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Introduction: Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare disorder of renal tubular development. ARRTD is a severe condition with high risk of fetal demise and early neonatal death, with only limited case reports of survival over 2 years [Clin Kidney J. 2012 Feb 1;5(1):56–8]. Prenatal diagnosis of ARRTD is challenging, and diagnosis has only previously been confirmed after postnatal or post-mortem investigation. Case: To the best of our knowledge, we describe the first reported case of utilizing targeted genetic testing on the chorionic villous sample (CVS) to identify a homozygous variant in the angiotensinogen (AGT) gene. Discussion: By substantiating the diagnosis of ARRTD prenatally, we allow timely and appropriate counseling during pregnancy.

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.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is common, with a prevalence of 1/1000 and predominantly caused by disease-causing variants in PKD1 or PKD2. Clinical diagnosis is usually by age-dependent imaging criteria, which is challenging in patients with atypical clinical features, without family history, or younger age. However, there is increasing need for definitive diagnosis of ADPKD with new treatments available. Sequencing is complicated by six pseudogenes that share 97% homology to PKD1 and by recently identified phenocopy genes. Whole-genome sequencing can definitively diagnose ADPKD, but requires validation for clinical use. We initially performed a validation study, in which 42 ADPKD patients underwent sequencing of PKD1 and PKD2 by both whole-genome and Sanger sequencing, using a blinded, cross-over method. Whole-genome sequencing identified all PKD1 and PKD2 germline pathogenic variants in the validation study (sensitivity and specificity 100%). Two mosaic variants outside pipeline thresholds were not detected. We then examined the first 144 samples referred to a clinically-accredited diagnostic laboratory for clinical whole-genome sequencing, with targeted-analysis to a polycystic kidney disease gene-panel. In this unselected, diagnostic cohort (71 males :73 females), the diagnostic rate was 70%, including a diagnostic rate of 81% in patients with typical ADPKD (98% with PKD1/PKD2 variants) and 60% in those with atypical features (56% PKD1/PKD2; 44% PKHD1/HNF1B/GANAB/ DNAJB11/PRKCSH/TSC2). Most patients with atypical disease did not have clinical features that predicted likelihood of a genetic diagnosis. These results suggest clinicians should consider diagnostic genomics as part of their assessment in polycystic kidney disease, particularly in atypical disease.

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 individuals) 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 individuals. 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.

Early identification of genetic kidney disease allows personalised management, clarification of risk for relatives, and guidance for family planning. Genetic disease is underdiagnosed, and recognition of genetic disease is particularly challenging in patients with kidney failure without distinguishing diagnostic features. To address this challenge, the primary aim of this study is to determine the proportion of genetic diagnoses amongst patients with kidney failure of unknown aetiology, using whole genome sequencing (WGS). A cohort of up to 100 Australian patients with kidney failure of unknown aetiology, with onset via 18 centres nationally. Clinically accredited WGS will be undertaken with analysis targeted to a priority list of ∼388 genes associated with genetic kidney disease. The primary outcome will be the proportion of patients who receive a molecular diagnosis (diagnostic rate) via WGS compared with usual -care (no further diagnostic investigation). Participant surveys will be undertaken at consent, after test result return and 1 year subsequently. Where there is no or an uncertain diagnosis, future research genomics will be considered to identify candidate genes and new pathogenic variants in known genes. All results will be relayed to participants via the recruiting clinician and/or kidney genetics clinic. The study is ethically approved (HREC/16/MH/251) with local site governance approvals in place. The future results of this study will be disseminated and inform practical understanding of the potential monogenic contribution to kidney failure of unknown aetiology. These findings are anticipated to impact clinical practice and healthcare policy.Study Registration[https://dora.health.qld.gov.au], identifier [HREC/16/MH/251].

The choices of participants in nephrology research genomics studies about receiving additional findings (AFs) are unclear as are participant factors that might influence those choices. Methods: Participant choices and factors potentially impacting decisions about AFs were examined in an Australian study applying research genomic testing following uninformative diagnostic genetic testing for suspected monogenic kidney disease. Results: 93% of participants (195/210) chose to receive potential AFs. There were no statistically significant differences between those consenting to receive AFs or not in terms of gender (p = 0.97), median age (p = 0.56), being personally affected by the inherited kidney disease of interest (p = 0.38), or by the inheritance pattern (p = 0.12–0.19). Participants were more likely to choose not to receive AFs if the family proband presented in adulthood (p = 0.01), if there was family history of another genetic disorder (p = 0.01), and where the consent process was undertaken by an adult nephrologist (p = 0.01). Conclusion: The majority of participants in this nephrology research genomics study chose to receive potential AFs. Younger age of the family proband, family history of an alternate genetic disorder, and consenting by some multidisciplinary team members might impact upon participant choices.

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 individuals 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 individuals 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.

Introduction: Genomic testing is becoming widely available as a diagnostic tool, although widespread implementation is not yet established in nephrology. Methods: An anonymous electronic survey was administered to investigate experience and confidence with genomic tests, perceived clinical utility of genomic services, preferences for service delivery models, and readiness for implementation among nephrologists. Questions were guided by a comprehensive literature review and published tools, including a validated theoretical framework for implementation of genomic medicine: Consolidated Framework for Implementation Research (CFIR). Results: Responses were received from 224 clinicians, of which 172 were eligible for analysis. Most clinicians (132 [76%]) had referred at least one patient to a genetics clinic. Despite most clinicians (136 [85%]) indicating that they believed genetic testing would be useful, only 39 (23%) indicated they felt confident to use results of genomic testing, with pediatric clinicians feeling more confident compared with adult clinicians (12 of 20 [60%] vs. 27 of 149 [18%]), P < 0.01, Fisher exact). A multidisciplinary renal genetics clinic was the preferred model among clinicians surveyed (98 of 172 [57%]). A key implementation barrier highlighted related to the hospital or organizational culture and/or environment. Specific barriers noted in quantitative and qualitative responses included inadequate staffing, learning resources, and funding. Conclusions: Our findings suggest support for genomic testing among nephrologists, with a strong preference for a multidisciplinary model (involving a nephrologist, clinical geneticist, and genetic counselor). Broad-ranging interventions are urgently required to shift the current culture and ensure successful implementation of genomics in nephrology, including reducing knowledge gaps, increased funding and resources, disease-specific guidelines, and streamlining of testing processes.

A 19-year-old female university student presented with a 5-week history of generalised weakness, unsteady gait and breathlessness. There were no symptoms of recent infection. Her only medical history was long-standing symmetrical 40 dB sensorineural hearing loss. On neurological examination, she had hyperpnoea, mild non-fatigable global weakness, bilateral ptosis, soft speech and absent lower limb reflexes. The MR scan of brain showed symmetric T2-hyperintensities surrounding the third ventricle, hypothalamus and brainstem on fluid-attenuated inversion recovery sequences, suggestive of Leigh syndrome (figure 1). Lumbar puncture showed an opening pressure of 8 cm water. Cerebrospinal fluid (CSF) was acellular, protein 0.38 g/L (normal

There have been few new therapies for patients with chronic kidney disease in the last decade. However, the management of patients affected by genetic kidney disease is rapidly evolving. Inherited or genetic kidney disease affects around 10% of adults with end-stage kidney disease and up to 70% of children with early onset kidney disease. Advances in next-generation sequencing have enabled rapid and cost-effective sequencing of large amounts of DNA. Next-generation sequencing-based diagnostic tests now enable identification of a monogenic cause in around 20% of patients with early-onset chronic kidney disease. A definitive diagnosis through genomic testing may negate the need for prolonged diagnostic investigations and surveillance, facilitate reproductive planning and provide accurate counselling for at-risk relatives. Genomics has allowed the better understanding of disease pathogenesis, providing prognostic information and facilitating development of targeted treatments for patients with inherited or genetic kidney disease. Although genomic testing is becoming more readily available, there are many challenges to implementation in clinical practice. Multidisciplinary renal genetics clinics serve as a model of how some of these challenges may be overcome. Such clinics are already well established in most parts of Australia, with more to follow in future. With the rapid pace of new technology and gene discovery, collaboration between expert clinicians, laboratory and research scientists is of increasing importance to maximize benefits to patients and health-care systems.

A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibres with striking nemaline rods and hypertrophy of slow fibres that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G>A, NM_006757.3:c.681+1G>A). TNNT3 encodes skeletal troponin-T(fast) and is associated with autosomal dominant distal arthrogryposis. TNNT3 has not previously been associated with nemaline myopathy, a rare congenital myopathy linked to defects in proteins associated with thin filament structure and regulation. cDNA studies confirmed pathogenic consequences of the splice variant, eliciting exon-skipping and intron retention events leading to a frameshift. Western blot showed deficiency of troponin-T(fast) protein with secondary loss of troponin-I(fast). We establish a homozygous splice variant in TNNT3 as the likely cause of severe congenital nemaline myopathy with distal arthrogryposis (NM-DA), characterised by specific involvement of Type-2 fibres and deficiency of troponin-T(fast).

The purpose of this review was to compare existing strategies for evaluation of complex paediatric patients with newer techniques. Comparative genomic hybridization (CGH) array is the currently accepted first tier genetic test in the evaluation of a pediatric patient with complex physical and developmental anomalies. CGH provides an answer in only 15–20 % cases, and further genetic testing is required in the majority of cases. This has previously involved sequential single-gene tests, with low yield, significant costs and delay in diagnosis. New genetic techniques allowing massively parallel sequencing of multiple genes are becoming a part of medical practice as they provide a reduction in cost and time. Current medical practice supports the use of limited genomic testing—‘gene panels’ and ‘clinical exomes’, as a second tier approach after CGH array testing. These approaches have already been shown to improve the diagnostic yield providing an answer for an additional 25 % of patients. Ultimately, it is likely that whole genome sequencing as a single genomic test could replace CGH array and more restricted genomic tests, as research experience is translated into medical practice. Several factors need to be overcome to make this a reality to ensure equitable access to a reliable test with appropriate diagnostic interpretation.

There have been few new therapies for patients with chronic kidney disease in the last decade. However, the management of patients affected by genetic kidney disease is rapidly evolving. Inherited or genetic kidney disease affects around 10% of adults with end‐stage kidney disease and up to 70% of children with early onset kidney disease. Advances in next‐generation sequencing have enabled rapid and cost‐effective sequencing of large amounts of DNA. Next‐generation sequencing‐based diagnostic tests now enable identification of a monogenic cause in around 20% of patients with early‐onset chronic kidney disease. A definitive diagnosis through genomic testing may negate the need for prolonged diagnostic investigations and surveillance, facilitate reproductive planning and provide accurate counselling for at‐risk relatives. Genomics has allowed the better understanding of disease pathogenesis, providing prognostic information and facilitating development of targeted treatments for patients with inherited or genetic kidney disease. Although genomic testing is becoming more readily available, there are many challenges to implementation in clinical practice. Multidisciplinary renal genetics clinics serve as a model of how some of these challenges may be overcome. Such clinics are already well established in most parts of Australia, with more to follow in future. With the rapid pace of new technology and gene discovery, collaboration between expert clinicians, laboratory and research scientists is of increasing importance to maximize benefits to patients and health‐care systems., Summary at a Glance The authors reckoned the importance of genomic testing as it allows better understanding of disease pathogenesis, provides prognostic information and facilitates development of targeted treatment, particularly for patients with inherited or genetic kidney disease.

The proband (patient 1), a 25-year-old woman, was the product of normal pregnancy and delivery. Her parents were first cousins from Lebanon. She sat at 6 months and crawled at 12 months. At age 3, she was noted to have developmental delay, hypotonia, and ataxia. The following year, she had a febrile illness and suspected absence seizure. EEG showed 4–5 Hz spike and slow wave complexes and she was treated with sodium valproate. At age 6, seizure frequency increased but improved with the addition of ethosuximide. Brain MRI at age 10 revealed increased T2 signal in both thalami and upper brainstem (figure). Serum and urinary amino acids, white blood cell lysosomal enzymes, serum lactate and pyruvate, liver function, and ammonia were normal. CSF neurotransmitters, glucose, and lactate were normal, although GABA was not measured. Her condition then remained static with occasional absence seizures. At age 22, she developed paroxysmal episodes of chorea in the neck, arms, and trunk associated with drowsiness, triggered by fever or hot weather (video 1). These occurred 4–5 times a year, lasting from 1 to 10 minutes. In all episodes, she remained responsive to verbal stimuli. Prolonged interictal video EEGs showed intermittent 4–6 Hz generalized epileptiform discharges, although no motor events were recorded.

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 individualized 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.

We describe the clinical course and response to treatment of atypical haemolytic uraemic syndrome (aHUS) in two sisters presenting to our hospital 6 years apart with a novel complement factor H mutation that has not been described previously in literature and demonstrates the genetic complexity of this ultra-rare disease. The contrast in course and outcome of disease between the two sisters highlights the rapid evolution of management of aHUS, the importance of rapidly establishing a diagnosis, and how minimizing time to eculizumab therapy significantly reduces associated morbidity and mortality.