Suspected Autosomal Recessive Polycystic Kidney Disease but Cerebellar Vermis Hypoplasia, Oligophrenia Ataxia, Coloboma, and Hepatic Fibrosis (COACH) Syndrome in Retrospect, A Delayed Diagnosis Aided by Genotyping and Reverse Phenotyping: A Case Report and A Review of the Literature.

The clinical features of cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis (COACH) characterize the rare autosomal recessive multisystem disorder called COACH syndrome. COACH syndrome belongs to the spectrum of Joubert syndrome and related disorders (JSRDs) and liver involvement distinguishes COACH syndrome from the rest of the JSRD spectrum. Developmental delay and oculomotor apraxia occur early but with time, these can improve and may not be readily apparent or no longer need active medical management. Congenital hepatic fibrosis and renal disease, on the other hand, may develop late, and the temporal incongruity in organ system involvement may delay the recognition of COACH syndrome. We present a case of a young adult presenting late to a Renal Genetics Clinic for evaluation of renal cystic disease with congenital hepatic fibrosis, clinically suspected to have autosomal recessive polycystic kidney disease. Following genetic testing, a reevaluation of his medical records from infancy, together with reverse phenotyping and genetic phasing, led to a diagnosis of COACH syndrome.

Genetic evaluation of living kidney donor candidates: A review and recommendations for best practices.

The growing accessibility and falling costs of genetic sequencing techniques has expanded the utilization of genetic testing in clinical practice. For living kidney donation, genetic evaluation has been increasingly used to identify genetic kidney disease in potential candidates, especially in those of younger ages. However, genetic testing on asymptomatic living kidney donors remains fraught with many challenges and uncertainties. Not all transplant practitioners are aware of the limitations of genetic testing, are comfortable with selecting testing methods, comprehending test results, or providing counsel, and many do not have access to a renal genetic counselor or a clinical geneticist. Although genetic testing can be a valuable tool in living kidney donor evaluation, its overall benefit in donor evaluation has not been demonstrated and it can also lead to confusion, inappropriate donor exclusion, or misleading reassurance. Until more published data become available, this practice resource should provide guidance for centers and transplant practitioners on the responsible use of genetic testing in the evaluation of living kidney donor candidates.

Sequential genetic testing of living-related donors for inherited renal disease to promote informed choice and enhance safety of living donation.

Living kidney donors (LKDs) with a family history of renal disease are at risk of kidney disease as compared to LKDs without such history suggesting that some LKDs may be pre-symptomatic for monogenic kidney disease. LKDs with related transplant candidates whose kidney disease was considered genetic in origin were selected for genetic testing. In each case, the transplant candidate was first tested to verify the genetic diagnosis. A genetic diagnosis was confirmed in 12 of 24 transplant candidates (ADPKD-PKD1: 6, ALPORT-COL4A3: 2, ALPORT-COL4A5: 1: nephronophthisis-SDCCAG8: 1; CAKUT-HNF1B and ADTKD-MUC1: 1 each) and 2 had variants of unknown significance (VUS) in phenotype-relevant genes. Focused genetic testing was then done in 20 of 34 LKDs. 12 LKDs screened negative for the familial variant and were permitted to donate; seven screened positive and were counseled against donation. One, the heterozygous carrier of a recessive disorder was also cleared. Six of seven LKDs with a family history of ADPKD were under 30 years and in 5, by excluding ADPKD, allowed donation to safely proceed. The inclusion of genetic testing clarified the diagnosis in recipient candidates, improving safety or informed decision-making in LKDs.

Targeted broad-based genetic testing by next-generation sequencing informs diagnosis and facilitates management in patients with kidney diseases.

BACKGROUND: The clinical diagnosis of genetic renal diseases may be limited by the overlapping spectrum of manifestations between diseases or by the advancement of disease where clues to the original process are absent. The objective of this study was to determine whether genetic testing informs diagnosis and facilitates management of kidney disease patients. METHODS: We developed a comprehensive genetic testing panel (KidneySeq) to evaluate patients with various phenotypes including cystic diseases, congenital anomalies of the kidney and urinary tract (CAKUT), tubulointerstitial diseases, transport disorders and glomerular diseases. We evaluated this panel in 127 consecutive patients ranging in age from newborns to 81 years who had samples sent in for genetic testing. RESULTS: The performance of the sequencing pipeline for single-nucleotide variants was validated using CEPH (Centre de'Etude du Polymorphism) controls and for indels using Genome-in-a-Bottle. To test the reliability of the copy number variant (CNV) analysis, positive samples were re-sequenced and analyzed. For patient samples, a multidisciplinary review board interpreted genetic results in the context of clinical data. A genetic diagnosis was made in 54 (43%) patients and ranged from 54% for CAKUT, 53% for ciliopathies/tubulointerstitial diseases, 45% for transport disorders to 33% for glomerulopathies. Pathogenic and likely pathogenic variants included 46% missense, 11% nonsense, 6% splice site variants, 23% insertion-deletions and 14% CNVs. In 13 cases, the genetic result changed the clinical diagnosis. CONCLUSION: Broad genetic testing should be considered in the evaluation of renal patients as it complements other tests and provides insight into the underlying disease and its management.

Initial experience from a renal genetics clinic demonstrates a distinct role in patient management.

PURPOSE: A Renal Genetics Clinic (RGC) was established to optimize diagnostic testing, facilitate genetic counseling, and direct clinical management. METHODS: Retrospective review of patients seen over a two-year period in the RGC. RESULTS: One hundred eleven patients (mean age: 39.9 years) were referred to the RGC: 65 for genetic evaluation, 19 for management of a known genetic disease, and 18 healthy living kidney donors (LKDs) and their 9 related transplant candidates for screening. Forty-three patients underwent genetic testing with a diagnosis in 60% of patients including 9 with Alport syndrome, 7 with autosomal dominant polycystic kidney disease (ADPKD), 2 with genetic focal segmental glomerulosclerosis (FSGS), 2 with PAX2-mediated CAKUT, and 1 each with autosomal recessive polycystic kidney disease (ARPKD), Dent, Frasier, Gordon, Gitelman, and Zellweger syndromes. Four of 18 LKDs were referred only for APOL1 screening. For the remaining 14 LKDs, their transplant candidates were first tested to establish a genetic diagnosis. Five LKDs tested negative for the familial genetic variant, four were positive for their familial variant. In five transplant candidates, a genetic variant could not be identified. CONCLUSION: An RGC that includes genetic counseling enhances care of renal patients by improving diagnosis, directing management, affording presymptomatic family focused genetic counseling, and assisting patients and LKDs to make informed decisions.