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Carolyn J Brown

Publications and source records attributed to Carolyn J Brown.

At least 19 recordsLinked to original sources
PubMed2006

A comprehensive analysis of common copy-number variations in the human genome.

Segmental copy-number variations (CNVs) in the human genome are associated with developmental disorders and susceptibility to diseases. More importantly, CNVs may represent a major genetic component of our phenotypic diversity. In this study, using a whole-genome array comparative genomic hybridization assay, we identified 3,654 autosomal segmental CNVs, 800 of which appeared at a frequency of at least 3%. Of these frequent CNVs, 77% are novel. In the 95 individuals analyzed, the two most diverse genomes differed by at least 9 Mb in size or varied by at least 266 loci in content. Approximately 68% of the 800 polymorphic regions overlap with genes, which may reflect human diversity in senses (smell, hearing, taste, and sight), rhesus phenotype, metabolism, and disease susceptibility. Intriguingly, 14 polymorphic regions harbor 21 of the known human microRNAs, raising the possibility of the contribution of microRNAs to phenotypic diversity in humans. This in-depth survey of CNVs across the human genome provides a valuable baseline for studies involving human genetics.

Chromosome Mapping↗
PubMed2006

Epigenomics: mapping the methylome.

DNA methylation is integral to normal development and disease processes. However, the genomic distribution of methylated sequences--the methylome--is poorly understood. We have recently developed a platform technology for rapid assessment of methylation status throughout the human genome in a high-resolution, high-throughput manner. This is achieved by coupling a methylated DNA immunoprecipitation (MeDIP) method for isolating methyl cytosine rich fragments with array-based comparative genomic hybridization (array CGH). Using a combination of whole genome tiling path BAC arrays and CpG island microarrays, DNA methylation profiles are obtained simultaneously at both genome-wide and locus-specific levels. A comparison between male and female DNA using MeDIP-array CGH revealed unexpected hypomethylation of the inactive x-chromosome in gene-poor regions. Furthermore, comparisons between cancer and noncancer cell types yielded differential methylation patterns that link genetic and epigenetic instability offering a new approach to decipher misregulation in cancer. Finally, we provide new data showing epigenomic instability in lung cancer cells with concurrent regions of genetic and epigenetic alterations harboring known oncogenes.

Chromatin Immunoprecipitation↗
PubMed2006

Mechanisms of X-chromosome inactivation.

Mammalian X-chromosome inactivation is an impressive example of epigenetic gene regulation, whereby the majority of genes on the approximately 160 Mb X chromosome are silenced in a strictly cis-limited fashion. In this review we will discuss the important players involved in the silencing process. The process is initiated by transcription and cis-localization of the non-coding XIST RNA, which then recruits many of the epigenetic features generally associated with heterochromatin, including histone modifications, histone variants and DNA methylation.

Animals↗
PubMed2006

Auditory neuropathy characteristics in children with cochlear nerve deficiency.

OBJECTIVE: To describe a group of children exhibiting electrophysiologic responses characteristic of auditory neuropathy (AN) who were subsequently identified as having absent or small cochlear nerves (i.e., cochlear nerve deficiency). DESIGN: A retrospective review of the clinical records, audiological testing results, and magnetic resonance imaging (MRI) studies. Fifty-one of 65 children with AN characteristics on auditory brain stem response (ABR) testing had MRI available for review. Nine (18%) of these 51 children with ABR characteristic of AN have been identified as having small (N = 2; 4%) or absent (N = 7; 14%) cochlear nerves on MRI. RESULTS: Of the nine children with cochlear nerve deficiency, five (56%) were affected unilaterally and four (44%) bilaterally. Eight of nine presented after failing a newborn infant hearing screening, whereas one presented at 3 yr of age. On diagnostic ABR testing, all 9 children (9 of 13 affected ears; 69%) had evidence of a cochlear microphonic (CM) and absent neural responses in at least one ear. In the unilateral cases, AN characteristics were detected in all affected ears. In bilateral cases, at least one of the ears in each child demonstrated the AN phenotype, whereas the contralateral ear had no CM identified. Only one ear with cochlear nerve deficiency had present otoacoustic emissions as measured by distortion-product otoacoustic emissions. In children with appropriate available behavioral testing results, all ears without cochlear nerves were identified as having a profound hearing loss. Only 4 (31%) of the 13 ears with cochlear nerve deficiency had a small internal auditory canal on MRI. CONCLUSIONS: Children with cochlear nerve deficiency can present with electrophysiologic evidence of AN. These children frequently refer on newborn screening examinations that use ABR-based testing methods. Similar to other causes of AN, diagnostic ABR testing will show a CM with absent neural responses. Given that 9 (18%) of 51 children with available MRI and electrophysiologic characteristics of AN in our program have been identified as having cochlear nerve deficiency makes this a relatively common diagnosis. These findings suggest that MRI is indicated for all children diagnosed with AN. Moreover, electrophysiologic evidence of unilateral AN in association with a profound hearing loss should make the clinician highly suspicious for this problem. Although children with cochlear nerve deficiency who have a small nerve may benefit from cochlear implantation or amplification, these interventions are obviously contraindicated in children with completely absent cochlear nerves.

Audiometry, Pure-Tone↗
PubMed2006

Internal auditory canal morphology in children with cochlear nerve deficiency.

OBJECTIVE: To describe the internal auditory canal (IAC) and inner ear morphologic characteristics of children with cochlear nerve (CN) deficiency. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Fourteen children with small or absent (deficient) CNs have been identified by means of high-resolution magnetic resonance imaging (MRI). INTERVENTIONS: MRI of the brain. Clinical evaluation. MAIN OUTCOME MEASURES: Review of medical records, audiological testing results, and imaging studies. Images were evaluated for the structure of the cochlear, vestibular and facial nerves, IACs and inner ears. Audiometric thresholds were evaluated in all subjects. METHODS: Fourteen children with small or absent (deficient) CNs have been identified by means of high-resolution MRI. A review of the medical records, audiologic testing results, and imaging studies was undertaken. The images were evaluated for the structure of the cochlear, vestibular and facial nerves, IACs, and inner ears. The audiometric thresholds were evaluated in all subjects. RESULTS: Among the 14 patients, 5 had known syndromes. MRI allowed an exact specification of the nervous structures within all ears with normal-size IACs. Precise characterization of the nerves in ears with small IACs was more difficult, requiring a consideration of both imaging findings and functional parameters. Five children had bilateral deficient CNs, whereas the remaining 9 subjects were affected unilaterally. Thus, 19 ears had CN deficiency (absent CN, 16; small CN, 3). Eleven ears had normal-size IACs and deficient CNs. Of the 9 ears with small IACs, 8 had deficient CNs (absent, 7; small, 1) on the basis of both MRI and functional assessments. Two ears with small IACs had clear morphologic and/or functional evidence for the presence of a CN: one had a small-size CN on MRI, whereas another had a single nerve in a small IAC with present facial and auditory functions. CONCLUSION: The findings of this study suggest that CN deficiency is not an uncommon cause of congenital hearing loss. The findings that most ears with CN deficiency had normal IAC morphology and that two ears with small IACs had CNs present indicate that IAC morphology is an unreliable surrogate marker of CN integrity. On the basis of these findings, we think that high-resolution MRI, rather than CT imaging, should be performed in all cases of pediatric hearing loss, especially in those cases where profound hearing loss has been documented. For ears with small IACs, the resolution of MRI currently remains limiting. In these cases, the determination of CN status frequently requires a variety of anatomic (CT and MRI) and functional tests (auditory brainstem response, otoacoustic emissions, behavioral audiometry, and physical examination).

Audiometry↗
PubMed2005

Epigenetic predisposition to expression of TIMP1 from the human inactive X chromosome.

BACKGROUND: X inactivation in mammals results in the transcriptional silencing of an X chromosome in females, and this inactive X acquires many of the epigenetic features of silent chromatin. However, not all genes on the inactive X are silenced, and we have examined the TIMP1 gene, which has variable inactivation amongst females. This has allowed us to examine the features permitting expression from the otherwise silent X by comparing inactive X chromosomes with and without TIMP1 expression. RESULTS: Expression was generally correlated with euchromatic chromatin features, including DNA hypomethylation, nuclease sensitivity, acetylation of histone H3 and H4 and hypomethylation of H3 at lysines 9 and 27. Demethylation of the TIMP1 gene by 5-azacytidine was able to induce expression from the inactive X chromosome in somatic cell hybrids, and this expression was also accompanied by features of active chromatin. Acetylated histone H3 continued to be observed even when expression was lost in cells that naturally expressed TIMP1; while acetylation was lost upon TIMP1 silencing in cells where expression from the inactive X had been induced by demethylation. Thus ongoing acetylation of inactive X chromosomes does not seem to be simply a 'memory' of expression. CONCLUSION: We propose that acetylation of H3 is an epigenetic mark that predisposes to TIMP1 expression from the inactive X chromosome in some females.

Acetylation↗
PubMed2005

Investigations of the genomic region that contains the clf1 mutation, a causal gene in multifactorial cleft lip and palate in mice.

BACKGROUND: Human nonsyndromic cleft lip and palate, CL(P), is genetically complex, with one contributing gene on chromosome 17q. A potentially homologous gene, clf1 on distal chromosome 11, is part of the digenic cause of the 10-30% CL(P) in the A/WySn mouse strain. Here we report our progress toward identifying the clf1 mutation. METHODS: Transcription from all of the known and predicted genes in the 1.5-Mb candidate region was examined in A/WySn and control (AXB-4/Pgn) ED10-11 embryo heads. The marker haplotype for 28 inbred strains across the clf1 region was obtained. The entire transcripts of Wnt9b and Wnt3 in A/WySn were sequenced. Using long PCR, the genomic region from Wnt3 throughWnt9b was screened in A/WySn for an inserted retrotransposon. RESULTS: Gosr2, Wnt9b, Wnt3, Nsf, Arf2, Crhr1, Mapt, Cdc27, Myl4, Itgb3, chr11_20.152, chr11_20.154, chr11_20.155, and chr11_20.156 are expressed in ED10-11 heads. None is absent or detectably reduced in A/WySn. The ancestral pre-clf1 mutation haplotype was found in CBA/J mice. By a test-cross, CBA/J was confirmed to lack the clf1 mutation. Three single-nucleotide variants in A/WySn (vs. C57BL/6J) were found in each of the 3' untranslated regions (3'UTRs) of Wnt3 and of Wnt9b, respectively; their presence in CBA/J shows that none are the clf1 mutation. An inserted intracisternal A particle (IAP) retrotransposon located 6.6 kb from the 3' end of Wnt9b was found in A/WySn and in all clf1 strains tested. This IAP is absent in C57BL/6J and CBA/J. CONCLUSIONS: The clf1 mutation is a genomic alteration present in A/WySn and absent in the ancestral chromosomal segment in CBA/J. The IAP retrotransposon insertion near Wnt9b in A/WySn fits this criterion; we predict that interference with Wnt9b function by this IAP is the clf1 mutation.

Animals↗
PubMed2005

Effect of audiometric configuration on threshold and suprathreshold auditory steady-state responses.

OBJECTIVE: The purpose of this study was to examine the correlation between auditory steady-state response (ASSR) thresholds and behavioral thresholds in hearing-impaired adults with two common audiometric configurations. A second goal was to compare suprathreshold ASSR growth functions in these two subject groups and to determine whether these growth functions could be used clinically to improve threshold estimation. DESIGN: Thirty adults participated, including 10 subjects with normal hearing, 10 subjects with flat moderately severe sensorineural hearing loss, and 10 subjects with sloping high-frequency sensorineural hearing loss. The accuracy of ASSR threshold estimations for the frequencies of 500, 1000, 2000, and 4000 Hz was compared across groups. In addition, ASSRs were recorded at multiple suprathreshold intensity levels, and the growth of the response was compared across subject groups. RESULTS: ASSR and behavioral thresholds were strongly correlated across all subjects, with no significant difference by audiometric configuration. Slightly poorer correlations were obtained in the normal-hearing subjects than in hearing-impaired subjects and for the 500-Hz test frequency compared with the higher stimulus frequencies. Subtraction and regression methods for predicting behavioral thresholds from ASSR thresholds were equally accurate. Suprathreshold amplitude growth was variable among individuals, but mean growth functions showed steeper slopes in hearing-impaired subjects than in normal-hearing subjects, particularly for the higher frequencies (2000 to 4000 Hz). However, there was not a significant difference in the slopes of amplitude growth functions between subjects with sloping versus flat audiometric configurations for these frequencies, and estimation of threshold from suprathreshold ASSR amplitude growth functions was not advantageous. CONCLUSIONS: ASSR thresholds accurately predicted behavioral threshold equally well for flat or sloping audiometric configurations. The accuracy of threshold estimation for either audiometric configuration and the similar growth function slopes may suggest that there is little spread of activation to neighboring regions of the cochlea when using multiple 100% AM stimuli in subjects with moderately sloping losses. The small amplitude of the ASSR response and individual variability may make threshold estimation based on extrapolation from suprathreshold ASSR responses impractical.

Acoustic Stimulation↗
PubMed2005

Threshold prediction using the auditory steady-state response and the tone burst auditory brain stem response: a within-subject comparison.

OBJECTIVE: The purpose of this study was to evaluate the accuracy with which auditory steady-state response (ASSR) and tone burst auditory brain stem response (ABR) thresholds predict behavioral thresholds, using a within-subjects design. Because the spectra of the stimuli used to evoke the ABR and the ASSR differ, it was hypothesized that the predictive accuracy also would differ, particularly in subjects with steeply sloping hearing losses. DESIGN: ASSR and ABR thresholds were recorded in a group of 14 adults with normal hearing, 10 adults with flat, sensorineural hearing losses, and 10 adults with steeply sloping, high-frequency, sensorineural hearing losses. Evoked-potential thresholds were recorded at 1, 1.5, and 2 kHz and were compared with behavioral, pure-tone thresholds. The predictive accuracy of two ABR protocols was evaluated: Blackman-gated tone bursts and linear-gated tone bursts presented in a background of notched noise. Two ASSR stimulation protocols also were evaluated: 100% amplitude-modulated (AM) sinusoids and 100% AM plus 25% frequency-modulated (FM) sinusoids. RESULTS: The results suggested there was no difference in the accuracy with which either ABR protocol predicted behavioral threshold, nor was there any difference in the predictive accuracy of the two ASSR protocols. On average, ABR thresholds were recorded 3 dB closer to behavioral threshold than ASSR thresholds. However, in the subjects with the most steeply sloping hearing losses, ABR thresholds were recorded as much as 25 dB below behavioral threshold, whereas ASSR thresholds were never recorded more than 5 dB below behavioral threshold, which may reflect more spread of excitation for the ABR than for the ASSR. In contrast, the ASSR overestimated behavioral threshold in two subjects with normal hearing, where the ABR provided a more accurate prediction of behavioral threshold. CONCLUSIONS: Both the ABR and the ASSR provided reasonably accurate predictions of behavioral threshold across the three subject groups. There was no evidence that the predictive accuracy of the ABR evoked using Blackman-gated tone bursts differed from the predictive accuracy observed when linear-gated tone bursts were presented in conjunction with notched noise. Similarly, there was no evidence that the predictive accuracy of the AM ASSR differed from the AM/FM ASSR. In general, ABR thresholds were recorded at levels closer to behavioral threshold than the ASSR. For certain individuals with steeply sloping hearing losses, the ASSR may be a more accurate predictor of behavioral thresholds; however, the ABR may be a more appropriate choice when predicting behavioral thresholds in a population where the incidence of normal hearing is expected to be high.

Acoustic Stimulation↗
PubMed2005

An analysis of the impact of auditory-nerve adaptation on behavioral measures of temporal integration in cochlear implant recipients.

The objective of this study was to determine the impact that auditory-nerve adaptation has on behavioral measures of temporal integration in Nucleus 24 cochlear implant recipients. It was expected that, because the auditory nerve serves as the input to central temporal integrator, a large degree of auditory-nerve adaptation would reduce the amount of temporal integration. Neural adaptation was measured by tracking amplitude changes of the electrically evoked compound action potential (ECAP) in response to 1000-pps biphasic pulse trains of varying durations. Temporal integration was measured at both suprathreshold and threshold levels by an adaptive procedure. Although varying degrees of neural adaptation and temporal integration were observed across individuals, results of this investigation revealed no correlation between the degree of neural adaptation and psychophysical measures of temporal integration.

Acoustic Stimulation↗
PubMed2005

Silencing of the mammalian X chromosome.

Mammalian X chromosome inactivation is one of the most striking examples of epigenetic gene regulation. Early in development one of the pair of approximately 160-Mb X chromosomes is chosen to be silenced, and this silencing is then stably inherited through subsequent somatic cell divisions. Recent advances have revealed many of the chromatin changes that underlie this stable silencing of an entire chromosome. The key initiator of these changes is a functional RNA, XIST, which is transcribed from, and associates with, the inactive X chromosome, although the mechanism of association with the inactive X and recruitment of facultative heterochromatin remain to be elucidated. This review describes the unique evolutionary history and resulting genomic structure of the X chromosome as well as the current understanding of the factors and events involved in silencing an X chromosome in mammals.

Animals↗
PubMed2004

Cochlear implantation in children with congenital inner ear malformations.

OBJECTIVE/HYPOTHESIS: To assess the audiologic and surgical outcomes for pediatric cochlear implant patients with inner ear malformations. STUDY DESIGN: Retrospective review of 315 pediatric cochlear implant cases from 1994 to 2002. METHODS: Twenty-eight pediatric cochlear implant patients with known inner ear malformations determined on high-resolution computed tomography (HRCT) of the temporal bone were the subjects of review. Results of HRCT findings, intraoperative findings, postoperative complications, and objective measures of both closed- and open-set testing of speech perception were analyzed. RESULTS: Patients with the constellation of an incompletely partitioned (IP) cochlea, enlarged vestibular aqueduct (EVA), and a dilated vestibule (i.e., Mondini's malformation) as well as those with an isolated EVA or partial semicircular canal aplasia have relatively good levels of speech perception. Patients with total semicircular canal aplasia, isolated IP, cochlear hypoplasia, or common cavity demonstrated lower levels of performance. Poor performance may be related to associated developmental delays rather than labyrinthine anatomy alone. Complications of surgery were relatively limited. CONCLUSIONS: Cochlear implantation can be successfully performed in children with inner ear malformations. These children and their parents can expect significant auditory benefits from this intervention. The various types of inner ear malformations may have quite different prognoses for good auditory performance.

Adolescent↗
PubMed2004

Cochlear implantation for children with GJB2-related deafness.

OBJECTIVES/HYPOTHESIS: Mutations in GJB2 are a common cause of congenital sensorineural hearing loss. Many children with these mutations receive cochlear implants for auditory habilitation. The purpose of the study was to compare the speech perception performance of cochlear implant patients with GJB2-related deafness to patients without GJB2-related deafness. STUDY DESIGN: Retrospective case review. METHODS: Pediatric cochlear implant recipients who have been tested for GJB2 mutation underwent chart review. All patients received cochlear implantation at a tertiary referral center, followed by outpatient auditory habilitation. Charts were reviewed for cause and duration of deafness, age at time of cochlear implantation, intraoperative and postoperative complications, duration of use, and current age. Results of standard tests of speech perception administered as a part of the patients' auditory habilitation were reviewed. RESULTS: Twenty patients with GJB2 mutations were compared with 27 patients without GJB2 mutations. There was no statistical difference between patients with and without GJB2-related congenital sensorineural hearing loss with regard to open-set and closed-set speech recognition performance at 12, 24, and 36 months after cochlear implantation. Surgical complications were uncommon. CONCLUSION: Pediatric patients with congenital sensorineural hearing loss without other comorbid conditions (eg, developmental delay, inner ear malformations) perform well when they receive cochlear implantation and auditory habilitation. The presence or absence of GJB2 mutation does not appear to impact speech recognition performance at 12, 24, and 36 months after implantation.

Child, Preschool↗
PubMed2004

Sensitivity and specificity of averaged electrode voltage measures in cochlear implant recipients.

OBJECTIVE: The primary purpose of this study was to evaluate the diagnostic accuracy of averaged electrode voltages (AEVs) for identifying malfunctioning electrodes in cochlear implant users. DESIGN: AEVs were measured using common ground (N = 33 ears) and monopolar stimulation modes (N = 40 ears) in adult subjects implanted with the Nucleus 24M or Nucleus 24R(CS) cochlear implant. AEV measures were then compared with common ground electrode impedance measures as well as to subjective judgments of electrode sound quality to determine the sensitivity and specificity of AEVs. RESULTS: Results showed excellent specificity for both modes of AEV testing: 97.9% for common ground and 99.8% for monopolar. Sensitivity for common ground AEV testing was 91.7%; however the sensitivity of monopolar AEVs was very poor, at 7.7%. Monopolar AEVs accurately identified open circuits but missed all short circuits. These results are consistent with the sensitivity of impedance measures made with each of the two stimulation modes. CONCLUSIONS: Common ground AEVs are more reliable than monopolar AEVs for identifying malfunctioning electrodes.

Adolescent↗
PubMed2003

Beyond sense: the role of antisense RNA in controlling Xist expression.

The Xist RNA is a critical component of X inactivation, and Tsix is a non-coding antisense RNA to the Xist gene. We review the data from mouse that demonstrates that Tsix serves to regulate Xist expression. TSIX antisense transcripts have also been detected in humans, but without a manipulatable system to study the inactivation process in humans it remains unknown whether these antisense transcripts are functional in regulating human XIST. After a review of the differences between the human and mouse antisense, we discuss how the question of whether or not the human TSIX is functional impacts models of Tsix function.

Animals↗
PubMed2003

A stain upon the silence: genes escaping X inactivation.

X-chromosome inactivation is a remarkable epigenetic event in mammalian females that results in the transcriptional silencing of one of the pair of X chromosomes. However, not all X-linked genes are subject to inactivation, and in humans, the proportion of genes on the X chromosome that escapes inactivation is more than 15%. Here we examine the causes and consequences of failure to silence the entire X chromosome. We discuss the impact of the evolutionary history of the X (and Y) chromosome, and the bioinformatic approaches that promise to provide new insights into the genomic architecture of genes or regions that escape X-chromosome inactivation.

Animals↗
PubMed2003

Characterization of expression at the human XIST locus in somatic, embryonal carcinoma, and transgenic cell lines.

X inactivation requires XIST, a functional RNA that is expressed exclusively from, and localizes to, the inactive X in female somatic cells. In mouse, low-level unstable transcription of Xist is observed prior to the time of inactivation, and an antisense transcript, Tsix, is a critical regulator of early Xist expression. To examine the presence and impact of an antisense transcript in humans we have characterized the extent of sense and antisense transcription in human somatic, transgenic, and embryonal carcinoma (EC) cell lines. Downstream antisense expression at the human XIST locus was not detected in somatic cells, but was detected in the EC line N-Tera2D1 and in somatic cells with an ectopic XIST locus. Presence of the antisense did not disrupt the stability or localization of the sense transcript. We have also identified additional sense transcripts in EC and female somatic cells and demonstrate that the 5' flanking JPX/ENOX gene is expressed from both the active and the inactive X chromosome in somatic cell hybrids, delimiting the extent of inactive X-specific transcriptional control in somatic cells. These analyses reveal similarities to and differences from the murine Xist and Tsix transcripts and generate a complex picture of developmentally regulated transcription through the region.

Animals↗