ORCID Profile
0000-0002-1229-1701
Current Organisations
Royal Prince Alfred Hospital
,
Royal Australasian College of Physicians
,
Garvan Institute of Medical Research
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Publisher: Hindawi Limited
Date: 13-01-2018
DOI: 10.1002/HUMU.23385
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-08-2022
DOI: 10.1212/WNL.0000000000200745
Abstract: Mitochondrial diseases (MDs) are the commonest group of heritable metabolic disorders. Phenotypic ersity can make molecular diagnosis challenging, and causative genetic variants may reside in either mitochondrial or nuclear DNA. A single comprehensive genetic diagnostic test would be highly useful and transform the field. We applied whole-genome sequencing (WGS) to evaluate the variant detection rate and diagnostic capacity of this technology with a view to simplifying and improving the MD diagnostic pathway. Adult patients presenting to a specialist MD clinic in Sydney, Australia, were recruited to the study if they satisfied clinical MD (Nijmegen) criteria. WGS was performed on blood DNA, followed by clinical genetic analysis for known pathogenic MD-associated variants and MD mimics. Of the 242 consecutive patients recruited, 62 participants had “definite,” 108 had “probable,” and 72 had “possible” MD classification by the Nijmegen criteria. Disease-causing variants were identified for 130 participants, regardless of the location of the causative genetic variants, giving an overall diagnostic rate of 53.7% (130 of 242). Identification of causative genetic variants informed precise treatment, restored reproductive confidence, and optimized clinical management of MD. Comprehensive bigenomic sequencing accurately detects causative genetic variants in affected MD patients, simplifying diagnosis, enabling early treatment, and informing the risk of genetic transmission.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Wiley
Date: 18-10-2018
DOI: 10.1111/NEP.13494
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.KINT.2017.06.013
Abstract: Inherited kidney disease encompasses a broad range of disorders, with both multiple genes contributing to specific phenotypes and single gene defects having multiple clinical presentations. Advances in sequencing capacity may allow a genetic diagnosis for familial renal disease, by testing the increasing number of known causative genes. However, there has been limited translation of research findings of causative genes into clinical settings. Here, we report the results of a national accredited diagnostic genetic service for familial renal disease. An expert multidisciplinary team developed a targeted exomic sequencing approach with ten curated multigene panels (207 genes) and variant assessment in idualized to the patient's phenotype. A genetic diagnosis (pathogenic genetic variant[s]) was identified in 58 of 135 families referred in two years. The genetic diagnosis rate was similar between families with a pediatric versus adult proband (46% vs 40%), although significant differences were found in certain panels such as atypical hemolytic uremic syndrome (88% vs 17%). High diagnostic rates were found for Alport syndrome (22 of 27) and tubular disorders (8 of 10), whereas the monogenic diagnostic rate for congenital anomalies of the kidney and urinary tract was one of 13. Quality reporting was aided by a strong clinical renal and genetic multidisciplinary committee review. Importantly, for a diagnostic service, few variants of uncertain significance were found with this targeted, phenotype-based approach. Thus, use of targeted massively parallel sequencing approaches in inherited kidney disease has a significant capacity to diagnose the underlying genetic disorder across most renal phenotypes.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Elsevier BV
Date: 02-2021
Publisher: American Astronomical Society
Date: 18-12-2017
Publisher: Springer Science and Business Media LLC
Date: 11-05-2016
DOI: 10.1038/EJHG.2016.48
Publisher: IOP Publishing
Date: 12-04-2017
Publisher: BMJ
Date: 08-2019
DOI: 10.1136/BMJOPEN-2019-029541
Abstract: Recent advances in genomic technology have allowed better delineation of renal conditions, the identification of new kidney disease genes and subsequent targets for therapy. To date, however, the utility of genomic testing in a clinically ascertained, prospectively recruited kidney disease cohort remains unknown. The aim of this study is to explore the clinical utility and cost-effectiveness of genomic testing within a national cohort of patients with suspected genetic kidney disease who attend multidisciplinary renal genetics clinics. This is a prospective observational cohort study performed at 16 centres throughout Australia. Patients will be included if they are referred to one of the multidisciplinary renal genetics clinics and are deemed likely to have a genetic basis to their kidney disease by the multidisciplinary renal genetics team. The expected cohort consists of 360 adult and paediatric patients recruited by December 2018 with ongoing validation cohort of 140 patients who will be recruited until June 2020. The primary outcome will be the proportion of patients who receive a molecular diagnosis via genomic testing (diagnostic rate) compared with usual care. Secondary outcomes will include change in clinical diagnosis following genomic testing, change in clinical management following genomic testing and the cost-effectiveness of genomic testing compared with usual care. The project has received ethics approval from the Melbourne Health Human Research Ethics Committee as part of the Australian Genomics Health Alliance protocol: HREC/16/MH/251. All participants will provide written informed consent for data collection and to undergo clinically relevant genetic/genomic testing. The results of this study will be published in peer-reviewed journals and will also be presented at national and international conferences.
Publisher: Springer Science and Business Media LLC
Date: 16-10-2017
DOI: 10.1038/NATURE24471
Abstract: On 17 August 2017, the Advanced LIGO and Virgo detectors observed the gravitational-wave event GW170817-a strong signal from the merger of a binary neutron-star system. Less than two seconds after the merger, a γ-ray burst (GRB 170817A) was detected within a region of the sky consistent with the LIGO-Virgo-derived location of the gravitational-wave source. This sky region was subsequently observed by optical astronomy facilities, resulting in the identification of an optical transient signal within about ten arcseconds of the galaxy NGC 4993. This detection of GW170817 in both gravitational waves and electromagnetic waves represents the first 'multi-messenger' astronomical observation. Such observations enable GW170817 to be used as a 'standard siren' (meaning that the absolute distance to the source can be determined directly from the gravitational-wave measurements) to measure the Hubble constant. This quantity represents the local expansion rate of the Universe, sets the overall scale of the Universe and is of fundamental importance to cosmology. Here we report a measurement of the Hubble constant that combines the distance to the source inferred purely from the gravitational-wave signal with the recession velocity inferred from measurements of the redshift using the electromagnetic data. In contrast to previous measurements, ours does not require the use of a cosmic 'distance ladder': the gravitational-wave analysis can be used to estimate the luminosity distance out to cosmological scales directly, without the use of intermediate astronomical distance measurements. We determine the Hubble constant to be about 70 kilometres per second per megaparsec. This value is consistent with existing measurements, while being completely independent of them. Additional standard siren measurements from future gravitational-wave sources will enable the Hubble constant to be constrained to high precision.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2021
DOI: 10.1038/S41525-021-00184-X
Abstract: Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 in iduals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.
Publisher: Hindawi Limited
Date: 25-11-2019
DOI: 10.1002/HUMU.23936
Publisher: American Astronomical Society
Date: 16-10-2017
Publisher: BMJ
Date: 17-07-2020
Publisher: Research Square Platform LLC
Date: 17-01-2023
DOI: 10.21203/RS.3.RS-2397081/V1
Abstract: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common monogenic cause of kidney failure and primarily associated with PKD1 or PKD2. Approximately 10% of patients remain undiagnosed after standard genetic testing. We aimed to utilise short and long read genome sequencing and RNA studies to investigate undiagnosed families. Patients with typical ADPKD phenotype and undiagnosed after genetic diagnostics were recruited. Probands underwent short-read genome sequencing, PKD1 and PKD2 coding and non-coding analyses and then genome-wide analysis. Targeted RNA studies investigated variants suspected to impact splicing. Those undiagnosed then underwent Oxford Nanopore Technologies long-read genome sequencing. From over 172 probands, 9 met inclusion criteria and consented. A genetic diagnosis was made in 8 of 9 (89%) families undiagnosed on prior genetic testing. Six had variants impacting splicing, five in non-coding regions of PKD1. Short-read genome sequencing identified novel branchpoint, AG-exclusion zone and missense variants generating cryptic splice sites and a deletion causing critical intron shortening. Long-read sequencing confirmed the diagnosis in one family. Most undiagnosed families with typical ADPKD have splice-impacting variants in PKD1. We describe a pragmatic method for diagnostic laboratories to assess PKD1 and PKD2 non-coding regions and validate suspected splicing variants through targeted RNA studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-01-2019
Publisher: Oxford University Press (OUP)
Date: 02-03-2017
DOI: 10.1093/CKJ/SFW132
Publisher: Springer Science and Business Media LLC
Date: 12-01-2021
Publisher: The Company of Biologists
Date: 2020
DOI: 10.1242/DEV.189183
Abstract: Laminin alpha 5 (LAMA5) is a member of a large family of proteins which trimerize and then polymerise to form a central component of all basement membranes. Consequently, the protein plays an instrumental role in shaping the normal development of the kidney, skin, neural tube, lung, limb and many other organs and tissues. Pathogenic mutations in some laminins have been shown to cause a range of largely syndromic conditions affecting the competency of the basement membranes to which they contribute. We report the identification of a mutation in the polymerization domain of LAMA5 in a patient with a complex syndromic disease characterised by defects in kidney, craniofacial and limb development and by a range of other congenital defects. Using CRISPR generated mouse models and biochemical assays we demonstrate the pathogenicity of this variant, showing that the change results in a failure of the polymerisation of α/β/γ laminin trimers. Comparing these in vivo phenotypes with those apparent upon gene deletion provides insights into the specific functional importance of laminin polymerization during development and tissue homeostasis.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2019
DOI: 10.1007/S12311-019-01038-0
Abstract: Inherited disorders of spasticity or ataxia exist on a spectrum with overlapping causative genes and phenotypes. We investigated the use of whole-genome sequencing (WGS) to detect a genetic cause when considering this spectrum of disorders as a single group. We recruited 18 Korean in iduals with spastic paraplegia with or without cerebellar ataxia in whom common causes of hereditary cerebellar ataxia and hereditary spastic paraplegia had been excluded. We performed WGS with analysis for single nucleotide variants, small insertions and deletions, copy number variants (CNVs), structural variants (SVs) and intronic variants. Disease-relevant variants were identified in ABCD1 (n = 3), CAPN1 (n = 2), NIPA1 (n = 1) and PLA2G6 (n = 1) for 7/18 patients (38.9%). A 'reverse phenotyping' approach was used to clarify the diagnosis in in iduals with PLA2G6 and ABCD1 variants. One of the ABCD1 disease-relevant variants was detected on analysis for intronic variants. No CNV or SV causes were found. The two males with ABCD1 variants were initiated on monitoring for adrenal dysfunction. This is one of only a few studies to analyse spastic-ataxias as a continuous spectrum using a single approach. The outcome was improved diagnosis of unresolved cases for which common genetic causes had been excluded. This includes the detection of ABCD1 variants which had management implications. Therefore, WGS may be particularly relevant to diagnosing spastic ataxias given the large number of genes associated with this condition and the relatively high diagnostic yield.
Publisher: Springer Science and Business Media LLC
Date: 07-07-2023
DOI: 10.1038/S41525-023-00362-Z
Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure and is primarily associated with PKD1 or PKD2 . Approximately 10% of patients remain undiagnosed after standard genetic testing. We aimed to utilise short and long-read genome sequencing and RNA studies to investigate undiagnosed families. Patients with typical ADPKD phenotype and undiagnosed after genetic diagnostics were recruited. Probands underwent short-read genome sequencing, PKD1 and PKD2 coding and non-coding analyses and then genome-wide analysis. Targeted RNA studies investigated variants suspected to impact splicing. Those undiagnosed then underwent Oxford Nanopore Technologies long-read genome sequencing. From over 172 probands, 9 met inclusion criteria and consented. A genetic diagnosis was made in 8 of 9 (89%) families undiagnosed on prior genetic testing. Six had variants impacting splicing, five in non-coding regions of PKD1 . Short-read genome sequencing identified novel branchpoint, AG-exclusion zone and missense variants generating cryptic splice sites and a deletion causing critical intron shortening. Long-read sequencing confirmed the diagnosis in one family. Most undiagnosed families with typical ADPKD have splice-impacting variants in PKD1 . We describe a pragmatic method for diagnostic laboratories to assess PKD1 and PKD2 non-coding regions and validate suspected splicing variants through targeted RNA studies.
Publisher: Elsevier BV
Date: 09-2018
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.KINT.2020.02.022
Abstract: Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected in iduals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75) without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 in iduals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.
Publisher: American Astronomical Society
Date: 07-04-2017
No related grants have been discovered for Amali Mallawaarachchi.