Two Cases of Ocular Manifestations in Patients with Microdeletion of the Chromosome 7 Long Arm

Purpose: We report ocular manifestations in two patients with 7q microdeletion. Case summary: (Case 1) A 62-day-old male infant was admitted to the ophthalmology outpatient department for ocular examination after being diagnosed with microdeletion of chromosome seven (7q36.2q36.3 deletion) in DNA microarray comparative genomic hybridization (DNA microarray CGH) and fluorescence in situ hybridization (FISH) tests. Fundus examination showed optic disc hypoplasia in both eyes and retinopathy of prematurity, accompanied by retinal hemorrhage in his right eye. Around the age of 24 months, the patient was diagnosed with intermittent exotropia with anisometropia and was prescribed spectacles. (Case 2) A 3-year-old male infant was referred to the ophthalmology clinic to evaluate poor fixation, which was found during rehabilitation therapy for cerebral palsy and developmental delay. Fundus examination showed an increased cup/disc ratio bilaterally. A flash visual evoked potential test indicated a decrease in amplitude in his right eye. Intermittent exotropia of forty prism diopters was observed. DNA microarray CGH and FISH tests performed at another hospital revealed microdeletion of chromosome seven (7q35 microdeletion) and CNTNAP2 gene loss. Conclusions: When genetic anomalies associated with ocular development are identified, it is necessary to detect the ophthalmic abnormalities early and provide the appropriate treatment to allow for the development of normal visual function.

Chromosomal Microarray Analysis on Intergenerational Effects of Oligomeric Proanthocyanidins Against Bisphenol-A Induced Brain Deformities

Oligomeric Proanthocyanidins (OPC) is a type of polyphenolic compound which have been demonstrated to have anti-cancer, anti-oxidant, anti-inflammatory and anti-mutagenic properties that may have the potential to reduce intergenerational effect of BPA towards DNA. This study was conducted to determine the effect of OPC on the DNA damage of BPA-induced rats using microarray CGH Chromosome Karyotyping. Adult Male Sprague Dawley rats were divided into six groups which are Normal, BPA, OPC10, OPC20, BPA+OPC10 and BPA+OPC20. The administration of BPA and/or OPC were conducted for 21 days using oral gavage before being mated with female rats of the same age at 1:1 mating ratio. Once the female rats were confirmed pregnant, the male rats were decapitated and their blood were collected for chromosome microarray analysis. The male offspring (F1 generation) were allowed to grow until 10 weeks old and their blood were also collected for chromosome microarray analysis. BPA group had a deletion of Vomeronasal receptor genes in which the deletion magnitude increased from P to F1 generation may affect the ability of the rats to detect chemosensory cues during neurobehavioral test. The amplification of Major Histocompatibility complex (MHC) class I gene in BPA+OPC20 group may aid in a better performance during hippocampal-dependent memory tests. These results suggested that OPC could be a potential agent in reducing the intergenerational effect of BPA. Current finding may enrich our understanding particularly in the possible mechanism of OPC on BPA-induced memory impairment Keywords: Bisphenol-A, Brain, microarray CGH Chromosome Karyotyping, Oligomeric Proanthocyanidins, Intergenerational

Detection of large rearrangements in a hereditary pan-cancer panel using next-generation sequencing

Background Healthcare providers increasingly use information about pathogenic variants in cancer predisposition genes, including sequence variants and large rearrangements (LRs), in medical management decisions. While sequence variant detection is typically robust, LRs can be difficult to detect and characterize and may be underreported as a cause for hereditary cancer risk. This report describes the outcomes of hereditary cancer genetic testing using a comprehensive strategy that employs next-generation sequencing (NGS) for LR detection, coupled with LR confirmation using repeat hybrid capture NGS, microarray comparative genomic hybridization (microarray-CGH), and/or multiplex ligation-dependent probe amplification (MLPA). Methods Sequencing and LR analysis were conducted in a consecutive series of 376,159 individuals who received clinical testing with a hereditary pan-cancer gene panel from September 2013 through May 2017. NGS dosage analysis was used to evaluate potential deletions or duplications, with controls in place to exclude pseudogene reads. Samples positive for a putative LR based on NGS were confirmed using a comprehensive approach that included targeted microarray-CGH and/or MLPA analysis, with further examination as needed to ascertain the nature of the LR. Results A total of 3461 LRs were identified and classified as a deleterious mutation (DM), suspected deleterious mutation (SDM) or variant of uncertain significance. Pathogenic LRs (DM/SDM) accounted for the majority of LRs (67.7%), the largest proportion of which were deletions (86.1%), followed by duplications (11.3%), insertions (1.8%), triplications (0.5%), and inversions (0.3%). Several cases presented illustrate that the laboratory approach employed here can ensure consistent identification and accurate characterization of LRs. In the absence of this comprehensive testing strategy, 9% of LRs identified in this testing population might have been missed, potentially leading to inappropriate medical management in as many as 210 individuals referred for hereditary cancer testing. Conclusions These data show that copy number analysis using NGS coupled with confirmatory testing reliably detects and characterizes LRs. Further, LRs comprise a substantial proportion (7.2%) of pathogenic variants identified by the test. A robust and accurate LR identification strategy is an essential component of a high-quality genetic testing program, enabling clinicians to optimize patient medical management decisions.

Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma

Background: Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. Material and methods: Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. Results: Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. Conclusion: ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.