PubMed Health⌕ Search

Biomedical subjects

Lisa G Shaffer

Publications and source records attributed to Lisa G Shaffer.

At least 37 records · Page 2Linked to original sources
PubMed2005

Delineation of mechanisms and regions of dosage imbalance in complex rearrangements of 1p36 leads to a putative gene for regulation of cranial suture closure.

Structural chromosome abnormalities have aided in gene identification for over three decades. Delineation of the deletion sizes and rearrangements allows for phenotype/genotype correlations and ultimately assists in gene identification. In this report, we have delineated the precise rearrangements in four subjects with deletions, duplications, and/or triplications of 1p36 and compared the regions of imbalance to two cases recently published. Fluorescence in situ hybridization (FISH) analysis revealed the size, order, and orientation of the duplicated/triplicated segments in each subject. We propose a premeiotic model for the formation of these complex rearrangements in the four newly ascertained subjects, whereby a deleted chromosome 1 undergoes a combination of multiple breakage-fusion-bridge (BFB) cycles and inversions to produce a chromosome arm with a complex rearrangement of deleted, duplicated and triplicated segments. In addition, comparing the six subjects' rearrangements revealed a region of overlap that when triplicated is associated with craniosynostosis and when deleted is associated with large, late-closing anterior fontanels. Within this region are the MMP23A and -B genes. We show MMP23 gene expression at the cranial sutures and we propose that haploinsufficiency results in large, late-closing anterior fontanels and overexpression results in craniosynostosis. These data emphasize the important role of cytogenetics in investigating and uncovering the etiologies of human genetic disease, particularly cytogenetic imbalances that reveal potentially dosage-sensitive genes.

Animals↗
PubMed2005

Construction of a natural panel of 11p11.2 deletions and further delineation of the critical region involved in Potocki-Shaffer syndrome.

Potocki-Shaffer syndrome (PSS) is a contiguous gene deletion syndrome that results from haploinsufficiency of at least two genes within the short arm of chromosome 11[del(11)(p11.2p12)]. The clinical features of PSS can include developmental delay, mental retardation, multiple exostoses, parietal foramina, enlarged anterior fontanel, minor craniofacial anomalies, ophthalmologic anomalies, and genital abnormalities in males. We constructed a natural panel of 11p11.2-p13 deletions using cell lines from 10 affected individuals, fluorescence in situ hybridization (FISH), microsatellite analyses, and array-based comparative genomic hybridization (array CGH). We then compared the deletion sizes and clinical features between affected individuals. The full spectrum of PSS manifests when deletions are at least 2.1 Mb in size, spanning from D11S1393 to D11S1385/D11S1319 (44.6-46.7 Mb from the 11p terminus) and encompassing EXT2, responsible for multiple exostoses, and ALX4, causing parietal foramina. Yet one subject with parietal foramina whose deletion does not include ALX4 indicates that ALX4 in this subject may be rendered functionally haploinsufficient by a position effect. Based on comparative deletion mapping of eight individuals with the full PSS syndrome including mental retardation and two PSS families with no mental retardation, at least one gene related to mental retardation is likely located between D11S554 and D11S1385/D11S1319, 45.6-46.7 Mb from the 11p terminus.

Abnormalities, Multiple↗
PubMed2005

Array-based comparative genomic hybridization in clinical diagnosis.

The sequencing of the human genome and development of high-throughput microarray technologies have enhanced the detection of copy number alterations in cancer research and the study of constitutional chromosomal abnormalities. Microarray-based comparative genomic hybridization (array CGH) has integrated molecular and traditional cytogenetics and has begun to impact the clinician's approach to medical genetics. Clinical applications of array CGH may define new genetic syndromes, expand the phenotype of existing syndromes and characterize a genomic signature of some cancers. As array CGH becomes the initial diagnostic approach for the investigation of constitutional and acquired chromosomal abnormalities, the combination of bioinformatics, robotics and microarray technology will set the stage for a new generation of high-resolution and high-throughput tools for genetic analysis, diagnosis and gene discovery.

Disease↗
PubMed2005

ATR-16 due to a de novo complex rearrangement of chromosome 16.

We describe a child with ATR-16 [alpha-thalassemia (thal)/mental retardation], who was referred for genetic evaluation because of minor anomalies and developmental delay. Cytogenetic analysis demonstrated a de novo complex rearrangement of chromosome 16. Fluorescence in situ hybridization (FISH) analysis, using chromosome 16 subtelomeric probes, showed that this patient had a deletion of the distal short arm of chromosome 16 that contains the alpha-globin genes and a duplication of 16q. Analysis of the alpha-globin locus by Southern blot showed a half normal dose of the alpha-globin gene. Microsatellite marker studies revealed that the duplicated 16q region was maternal in origin. Hematological studies revealed anemia, hypochromia and occasional cells with Hb H inclusion bodies. A hematological screening for alpha-thal should be considered in patients with mild developmental delay and a suggestive phenotype of ATR-16 with microcytic hypochromic anemia and normal iron status. The stellate pattern of the iris, a new finding in our patient, may contribute to a better clinical delineation of both syndromes, ATR-16 and/or duplication of 16qter.

Chromosome Aberrations↗
PubMed2004

A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A.

The genetic contribution to autism is often attributed to the combined effects of many loci (ten or more). This conclusion is based in part on the much lower concordance for dizygotic (DZ) than for monozygotic (MZ) twins, and is consistent with the failure to find strong evidence for linkage in genome-wide studies. We propose that the twin data are compatible with oligogenic inheritance combined with a major, genetic or epigenetic, de novo component to the etiology. Based on evidence that maternal but not paternal duplications of chromosome 15q cause autism, we attempted to test the hypothesis that autism involves oligogenic inheritance (two or more loci) and that the Angelman gene (UBE3A), which encodes the E6-AP ubiquitin ligase, is one of the contributing genes. A search for epigenetic abnormalities led to the discovery of a tissue-specific differentially methylated region (DMR) downstream of the UBE3A coding exons, but the region was not abnormal in autism lymphoblasts or brain samples. Based on evidence for allele sharing in 15q among sib-pairs, abnormal DNA methylation at the 5'-CpG island of UBE3A in one of 17 autism brains, and decreased E6-AP protein in some autism brains, we propose a mixed epigenetic and genetic model for autism with both de novo and inherited contributions. The role of UBE3A may be quantitatively modest, but interacting proteins such as those ubiquitinated by UBE3A may be candidates for a larger role in an oligogenic model. A mixed epigenetic and genetic and mixed de novo and inherited (MEGDI) model could be relevant to other "complex disease traits".

Alleles↗
PubMed2004

New syndrome: focal dermal hypoplasia, morning glory anomaly, and polymicrogyria.

Regional skin hypoplasia has been described in several genetic syndromes, including focal dermal hypoplasia (FDH), microphthalmia with linear skin defects (MLS), oculocerebrocutaneous syndrome (OCCS), and terminal osseous dysplasia and pigmentary defects (TODP). All but OCCS have been reported to follow an X-linked inheritance pattern. We describe a 14-year-old girl with clinical features overlapping with these disorders. She had mild mental retardation, macrocephaly, microphthalmia, right-sided morning glory optic disc anomaly, palmar and lip pits, and polysyndactyly. A swirling pattern of skin hypopigmentation, papular hypopigmented and herniated skin lesions reminiscent of FDH most prominent over her face, head, hands, and feet was evident. Brain magnetic resonance imaging (MRI) showed polymicrogyria (most severely in the perisylvian and mesial frontal regions), enlarged left lateral ventricle, partial agenesis of the corpus callosum, and optic nerve tumor on the right. Dermatopathologic examination of the skin lesions was consistent with basaloid follicular hamartomas. The skin and digit anomalies observed overlap with FDH, but polymicrogyria, basaloid follicular hamartomas, optic nerve tumor, and morning glory anomaly have not previously been described in FDH. Skin defects in MLS are linear and the eyes typically have sclerocornea. Polymicrogyria has been described in OCCS, but not in any of the other three syndromes. The limb anomalies in TODP are reductions rather than polysyndactyly. Skin defects are localized to the face, and digital fibromas usually occur. While significant overlap exists between all four of the syndromes discussed, we believe that the constellation of anomalies observed in this girl most likely comprises a newly recognized syndrome.

Abnormalities, Multiple↗
PubMed2004

Monosomy 1p36 breakpoints indicate repetitive DNA sequence elements may be involved in generating and/or stabilizing some terminal deletions.

Monosomy 1p36 is the most commonly observed terminal deletion syndrome in humans. Our previous molecular studies on a large cohort of subjects suggest that monosomy 1p36 can result from a variety of chromosomal rearrangements including terminal truncations, interstitial deletions, derivative chromosomes, inverted duplications, and complex rearrangements. However, the mechanism(s) by which rearrangements of 1p36 are generated and/or stabilized is not understood. Sequence analysis of breakpoint junctions may provide valuable clues to the underlying mechanisms of many chromosomal aberrations. In this report, we analyze the breakpoints at the DNA-sequence level in four subjects with variable-sized deletions of 1p36. All four breakpoints fall within repetitive DNA-sequence elements (LINEs, SINEs, etc). This suggests that repetitive DNA-sequence elements may play an important role in generating and/or stabilizing terminal deletions of 1p36. Mechanisms by which repetitive elements may be involved in the process of terminal deletion formation and stabilization are discussed.

Chromosome Breakage↗
PubMed2004

Trisomy 14 mosaicism: a case report and review of the literature.

Trisomy 14 mosaicism is a rare chromosomal abnormality with distinct and recognizable clinical features. We describe two previously unreported abnormalities in this condition and delineate physical and psychomotor features and concerns for medical management. Trisomy 14 mosaicism should be suspected in individuals who have the features described herein, thus prompting cytogenetic evaluation of blood, and possibly other tissues for diagnosis.

Chromosomes, Human, Pair 14↗
PubMed2003

Translocation breakpoint mapping and sequence analysis in three monosomy 1p36 subjects with der(1)t(1;1)(p36;q44) suggest mechanisms for telomere capture in stabilizing de novo terminal rearrangements.

Monosomy 1p36 results from a variety of chromosome rearrangements, including terminal deletions, interstitial deletions, derivative chromosomes, and complex rearrangements. Our previous molecular studies on a large cohort of monosomy 1p36 subjects suggest that a significant percentage of terminal deletions of 1p36 are stabilized by the acquisition of telomeric sequences from other chromosome ends, forming derivative chromosomes (i.e., "telomere capture"). However, the molecular mechanism(s) that results in and/or stabilizes terminal deletions of 1p36 by telomere capture is poorly understood. In this report, we have mapped the translocation breakpoints in three subjects with der(1)t(1;1)(p36;q44) chromosomes by fluorescence in situ hybridization (FISH). These results indicate that the breakpoint locations are variable in all three subjects, with no common 1p deletion or 1q translocation breakpoints. In addition, sequence analysis of the 1p and 1q breakpoint-containing clones did not identify homologous sequences or low-copy repeats in the breakpoint regions, suggesting that nonallelic homologous recombination did not play a role in mediating these rearrangements. Microsatellite marker analysis indicates that two of the three derivative chromosomes were formed by intra-chromosomal rearrangements. These data are consistent with a number of recent reports in other model organisms that suggest break-induced replication at the site of a double-strand break may act as a mechanism of telomere capture by generating nonreciprocal translocations from terminally deleted chromosomes. Alternative models are also discussed.

Chromosome Aberrations↗
PubMed2003

Under-ascertainment of mosaic carriers of balanced homologous acrocentric translocations and isochromosomes.

Acrocentric rearrangements are the most common chromosome abnormalities in humans. Carriers of homologous acrocentric rearrangements (Robertsonian translocations (ROBs) between homologous chromosomes and isochromosomes) are at very high risk of having multiple spontaneous abortions and chromosomally abnormal offspring. Parents of fetuses and children with unbalanced homologous acrocentric rearrangements are rarely found to be carriers or mosaic for the same rearrangement. Even though recurrent miscarriages may indicate a carrier parent, carriers are rarely identified. Comparison of non-chromosome 21 homologous rearrangements to rea(21q21q) culled from the literature revealed a 7-fold decrease in the number of mosaic cases among the parents of non-rea(21q21q) offspring. This under-ascertainment in parents may be due to low level mosaicism confined to the gonads, a true biological difference between chromosome 21 rearrangements and other homologous acrocentric rearrangements, or simply to the lack of rigorous clinical investigation of the parental karyotypes to uncover mosaicism. We recommend that polymorphic marker analysis be applied to apparently de novo acrocentric rearrangements to distinguish those resulting from biparental postzygotic formation from those resulting from meiotic formation; the latter of which may indicate a potential carrier parent. Parental chromosomal constitutions could then be screened in a large number of cells and in more than one tissue type to identify mosaicism. Identification of mosaicism allows for accurate genetic counseling and discussion of reproductive options. However, given that mosaicism may be restricted to the gonads, prenatal testing is likely to be desired by the family whether or not mosaicism is found.

Chromosome Aberrations↗
PubMed2003

Skeletal defects in paternal uniparental disomy for chromosome 14 are re-capitulated in the mouse model (paternal uniparental disomy 12).

Human paternal uniparental disomy for chromosome 14 (upd(14)pat) presents with skeletal abnormalities, joint contractures, dysmorphic facial features and developmental delay/mental retardation. Distal human chromosome 14 (HSA14) is homologous to distal mouse chromosome 12 (MMU12) and both regions have been shown to contain imprinted genes. In humans, consistent radiographic findings include a narrow, bell-shaped thorax with caudal bowing of the anterior ribs, cranial bowing of the posterior ribs and flaring of the iliac wings without shortening or dysplasia of the long bones. Mice with upd(12)pat have thin ribs with delayed ossification of the sternum, skull and feet. In both mice and humans, the axial skeleton is predominantly affected. We hypothesize that there is an imprinted gene or genes on HSA14/MMU12 that specifically affects rib/thorax development and the maturation of ossification centers in the sternum, feet and skull with little effect on long bone development.

Animals↗
PubMed2003

Frequent translocations occur between low copy repeats on chromosome 22q11.2 (LCR22s) and telomeric bands of partner chromosomes.

The chromosome 22q11.2 region is susceptible to rearrangements, mediated by low copy repeats (LCR22s). Deletions and duplications are mediated by homologous recombination events between LCR22s. The recurrent balanced constitutional translocation t(11;22)(q23;q11) breakpoint occurs in an LCR22 and is mediated by double strand breaks in AT-rich palindromes on both chromosomes 11 and 22. Recently, two cases of a t(17;22)(q11;q11) were reported, mediated by a similar mechanism (21). Except for these constitutional translocations, the molecular basis for non-recurrent, reciprocal 22q11.2 translocations is not known. To determine whether there are specific mechanisms that could mediate translocations, we analyzed cell lines derived from 14 different individuals by genotyping and FISH mapping. Somatic cell hybrid analysis was carried out for four cell lines. In five cell lines, the translocation breakpoints occurred in the same LCR22 as for the t(11;22) translocation, suggesting that similar molecular mechanisms are responsible. An additional three occurred in other LCR22s, and six were in non-LCR22 regions, mostly in the proximal half of the 22q11.2 region. The translocation breakpoints on the partner chromosomes were all located in the telomeric bands, proximal to the most telomeric unique sequence probe, in eight cell lines and distal to those loci in six. Therefore, several of the breakpoints were found to occur in the vicinity of highly dynamic regions of the genome, 22q11.2 and telomeric bands. We hypothesize that these regions are more susceptible to breakage and repair, resulting in translocations.

Base Sequence↗
PubMed2003

Development of a comparative genomic hybridization microarray and demonstration of its utility with 25 well-characterized 1p36 deletions.

Chromosomal abnormalities, such as deletions and duplications, are characterized by specific and often complex phenotypes resulting from an imbalance in normal gene dosage. However, routine chromosome banding is not sensitive enough to detect subtle chromosome aberrations (<5-10 Mb). Array-based comparative genomic hybridization (array CGH) is a powerful new technology capable of identifying chromosomal imbalance at a high resolution by co-hybridizing differentially labeled test and control DNAs to a microarray of genomic clones. We used a previously assembled contig of large-insert clones that span 10.5 Mb of the most distal region of 1p36 to design a microarray. The array includes 97 clones from 1p36, 41 clones from the subtelomeric regions of all human chromosomes, and three clones from each of the X and Y chromosomes. We used this microarray to study 25 subjects with well-characterized deletions of 1p36. All array CGH results agree with the deletion sizes and locations of the breakpoints in these subjects as determined previously by FISH and microsatellite analyses. Terminal deletions, interstitial deletions, derivative chromosomes and complex rearrangements were also identified. We anticipate that array CGH will change the diagnostic approach to many congenital and acquired genetic diseases such as mental retardation, birth defects and cancer.

Chromosome Aberrations↗
PubMed2003

Monosomy 1p36 breakpoint junctions suggest pre-meiotic breakage-fusion-bridge cycles are involved in generating terminal deletions.

Terminal deletions of 1p36 result in a mental retardation syndrome that is presumably caused by haploinsufficiency of a number of genes. Although monosomy 1p36 is the most commonly observed terminal deletion syndrome in humans, the molecular mechanism(s) that generates and stabilizes terminal deletions of 1p36 is not completely understood. Our previous molecular analysis of a large cohort of monosomy 1p36 subjects demonstrated that deletion sizes vary widely from approximately 1 Mb to >10.5 Mb in the most distal portion of 1p36 with no single common breakpoint. In this report, we have identified the precise breakpoint junctions in three subjects with apparently pure terminal deletions of 1p36 ranging from 2.5 to 4.25 Mb. These junctions revealed one deletion to be stabilized by telomeric repeat sequences and two to have terminal deletions associated with cryptic interrupted inverted duplications at the ends of the chromosomes. These interrupted inverted duplication/deletion breakpoints are reminiscent of those seen in tumor cell lines that have undergone breakage-fusion-bridge (BFB) cycles leading to gene amplification. We propose a pre-meiotic model for the formation of these deletions in which a terminally deleted chromosome is generated in the germ line and passes through at least one BFB cycle to produce gametes with terminal deletions associated with interrupted inverted duplications. These data suggest that, on a molecular level, seemingly pure terminal deletions visualized cytogenetically may be more complex, and BFB cycles may play an important role in generating terminal deletions associated with genetic disease in humans.

Animals↗
PubMed2003

Human chromosome 7: DNA sequence and biology.

DNA sequence and annotation of the entire human chromosome 7, encompassing nearly 158 million nucleotides of DNA and 1917 gene structures, are presented. To generate a higher order description, additional structural features such as imprinted genes, fragile sites, and segmental duplications were integrated at the level of the DNA sequence with medical genetic data, including 440 chromosome rearrangement breakpoints associated with disease. This approach enabled the discovery of candidate genes for developmental diseases including autism.

Animals↗
PubMed2003

Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome.

Monosomy 1p36 is the most common terminal deletion syndrome. This contiguous gene deletion syndrome is presumably caused by haploinsufficiency of a number of genes. We have constructed a contig of overlapping large-insert clones for the most distal 10.5 Mb of 1p36, evaluated the deletion sizes in 61 subjects with monosomy 1p36 from 60 families, and created a natural deletion panel. We found pure terminal deletions, interstitial deletions, derivative chromosomes, and more complex rearrangements. Breakpoints were "binned" into 0.5-Mb regions. Analyses revealed some clustering of breakpoints but no single common breakpoint. Determination of the parental origin showed that 60% of de novo 1p36 terminal deletions arose from the maternally inherited chromosome. Of the 61 subjects, 30 were examined systematically through a protocol at the Texas Children's Hospital General Clinical Research Center. Specifically, we report hearing evaluations, palatal and ophthalmological examinations, echocardiograms, neurological assessments, and thyroid function tests. To our knowledge, this systematic molecular and clinical characterization of monosomy 1p36 is the largest and most comprehensive study of this deletion syndrome to date. Many cytogenetically visible, apparent terminal deletions are more complex than anticipated by cytogenetics, as revealed at the molecular level by our study. Our clinical findings allow for the more accurate recognition of the syndrome and for proper medical evaluation.

Abnormalities, Multiple↗
PubMed2003

Cytogenetic analysis of obsessive-compulsive disorder (OCD): identification of a FRAXE fragile site.

Obsessive-compulsive disorder (OCD) is a chronic psychiatric disease characterized by recurrent obsessions, compulsions, or both. The prevalence rate of OCD is 2.1% in the general population. Here we report cytogenetic analysis of 26 patients affected with OCD. In one male patient (OCD-K33), we identified a fragile X chromosome by cytogenetic analysis with 21% of cells demonstrating a fragile site at Xq27-q28. Polymerase chain reaction (PCR) and Southern blot analysis demonstrated that the molecular basis of the OCD-K33 fragile X chromosome was expansion of the CCG repeat at FRAXE. The number of the expanded repeats was estimated to be more than 300 copies, qualifying it as a full FRAXE mutation. Further analysis of the family members of OCD-K33 revealed another member with a full FRAXE mutation (630-1,200 copies of the CCG repeat), who had the clinical phenotype of speech impairment, and two other members with normal phenotypes and no FRAXE expansion. The two FRAXE expansions lead to complete methylation at the CCG repeat. The co-segregation of the full FRAXE mutation with apparent neurologic disorders in the same family provides further support to the notion that FRAXE is a genetic neurologic condition. Our findings expand the spectrum of clinical phenotypes associated with FRAXE mutations.

Chromosomes, Human, X↗