Pamela R. Fain

Familial meningioma is not allelic to neurofibromatosis 2

Meningiomas frequently lose parts of chromosome 22 (CHR 22), suggesting that a meningioma tumor-suppressor gene is located on CHR 22. Since meningiomas are common in neurofibromatosis 2 (NF2) and the NF2 gene is mapped to CHR 22, the NF2 gene is a candidate for the meningioma gene. To determine whether NF2 and familial meningioma are allelic mutations, we studied a family with multiple meningiomas and ependymomas in two generations using genetic linkage analysis with DNA markers known to flank the NF2 locus. Multipoint linkage analysis resulted in location scores > −2 for a region of 15 cM including the NF2 region. These results support the existence of a familial meningioma locus that is distinct from the NF2 locus.

A genetic map of human chromosome 17p

A genetic linkage map was constructed with 18 loci from the short arm and pericentric region of chromosome 17 typed on the CEPH reference families. The genetic map includes three markers extracted from the CEPH public database. Nine loci could be ordered using a threshold of odds of at least 1000:1 against alternative orders during the map construction process. With a reduced tolerance of 100:1, a total of 13 loci could be placed on the map spanning a distance of approximately 60 cM in females and 46 cM in males. There were statistically significant differences between the male and the female genetic maps. The order inferred from the genetic data was consistent with the physical localizations of these probes obtained from somatic cell hybrids and tumor deletion studies. This map should be useful for genetic fine mapping of 17p loci.

Familial spinal neurofibromatosis: Clinical and DNA linkage analysis

We studied two families with an unusual variant of neurofibromatosis (NF). The first family had spinal neurofibromas and café au lait spots (CLS), the second spinal neurofibromas without CLS. Other signs of NF1 or NF2, such as cutaneous tumors, Lisch nodules, or acoustic tumors, were absent. The inheritance pattern in both pedigrees was consistent with autosomal dominant inheritance. Using genetic linkage analysis with DNA markers tightly linked to the NF1 and NF2 loci, we determined that the likely location for the mutation in the first family was in the NF1 gene with odds of 97:1, whereas the mutation in the second family was excluded from the NF1 locus with odds >100,000:1. Families such as these, in which a defined subset of the NF phenotype is passed on, are important for understanding the functional consequences of particular mutations in the NF genes.

Genetic analysis of NF1: Identification of close flanking markers on chromosome 17

The gene causing von Recklinghausen neurofibromatosis, or NF1, has been more precisely localized in the pericentromeric region of chromosome 17. Narrowing of the location for the disease became possible through the identification of eight new DNA probe genetic markers in the centromeric region. Markers that closely flank the centromere also closely flank the NF1 gene. Although there was evidence against this localization in one recombinant, a review of the clinical records revealed a borderline diagnosis of NF1. Significant sex differences in recombination were observed in the pericentric region, and odds for different orders were less discriminating when sex differences were considered in multilocus analyses. The location of the NF1 gene with respect to the centromere could not be determined because recombinants between NF1 and the centromere were not detected in the set of families tested.

Clinical variability of type 1 neurofibromatosis: is there a neurofibromatosis-Noonan syndrome?

Detailed clinical, ophthalmological, and molecular studies were performed on a multigeneration family in which there were many subjects with type 1 neurofibromatosis, a common autosomal dominant disorder. Affected family members displayed a wide range of clinical findings including, in two subjects, features seen in Noonan syndrome (triangular facies, downward slanting palpebral fissures, micrognathia, short stature, and learning disability). Subjects have been described previously whose features have overlapped with neurofibromatosis and Noonan syndrome, and it has been suggested that these persons might represent a separate condition. DNA haplotype analysis showed linkage of the neurofibromatosis phenotype seen in this family to the proximal long arm of chromosome 17 in the region where the type 1 neurofibromatosis gene has been mapped. These results imply that the Noonan phenotype seen in some patients with type 1 neurofibromatosis might be the result of variable or variant expression of the neurofibromatosis gene on chromosome 17. The possible role of non-specific factors, such as fetal hypotonia, in producing the neurofibromatosis-Noonan phenotype needs further investigation. The availability of closely linked and intragenic molecular markers for neurofibromatosis could potentially be useful in the diagnosis and characterisation of patients and families with atypical forms of neurofibromatosis.

High-density genetic and physical mapping of DNA markers near the X-linked Alport syndrome locus: definition and use of flanking polymorphic markers

SummaryTo refine the genetic and physical mapping of the locus for Alport syndrome (ATS), 22 X-chromosome restriction fragment length polymorphism (RFLP) markers that fall between Xq21.3 and Xq25 were tested for genetic linkage with the disease and also mapped with respect to a series of physical breakpoints in this region. The location of the COL4A5 gene, which has recently been shown to be mutated in at least some families with Alport syndrome, was determined with respect to the same physical breakpoints. Two large Utah kindreds were included in the genetic studies, kindreds P and C, with 125 and 63 potentially informative meioses, respectively. Both kindreds have essentially identical nephritis; however, kindred P has sensorineural hearing loss associated with the nephritis, while kindred C does not. A mutation in COL4A5 has been demonstrated for kindred P, but no change in this gene has yet been detected for kindred C. Twelve informative probes did not recombine with the disease locus in either kindred (θ= 0.0, with combined lod scores for the two kindreds ranging from 7.7 to 30.0). The closest markers that could be demonstrated to flank the disease locus were the same for each kindred and thus the locations of the mutations causing the two disease phenotypes are not distinguishable at the current level of genetic resolution. The flanking markers are also useful for the resolution of questionable diagnoses and allow accurate estimates for these families of the rate of sporadic hematuria in noncarrier females (7%) and the penetrance of hematuria for carrier females (93%).

Chiasma-based models of multilocus recombination: increased power for exclusion mapping and gene ordering.

Cytological evidence indicates that the number of chiasmata which can occur on any given chromosome arm is limited. In this paper a Monte-Carlo simulation study is used to compare the power of a model of multilocus recombination parameterized in terms of chromosome-specific chiasma distributions with the traditional model parameterized by recombination fractions in adjacent intervals. Two specific gene mapping problems are considered: excluding a test locus from a given chromosome map and ordering a test locus with respect to a fixed map of syntenic marker loci. We show that the chiasma-based models require significantly fewer observations to exclude or order a test locus and that they are quite robust to errors in specifying the underlying true chiasma distribution.

Consortium Fine Localization of X-Linked Charcot-Marie-Tooth Disease (CMTX1): Additional Support that Connexin32 Is the Defect in CMTX1

Charcot-Marie-Tooth (CMT) disease is the most common form of inherited motor and sensory neuropathy. X-linked CMT (CMTX1) has been localized to the pericentric region of the X chromosome. Recently, mutations have been defined in the connexin32 gene that cosegregate with the CMTX1 phenotype in several families. The present paper presents the results of an international consortium to fine map the gene for CMTX1 to a small segment of Xq12-13. The linkage data, together with the molecular genetic studies, support the hypothesis that connexin32 is the genetic defect in CMTX1.

Definition and mapping of STSs at STR and RFLP loci in Xp11-Xq22

New primer pair sequences specific for 25 loci in the Xp11-q22.1 region are described. Eighteen of the pairs span segments containing significant CA dinucleotide repeats, with 9 of these revealing polymorphisms of greater than 50% heterozygosity. Four of the CA-containing segments occur in probes previously reported to detect RFLPs, while the remaining 14 are from newly isolated clones. STSs were also developed for 7 other RFLP-only loci. All of these 25 STSs plus 11 other published STR markers have been fine-mapped with respect to chromosomal breakpoints, defining 15 subintervals in Xp11-Xq22. This map of 36 STSs, nearly all of which are associated with markers that are genetically mapped and/or highly polymorphic, will significantly aid efforts to construct a complete physical map of this region and to correlate it with the high-density genetic map.

A genomic search for linkage of neurofibromatosis to RFLPs.

Our initial attempt to map NF was directed towards chromosomes 4 and 19, both of which had provided positive evidence for linkage in previous reports. This analysis showed no evidence in support of either hypothesis. Our second attempt at mapping NF was a general search of the genome, analysing a set of markers selected according to their degree of polymorphism, chromosomal location, ease of use, and availability. Data for linkage analysis were obtained from 17 multiplex families which are segregating a gene for NF. Linkage analyses were performed using PAP. Of note is the lod score of +1.17 at a recombination fraction of 0.1 between NF and the centromere of chromosome 17.