Turner C.,Auckland City Hospital |
Mein R.,Guys Hospital |
Sharpe C.,Starship Childrens Hospital |
Love D.R.,Diagnostic Genetics
Journal of Clinical Neuroscience | Year: 2015
Merosin deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder characterized by mutations in the LAMA2 gene at chromosome 6q22-23. This gene spans 65 exons and encodes the α2 chain subunit of laminin-2. A variety of deletions, missense, nonsense and splice site mutations have been described in the LAMA2 gene, with resultant MDC1A. We describe a novel LAMA2 homozygous sequence variant in a Samoan patient with MDC1A and confirm its pathogenic effect with merosin immunohistochemistry on skeletal muscle biopsy. The likely effect of the sequence variant is modeled using in silico analysis. © 2015 Elsevier Ltd. All rights reserved.
Glamuzina E.,Starship Childrens Hospital |
Marquis-Nicholson R.,Diagnostic Genetics |
Knoll D.,Auckland City Hospital |
Love D.R.,Diagnostic Genetics |
And 4 more authors.
Journal of Paediatrics and Child Health | Year: 2011
Aim: The aim of this study was to develop and apply a mutation screening protocol for the ASS1 gene in order to confirm the diagnosis of citrullinaemia type I in neonates with elevated citrulline on expanded newborn screening (E-NBS). Methods: Three patients with an elevated citrulline level were identified via routine E-NBS between January and October 2008. Analysis of the ASS1 gene using a polymerase chain reaction and sequencing-based method was successfully applied to all three patients, together with a rapid mutation-specific detection method. Their clinical progress was followed for 16-22 months. Results: All three patients were homozygous for a previously reported missense mutation, c.787G>A (p.Val263Met), associated with a mild or asymptomatic clinical course. Conclusions: As a consequence of E-NBS, an increasing number of neonates with elevated citrulline of uncertain clinical significance are being identified. Rapid sequence analysis of the ASS1 gene can be used to confirm citrullinaemia type I and, increasingly, to infer phenotypic severity. Homozygosity for the same mutation was found in all three patients despite non-consanguinity and variable Pacific Island origin. These data suggest that this mutation may be relatively prevalent in these ethnic groups and imply a possible founder effect. © 2011 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
Marquis-Nicholson R.,University of Melbourne |
Prosser D.O.,Diagnostic Genetics |
Love J.M.,Diagnostic Genetics |
Zhang L.,Diagnostic Genetics |
And 10 more authors.
Circulation: Cardiovascular Genetics | Year: 2014
Background: Large gene rearrangements, not detectable by standard molecular genetic sequencing techniques, are present in a minority of patients with long QT syndrome. We aimed to screen for large rearrangements in genes responsible for long QT syndrome as part of the molecular autopsy of a 36-year-old woman who died suddenly and had a negative autopsy. A retrospective analysis of an ECG identified a long QT interval, but sequencing of known LQT genes was uninformative. Methods and Results: Array comparative genomic hybridization was used to screen for deletions and duplications in 101 genes implicated in cardiac disorders and sudden death using a postmortem blood sample. A 542 kb deletion encompassing the entire KCNJ2 gene was identified in the decedent. The mother had electrocardiographic U-wave changes consistent with Andersen-Tawil syndrome and exaggerated by exercise but none of the characteristic noncardiac features. Fluorescence in situ hybridization confirmed the deletion in the decedent and established its presence in the mother. Conclusions: A novel application of array comparative genomic hybridization and fluorescence in situ hybridization has identified that long QT syndrome and sudden cardiac death may occur as a result of a deletion of an entire gene. The case also supports recent research suggesting that noncardiac features of Andersen-Tawil syndrome occur only with missense or minor gene rearrangements in the KCNJ2 gene, resulting in a dominant negative effect on Kir2.x channels. © 2014 American Heart Association, Inc.
PubMed | Diagnostic Genetics, Starship Childrens Hospital, Auckland City Hospital and Guys Hospital
Type: Case Reports | Journal: Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | Year: 2015
Merosin deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder characterized by mutations in the LAMA2 gene at chromosome 6q22-23. This gene spans 65 exons and encodes the 2 chain subunit of laminin-2. A variety of deletions, missense, nonsense and splice site mutations have been described in the LAMA2 gene, with resultant MDC1A. We describe a novel LAMA2 homozygous sequence variant in a Samoan patient with MDC1A and confirm its pathogenic effect with merosin immunohistochemistry on skeletal muscle biopsy. The likely effect of the sequence variant is modeled using in silico analysis.
Wheeler B.J.,University of Otago |
Patterson N.,University of Otago |
Love D.R.,Diagnostic Genetics |
Love D.R.,University of Auckland |
And 4 more authors.
Journal of Diabetes and Metabolic Disorders | Year: 2013
Maturity-Onset Diabetes of the Young (MODY) is a monogenic form of diabetes, consisting of a heterogeneous group of autosomal dominant inherited disorders. Typical onset is in individuals prior to twenty five years, and presentation can mimic type 1 or 2 diabetes. Molecular genetic testing can allow precise identification of the different MODY sub-types. Making a specific diagnosis of MODY can have important implications for the guidance of appropriate treatment, prognosis and genetic counselling.We present the cases of three children and their families diagnosed with MODY over the past two years. These families highlight the features of three of the more common MODY subtypes, including two with novel mutations, one of which segregates in a kindred that is strongly affected by both MODY and classic autoimmune mediated diabetes. To date, we have identified a prevalence of MODY in the paediatric diabetes population of the lower South Island, New Zealand, of approximately 2.5%. This prevalence, along with increasing access to molecular genetic testing, highlights the importance of consideration of MODY in atypical diabetes presentations in the paediatric/adolescent population. © 2013 Wheeler et al.; licensee BioMed Central Ltd.
PubMed | Diagnostic Genetics
Type: Journal Article | Journal: Molecular syndromology | Year: 2012
The relatively rare proximal microdeletion of 17q12 (including deletion of the HNF1B gene) is associated with the renal cysts and diabetes syndrome. Recent reports have suggested that there may also be an association between this microdeletion and learning difficulties/autism. This case report describes one of only a few reported families segregating the 17q12 microdeletion, but which highlights the nonpenetrance and variable expressivity of multiple features of this condition.
PubMed | Diagnostic Genetics
Type: Case Reports | Journal: British journal of biomedical science | Year: 2011
The analysis of the human genome has largely been undertaken in a research environment, but recent developments in technology and associated workflow have allowed diagnostic laboratories to interrogate DNA at significantly improved levels of resolution. Principally, whole genome-based analysis of copy number changes using microarrays has led to this method replacing conventional karyotyping as a routine diagnostic workhorse. The resolution offered by microarrays is an improvement of at least an order of magnitude compared to karyotyping, but it comes at a cost in terms of the time spent in data interpretation. Overall, however, the die has been cast and cytogeneticists need to become familiar with the tools use by molecular geneticists and bioinformaticists. The following review provides a brief background to array technology, but uses a series of case studies to illustrate the usefulness and challenges of interpreting array data.