The Angelman (AS) and Prader-Willi (PWS) syndromes are two clinically distinct disorders that are caused by a differential parental origin of chromosome 15q11-q13 deletions. Both also can result from ...uniparental disomy (the inheritance of both copies of chromosome 15 from only one parent). Loss of the paternal copy of 15q11-q13, whether by deletion or maternal uniparental disomy, leads to PWS, whereas a maternal deletion or paternal uniparental disomy leads to AS. The differential modification in expression of certain mammalian genes dependent upon parental origin is known as genomic imprinting, and AS and PWS represent the best examples of this phenomenon in humans. Although the molecular mechanisms of genomic imprinting are unknown, DNA methylation has been postulated to play a role in the imprinting process. Using restriction digests with the methyl-sensitive enzymes HpaII and HhaI and probing Southern blots with several genomic and cDNA probes, we have systematically scanned segments of 15q11-q13 for DNA methylation differences between patients with PWS (20 deletion, 20 uniparental disomy) and those with AS (26 deletion, 1 uniparental disomy). The highly evolutionarily conserved cDNA, DN34, identifies distinct differences in DNA methylation of the parental alleles at the D15S9 locus. Thus, DNA methylation may be used as a reliable, postnatal diagnostic tool in these syndromes. Furthermore, our findings demonstrate the first known epigenetic event, dependent on the sex of the parent, for a locus within 15q11-q13. We propose that expression of the gene detected by DN34 is regulated by genomic imprinting and, therefore, that it is a candidate gene for PWS and/or AS.
Oculodentodigital dysplasia (ODDD) is an autosomal dominant condition with high penetrance and variable expressivity. The anomalies of the craniofacial region, eyes, teeth, and limbs indicate ...abnormal morphogenesis during early fetal development. Neurologic abnormalities occur later in life and appear to be secondary to white matter degeneration and basal ganglia changes. In familial cases, the dysmorphic and/or neurodegenerative components of the phenotype can be more severe and/or present at a younger age in subsequent generations, suggesting genetic anticipation. These clinical features suggest that the ODDD gene is pleiotropic with important functions throughout pre- and postnatal development. We have performed two-point linkage analysis with seven ODDD families and 19 microsatellite markers on chromosome 6q spanning a genetic distance of approximately 11 cM in males and 20 cM in females. We have refined the location of the ODDD gene between DNA markers D6S266/D6S261 (centromeric) and D6S1639 (telomeric), an interval of 1.01 (male) to 2.87 (female) cM. The strongest linkage was to DNA marker D6S433 (Zmax= 8.96, θmax= 0.001). Families show significant linkage to chromosome 6q22–q23 and no evidence for genetic heterogeneity.
The absence of a sex chromosome in conjunction with the presence of a marker chromosome generally implicates a sex chromosome origin for such marker chromosomes. These types of findings are ...frequently associated with Ullrich–Turner syndrome. We report a patient that presented with an atypical Ullrich–Turner phenotype and a cytogenetic mosaicism of 46,X,mar/46,XX. The marker chromosome was derived from chromosome 20, not from the X or Y chromosome. The patient's clinical features are described and discussed relative to the cytogenetic findings. This case further demonstrates the necessity of marker chromosome identification for accurate phenotype–karyotype correlation.
We have previously reported functional disomy for X-linked genes in females with tiny ring X chromosomes and a phenotype significantly more abnormal than Turner syndrome. In such cases the disomy ...results from failure of these X chromosomes to inactivate because they lack DNA sequences essential for cis X inactivation. Here we describe a novel molecular mechanism for functional X disomy that is associated with maternal isodisomy. In this case, the severe mental retardation and multiple congenital abnormalities in a female with a mosaic 45,X/ 46,X,del(X)(q21.3-qter)/ 46X,r(X) karyotype are associated with overexpression of the genes within Xpter to Xq21.31 in many of her cells. Her normal X, ring X, and deleted linear X chromosomes originate from the same maternal X chromosome, and all are transcriptionally active. None expresses X inactive specific transcript (XIST), although the locus and region of the putative X inactivation center (XIC) are present on both normal and linear deleted X chromosomes. To our knowledge, this is the first report of a functional maternal X isodisomy, and the largest X chromosome to escape inactivation. In addition, these results (1) show that cis inactivation does not invariably occur in human females with two X chromosomes, even when the XIC region is present on both of them; (2) provide evidence for a critical time prior to the visible onset of X inactivation in the embryo when decisions about X inactivation are made; and (3) support the hypothesis that the X chromosome counting mechanism involves chromosomal imprinting, occurs prior to the onset of random inactivation, and is required for subsequent inactivation of the chromosome.
We report on a 5-generation family with multiple musculoskeletal anomalies, including: Robin-type cleft palate, rib "dysplasia," scapular hypoplasia, and pectus excavatum. Robin-type clefts are known ...to be associated with various skeletal malformations; however, most of these include limb anomalies which are not present in this family. To our knowledge, there are no reports of similar conditions in the literature. The transmission through 5 generations and the presence of male-to-male transmission are consistent with autosomal-dominant transmission of a trait with variable expressivity.
Detailed chromosome studies were conducted for the Florida manatee (Trichechus manatus latirostris) utilizing primary chromosome banding techniques (G‐ and Q‐banding). Digital microscopic imaging ...methods were employed and a standard G‐banded karyotype was constructed for both sexes. Based on chromosome banding patterns and measurements obtained in these studies, a standard karyotype and ideogram are proposed. Characterization of additional cytogenetic features of this species by supplemental chromosome banding techniques, C‐banding (constitutive heterochromatin), Ag‐NOR staining (nucleolar organizer regions), and DA/DAPI staining, was also performed. These studies provide detailed cytogenetic data for T. manatus latirostris, which could enhance future genetic mapping projects and interspecific and intraspecific genomic comparisons by techniques such as zoo–FISH.
While the vast majority of cancers are believed to occur sporadically, most forms of cancer, both adult and paediatric, have a hereditary equivalent. In the case of adult malignancies, these include ...hereditary breast and ovarian cancer and syndromes such as the multiple endocrine neoplasias types 1 and 2 characterised by specific tumours of the endocrine gland system. In the case of paediatric malignancies, these include syndromes such as retinoblastoma and Wilms tumour. In a little over a single decade, we have seen a tremendous increase in the knowledge of the primary genetic basis of many of the familial cancer syndromes. The majority of familial syndromes are inherited as autosomal dominant traits including hereditary colon cancer and familial malignant melanoma, however, the genetics behind autosomal recessive disorders such as Bloom syndrome and Fanconi anaemia are also being elucidated. A third mode of inheritance less well understood in the setting of familial cancer is that of imprinting recently observed in a subset of families with inherited paraganglioma. In this review, we discuss 31 genes inherited in an autosomal dominant manner associated with 20 familial cancer syndromes. Genes inherited in an autosomal recessive manner linked to familial cancer syndromes are also discussed. The identification of genes associated with familial cancer syndromes has in some families enabled a ‘molecular diagnosis’ that complements clinical assessment and allows directed cancer surveillance for those individuals determined to be at-risk of disease.
Neurofibromatosis type 1 (NF1) is a dominant disorder caused by mutations in the NF1 gene; approximately 100 NF1 gene mutations have been published. The CpG C-to-T transition is a frequent mutation ...mechanism in genetic disorders. To estimate its frequency in NF1, we employed a PCR-restriction digestion method to examine 17 CpGs in 65 patients, and also screened for a CpG nonsense transition (R1947X) that occurs in 1-2% of patients. The analysis revealed disease-related CpG C-to-T transitions (including a nonsense mutation that may be as frequent as R1947X) as well as a benign variant and another mutation at a CpG. Four patients showed CpG mutations in analysis of 18 sites (17 surveyed by restriction digest, plus the R1947X assay), including three C-to-T transitions and one C-to-G transversion. These 18 sites represent one-fifth of the 91 CpGs at which a C-to-T transition would result in a nonsense or nonconservative missense mutation. Thus, it is feasible that the CpG mutation rate at NF1 might be similar to that seen in other disorders with a high mutation rate, and that recurrent NF1 mutations may frequently reside at CpG sites.
Previously, our group reported a five-generation family in which a balanced t(13;17) translocation is associated with a spectrum of skeletal abnormalities, including Robin sequence, hypoplastic ...scapulae, and a missing pair of ribs. Using polymerase chain reaction (PCR) with chromosome-specific markers to analyze DNA from somatic cell hybrids containing the derivative translocation chromosomes, we narrowed the breakpoint on each chromosome. Subsequent sequencing of PCR products spanning the breakpoints identified the breaks precisely. The chromosome 17 breakpoint maps ∼932 kb upstream of the sex-determining region Y (
SRY)–related high-mobility group b
ox gene (
SOX9) within a noncoding transcript represented by two IMAGE cDNA clones. A growing number of reports have implicated chromosome 17 breakpoints at a distance of up to 1 Mb from
SOX9 in some cases of campomelic dysplasia (CD). Although this multigeneration family has a disorder that shares some features with CD, their phenotype is significantly milder than any reported cases of (nonmosaic) CD. Therefore, this case may represent an etiologically distinct skeletal dysplasia or may be an extremely mild familial example of CD, caused by the most proximal translocation breakpoint from
SOX9 reported to date. In addition, we have refined the breakpoint in an acampomelic CD case described elsewhere and have found that it lies ∼900 kb upstream of
SOX9.
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