Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1 , SIX6 , and OTX2 resulting from a complex chromosomal rearrangement

We report on a 26-month-old boy with developmental delay and multiple congenital anomalies, including many features suggestive of either branchiootorenal syndrome (BOR) or oculoauriculovertebral spectrum (OAVS). Chromosomal microarray analysis (CMA) initially revealed a copy-number gain with a single BAC clone (RP11-79M1) mapping to 14q23.1. FISH analysis showed that the third copy of this genomic region was inserted into the long arm of one chromosome 13. The same pattern was also seen in the chromosomes of the father, who has mental retardation, short stature, hypernasal speech, and minor craniofacial anomalies, including tall forehead, and crowded dentition. Subsequent whole genome oligonucleotide microarray analysis revealed an ∼11.79 Mb duplication of chromosome 14q22.3–q23.3 and a loss of an ∼4.38 Mb sequence in 13q21.31–q21.32 in both the propositus and his father and FISH supported the apparent association of the two events. Chromosome 14q22.3–q23.3 contains 51 genes, including SIX1 , SIX6 , and OTX2 . A locus for branchiootic syndrome (BOS) has been mapped to 14q21.3–q24.3, and designated as branchiootic syndrome 3 (BOS3). Interestingly, mutations in SIX1 have been reported in patients with BOR/BOS3. We propose that the increased dosage of SIX1 , SIX6 , or OTX2 may be responsible for the BOR and OAVS-like features in this family. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/60991/1/32398_ftp.pd

Mosaicism for r(X) and der(X)del(X)(p11.23)dup(X)(p11.21p11.22) provides insight into the possible mechanism of rearrangement

We report a patient with a unique and complex cytogenetic abnormality involving mosaicism for a small ring X and deleted Xp derivative chromosome with tandem duplication at the break point. The patient presented with failure to thrive, muscular hypotonia, and minor facial anatomic anomalies, all concerning for Turner syndrome. Brain MRI revealed mild thinning of the corpus callosum, an apparent decrease in ventricular white matter volume, and an asymmetric myelination pattern. Array comparative genome hybridization analysis revealed mosaicism for the X chromosome, deletion of the short arm of an X chromosome, and a duplication of chromosome region Xp11.21-p11.22. G-banded chromosome and FISH analyses revealed three abnormal cell lines: 46,X,der(X)del(X)(p11.23)dup(X)(p11.21p11.22)/46,X,r(X)(q11.1q13.1)/45,X. The small ring X chromosome was estimated to be 5.2 Mb in size and encompassed the centromere and Xq pericentromeric region. X chromosome inactivation (XCI) studies demonstrated a skewed pattern suggesting that the ring X remained active, likely contributing to the observed clinical features of brain dysmyelination. We hypothesize that a prezygotic asymmetric crossing over within a loop formed during meiosis in an X chromosome with a paracentric inversion resulted in an intermediate dicentric chromosome. An uneven breakage of the dicentric chromosome in the early postzygotic period might have resulted in the formation of one cell line with the X chromosome carrying a terminal deletion and pericentromeric duplication of the short arm and the second cell line with the X chromosome carrying a complete deletion of Xp. The cell line carrying the deletion of Xp could have then stabilized through self-circularization and formation of the ring X chromosome

Hong Kong dentists' preparedness for medical emergency in dental clinics

Aim: The aim of this study was to investigate the Hong Kong dentists’ and dental clinics’ preparedness for medical emergency in the dental clinic. Methods: Two custom designed questionnaires were developed, one for dentists and another for dental clinics, to collect the required information. The sampling frame for participants was the list of registered dentists published by the Hong Kong Dental Council on its website in January 2016. A total of 434 dentists and 143 dental clinics were selected from the list by systematic random sampling. The latter sample was supplemented by 10 randomly selected government dental clinics. The questionnaires were mailed the selected dentists together with a cover letter and a stamped return envelope. A reminder letter and another copy of the questionnaire were sent out two weeks after the first mailing. Results: 167 (38%) completed dentist questionnaires and 53 (35%) clinic questionnaires were collected. Most of the respondent dentists had some deficient knowledge on basic life support (BLS), their mean score was 3.5 out of a maximum of 5. Most (>60%) of the respondents thought they were competent in performing medical emergency procedures except giving intravenous injection. Moreover, most (>60%) of them held positive attitude towards having immediate availability of essential medical emergency equipment and drugs in their clinic. Dentists who were more recent graduates, those with postgraduate qualifications, and those who work with accompaniment generally had higher mean BLS knowledge scores. In the dental clinics, the most commonly kept medical emergency equipment/drug was instant glucose (70%) and followed by antihistamine (62%). Only a quarter of the clinics were equipped with AED, and 45% were equipped with oxygen cylinder. For 8 out of the 11 items, a higher proportion of the bigger clinics (>2 dental chairs) than the smaller clinics had the medical emergency equipment/drug available (Chi-square test, p<0.05). Conclusion: Hong Kong dentists have a moderate level of knowledge on BLS which should be enhanced through regular attendance at CE courses. Their knowledge level is affected by a number of their background and professional activities factors. Most dental clinics in Hong Kong have only few of the essential medical emergency equipment and drugs while the larger clinics are better equipped than the smaller clinics.published_or_final_versio

Identification of Balanced Chromosomal Rearrangements Previously Unknown Among Participants in the 1000 Genomes Project: Implications for Interpretation of Structural Variation in Genomes and the Future of Clinical Cytogenetics

Purpose Recent studies demonstrate that whole-genome sequencing (WGS) enables detection of cryptic rearrangements in apparently balanced chromosomal rearrangements (also known as balanced chromosomal abnormalities, BCAs) previously identified by conventional cytogenetic methods. We aimed to assess our analytical tool for detecting BCAs in The 1000 Genomes Project without knowing affected bands. Methods: The 1000 Genomes Project provides an unprecedented integrated map of structural variants in phenotypically normal subjects, but there is no information on potential inclusion of subjects with apparently BCAs akin to those traditionally detected in diagnostic cytogenetics laboratories. We applied our analytical tool to 1,166 genomes from the 1000 Genomes Project with sufficient physical coverage (8.25-fold). Results: Our approach detected four reciprocal balanced translocations and four inversions ranging in size from 57.9 kb to 13.3 Mb, all of which were confirmed by cytogenetic methods and PCR studies. One of DNAs has a subtle translocation that is not readily identified by chromosome analysis due to similar banding patterns and size of exchanged segments, and another results in disruption of all transcripts of an OMIM gene. Conclusions: Our study demonstrates the extension of utilizing low-coverage WGS for unbiased detection of BCAs including translocations and inversions previously unknown in the 1000 Genomes Project

Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders

Interstitial deletions of the short arm of chromosome 6 are rare and have been associated with developmental delay, hypotonia, congenital anomalies, and dysmorphic features. We used array comparative genomic hybridization in a South Carolina Autism Project (SCAP) cohort of 97 subjects with autism spectrum disorders (ASDs) and identified an ~ 5.4 Mb deletion on chromosome 6p22.3-p23 in a 15-year-old patient with intellectual disability and ASDs. Subsequent database queries revealed five additional individuals with overlapping submicroscopic deletions and presenting with developmental and speech delay, seizures, behavioral abnormalities, heart defects, and dysmorphic features. The deletion found in the SCAP patient harbors ATXN1, DTNBP1, JARID2, and NHLRC1 that we propose may be responsible for ASDs and developmental delay

Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other Malformations

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal developmental disorder of the lung with defining histologic abnormalities typically associated with multiple congenital anomalies (MCA). Using array CGH analysis, we have identified six overlapping microdeletions encompassing the FOX transcription factor gene cluster in chromosome 16q24.1q24.2 in patients with ACD/MPV and MCA. Subsequently, we have identified four different heterozygous mutations (frameshift, nonsense, and no-stop) in the candidate FOXF1 gene in unrelated patients with sporadic ACD/MPV and MCA. Custom-designed, high-resolution microarray analysis of additional ACD/MPV samples revealed one microdeletion harboring FOXF1 and two distinct microdeletions upstream of FOXF1, implicating a position effect. DNA sequence analysis revealed that in six of nine deletions, both breakpoints occurred in the portions of Alu elements showing eight to 43 base pairs of perfect microhomology, suggesting replication error Microhomology-Mediated Break-Induced Replication (MMBIR)/Fork Stalling and Template Switching (FoSTeS) as a mechanism of their formation. In contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, probably due to haploinsufficiency for the neighboring FOXC2 and FOXL1 genes. These differences reveal the phenotypic consequences of gene alterations in cis