning strategy for FRA16B will now be based on YAC walking from D16S10 and D16S38. The location of FRA16B between D16S10 and D16S38 provides a physical reference point for the multipoint linkage map on the short arm of chromosome 16.

Chromosome Mapping↗
PubMed1991

Predictive diagnosis of myotonic dystrophy with flanking microsatellite markers.

Linkage was shown between the myotonic dystrophy locus (DM) and a highly polymorphic AC repeat marker within the kallikrein (KLK1) locus (Z = 3.00, theta = 0.0). Linkage between KLK1 and the highly polymorphic AC repeat marker within the apolipoprotein C2 (APOC2) locus, which had been established in normal families, was confirmed in myotonic dystrophy families (Z = 4.37, theta = 0.11). These highly polymorphic AC repeat markers flank DM on chromosome 19. The gene order is cen-APOC2 (0.03) DM (0.08) KLK1-qter with recombination frequencies shown in parentheses. Genotypes for the AC repeat markers can be determined simultaneously by multiplex PCR and separation of the two base pair differences between adjacent alleles on sequencing gels. In informative families, this approach provides rapid diagnosis and is more accurate than methods using markers restricted to the proximal side of the myotonic dystrophy gene.

Base Sequence↗
PubMed1990

Predictive diagnosis for polycystic kidney disease using DNA markers.

Two families in which the gene for the common, autosomal dominant form of polycystic kidney disease (PKD1) was present were examined using flanking DNA markers. The 5'HVR probe detects a linked DNA marker 8 map units distal to the PKD1 gene in males and 1 unit distal to the PKD1 gene in females. The 24-1 probe detects another linked DNA marker 4 map units proximal to the PKD1 gene in males and 0.5 map units proximal to the PKD1 gene in females. When each marker is informative they can be used as a pair flanking the disease gene to follow accurately its transmission through families for presymptomatic or prenatal prediction. For an asymptomatic individual tested in one family, DNA studies reduced the 50% prior risk of carrying the disease gene to 0.006%. An affected woman in a second family was shown to be fully informative for the flanking markers. In a future pregnancy, it will be possible to modify the 50% prior fetal risk to either 0.008% or 99.99% depending on which maternal chromosome 16 is transmitted, and provided that no cross-over occurs between the flanking markers (probability, 1.5%).

Chromosome Mapping↗
PubMed1989

A linkage group with FRA16B (the fragile site at 16q22.1).

Polymorphic DNA markers located in bands 16q13, 16q21 and 16q22 were examined for recombination with FRA16B, the fragile site at 16q22.100. A tight linkage cluster D16S10-FRA16B-D16S4-HP was established. There were no recombinants (theta = 0.0, z = 8.3) between D16S10 and D16S4, which flank FRA16B. The markers D16S10 and D16S4 are in close proximity on the genetic map and delineate a small chromosomal segment, which contains the distamycin A-inducible fragile site.

Chromosome Fragile Sites↗
PubMed1989

Mapping the short arm of human chromosome 16.

Physical mapping of 13 different breakpoints on the short arm of chromosome 16 using previously mapped probes and the subsequent mapping of additional probes enabled the division of this portion of the chromosome into six different intervals. D16S94 was mapped between HBA and D16S80 and is closer to PKD1 than either HBA or D16S80. A tight linkage group which includes FRA16A, D16S8, and D16S79 was identified. Seven breakpoints, including FRA16A, could not be separated by probe localizations. This study provides the basis for the development of detailed maps of the short arm of chromosome 16.

Animals↗
PubMed1988

Presymptomatic testing for myotonic dystrophy by means of the linked DNA marker APOC2.

A family in which the gene for myotonic dystrophy is segregating was tested with a DNA probe to the apolipoprotein-C2 (APOC2) gene. The APOC2 gene is linked closely to the myotonic dystrophy (DM) gene and can be used as a marker to follow the transmission of the DM gene within families. Results from DNA-marker studies were combined with information from clinical, ophthalmological and electromyographic examinations, with age-dependent penetrance and a recombinant frequency of 4% between the genes for myotonic dystrophy and apolipoprotein C2 being taken into account. The chance that an individual had inherited the gene for myotonic dystrophy was determined by means of the computer program, LINKAGE. This analysis altered dramatically the assessed risk that certain individuals in the family were carrying the DM gene. For four individuals in the family, the previous risks of 50% for each member were reduced to 0.9%, 0.9% and 0.2%, respectively, in three cases and increased to 91% in the fourth case. The importance of a complete clinical evaluation of potential gene carriers who donate blood for a DNA-linkage study is stressed.

Apolipoprotein C-II↗
PubMed1988

Application of DNA probes to carrier detection and prenatal diagnosis of Duchenne (and Becker) muscular dystrophy.

Thirty-four Duchenne and Becker muscular dystrophy families were initially ascertained from South Australia. These have been tested systematically with the DNA probes XJ1.1 and pERT87-15. DNA results from 21 informative families have been combined with results of CK testing. Pedigree analysis was carried out using the computer program LINKAGE to provide risk figures to potential female carriers. This simple approach separated potential carriers into low or high risk classes (familial cases) or low or moderate risk classes (isolated cases). No prenatal diagnoses were carried out. The detection of deletions in two probands out of 34 makes possible definitive prenatal diagnosis in those families. For the remaining families, prenatal diagnosis could only be offered in terms of a probability statement after linkage analysis. Risk figures presented from hypothetical pedigrees demonstrated that prenatal diagnosis by linkage usually provided reasonable reliability only where informative flanking markers are used.

Child↗
PubMed1987

Linkage and genetic counselling for the fragile X using DNA probes 52A, F9, DX13, and ST14.

Linkage data using the markers DXS51, F9, DXS15, and DXS52 are presented from 14 pedigrees segregating with the fragile X. Cytogenetic and DNA data were combined by two- or three-point linkage analysis for estimation of lod scores and carrier probabilities in potential carriers. Recombination frequencies (theta) corresponding to maximum z scores (zeta) were obtained for DXS51 (zeta = 3.45, theta = 0.0), DXS15 (zeta = 0.40, theta = 0.06), F9 (zeta = 3.15, theta = 0.09), and DXS52 (zeta = 3.60, theta = 0.11) with the fragile X. Considerable alterations to carrier probabilities occurred in some cases, especially when flanking markers were informative. The chance of mentally impaired offspring was reduced to 1% for five of eight women with prior carrier probabilities of 32%. Three pedigrees were identified in which mutation had possibly occurred. An alternative explanation for two of these was inheritance of the fragile X from normal males and for the other inheritance from a clinically normal woman. Probabilities were computed for each of these alternatives.

DNA↗