|
1
|
Miri Karam Z, Gohari A, Khabaz M, Yari A, Meybodi S, Attari R, Torabi M, Vafaeie F, Moraddahande F, Amiri S, Saeidi K. Identification of a Novel Deletion Variant (c.2999_3005delTGTGTGT/p.Asn1000SerfsTer4) in NPHP4 Associated With Nephronophthisis-4. J Clin Lab Anal 2024; 38:e25077. [PMID: 38895833 PMCID: PMC11252830 DOI: 10.1002/jcla.25077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 04/15/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Nephronophthisis-4 (NPHP4) is an inherited renal ciliopathy described by renal fibrosis and progressive impairment of kidney function. This study aimed to investigate the genetic basis and clinical manifestations of NPHP4 in two Iranian siblings. METHODS The proband was a 27-year-old male with features of end-stage renal disease, including anemia, uremia, polyuria, and polydipsia. It is worth mentioning that he has a 22-year-old sister with a similar presentation. Clinical diagnosis procedures, such as renal biopsy, brain imaging, blood and urine tests, cardiac evaluation, ophthalmic inspection, and auditory function assessment, were carried out to evaluate organ involvement and potential comorbidities. Whole-exome sequencing (WES) and segregation analysis were performed to identify and confirm genetic variants associated with the condition. Computational variant analysis was conducted to evaluate the pathogenicity of the candidate variant. Furthermore, the SWISS-MODEL server was utilized for protein modeling. RESULTS The brain, cardiac, ocular, and auditory functions were normal. Renal biopsy of the proband showed chronic interstitial inflammation and fibrosis. We found a novel homozygous 7-base pair deletion (c.2999_3005delTGTGTGT/ p.Asn1000SerfsTer4) in exon 21 of NPHP4 by WES. Segregation analysis confirmed homozygosity for the NPHP4 variant in affected individuals and heterozygous carrier status in parents, supporting autosomal recessive inheritance. 3D protein modeling indicated significant structural changes due to the variant. CONCLUSION This study expands the genetic causes and phenotypic spectrum of nephronophthisis-4 and reveals the importance of genetic analysis in diagnosing and managing rare inherited kidney disorders, particularly those involving consanguinity.
Collapse
Affiliation(s)
- Zahra Miri Karam
- Department of Medical Genetics, Afzalipour Faculty of MedicineKerman University of Medical SciencesKermanIran
- Neuroscience Research CenterInstitute of Neuropharmacology, Kerman University of Medical SciencesKermanIran
| | - Atieh Karimi Gohari
- Department of Medical Genetics, Afzalipour Faculty of MedicineKerman University of Medical SciencesKermanIran
| | | | - Abolfazl Yari
- Department of Medical Genetics, Afzalipour Faculty of MedicineKerman University of Medical SciencesKermanIran
- Cardiovascular Diseases Research CenterBirjand University of Medical SciencesBirjandIran
| | - Seyed Mahdi Emami Meybodi
- Yazd Cardiovascular Research CenterNon‐Communicable Diseases Research Institute, Shahid Sadoughi University of Medical SciencesYazdIran
| | | | - Maryam Torabi
- Department of Biology, Faculty of Science, Agriculture and New Technologies, Shiraz BranchIslamic Azad UniversityShirazIran
| | - Farzane Vafaeie
- Cardiovascular Diseases Research CenterBirjand University of Medical SciencesBirjandIran
| | - Fateme Moradi Moraddahande
- Department of Medical Laboratory SciencesSchool of Allied Medical Sciences, Shahid Beheshti University of Medical SciencesTehranIran
| | - Sara Amiri
- Department of Biology, Kerman BranchIslamic Azad UniversityKermanIran
| | - Kolsoum Saeidi
- Department of Medical Genetics, Afzalipour Faculty of MedicineKerman University of Medical SciencesKermanIran
- Neuroscience Research CenterInstitute of Neuropharmacology, Kerman University of Medical SciencesKermanIran
| |
Collapse
|
|
2
|
Mitrotti A, Giliberti M, Di Leo V, di Bari I, Pontrelli P, Gesualdo L. Hidden genetics behind glomerular scars: an opportunity to understand the heterogeneity of focal segmental glomerulosclerosis? Pediatr Nephrol 2024; 39:1685-1707. [PMID: 37728640 PMCID: PMC11026212 DOI: 10.1007/s00467-023-06046-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 05/02/2023] [Accepted: 05/30/2023] [Indexed: 09/21/2023]
Abstract
Focal segmental glomerulosclerosis (FSGS) is a complex disease which describes different kinds of kidney defects, not exclusively linked with podocyte defects. Since nephrin mutation was first described in association with early-onset nephrotic syndrome (NS), many advancements have been made in understanding genetic patterns associated with FSGS. New genetic causes of FSGS have been discovered, displaying unexpected genotypes, and recognizing possible site of damage. Many recent large-scale sequencing analyses on patients affected by idiopathic chronic kidney disease (CKD), kidney failure (KF) of unknown origin, or classified as FSGS, have revealed collagen alpha IV genes, as one of the most frequent sites of pathogenic mutations. Also, recent interest in complex and systemic lysosomal storage diseases, such as Fabry disease, has highlighted GLA mutations as possible causes of FSGS. Tubulointerstitial disease, recently classified by KDIGO based on genetic subtypes, when associated with UMOD variants, may phenotypically gain FSGS features, as well as ciliopathy genes or others, otherwise leading to completely different phenotypes, but found carrying pathogenic variants with associated FSGS phenotype. Thus, glomerulosclerosis may conceal different heterogeneous conditions. When a kidney biopsy is performed, the principal objective is to provide an accurate diagnosis. The broad spectrum of phenotypic expression and genetic complexity is demonstrating that a combined path of management needs to be applied. Genetic investigation should not be reserved only to selected cases, but rather part of medical management, integrating with clinical and renal pathology records. FSGS heterogeneity should be interpreted as an interesting opportunity to discover new pathways of CKD, requiring prompt genotype-phenotype correlation. In this review, we aim to highlight how FSGS represents a peculiar kidney condition, demanding multidisciplinary management, and in which genetic analysis may solve some otherwise unrevealed idiopathic cases. Unfortunately there is not a uniform correlation between specific mutations and FSGS morphological classes, as the same variants may be identified in familial cases or sporadic FSGS/NS or manifest a variable spectrum of the same disease. These non-specific features make diagnosis challenging. The complexity of FSGS genotypes requires new directions. Old morphological classification does not provide much information about the responsible cause of disease and misdiagnoses may expose patients to immunosuppressive therapy side effects, mistaken genetic counseling, and misguided kidney transplant programs.
Collapse
Affiliation(s)
- Adele Mitrotti
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy.
| | - Marica Giliberti
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Vincenzo Di Leo
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Ighli di Bari
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Paola Pontrelli
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Loreto Gesualdo
- Precision and Regenerative Medicine and Ionian Area, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| |
Collapse
|
|
3
|
Sambharia M, Rastogi P, Thomas CP. Monogenic focal segmental glomerulosclerosis: A conceptual framework for identification and management of a heterogeneous disease. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2022; 190:377-398. [PMID: 35894442 PMCID: PMC9796580 DOI: 10.1002/ajmg.c.31990] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/31/2022] [Accepted: 06/30/2022] [Indexed: 01/29/2023]
Abstract
Focal segmental glomerulosclerosis (FSGS) is not a disease, rather a pattern of histological injury occurring from a variety of causes. The exact pathogenesis has yet to be fully elucidated but is likely varied based on the type of injury and the primary target of that injury. However, the approach to treatment is often based on the degree of podocyte foot process effacement and clinical presentation without sufficient attention paid to etiology. In this regard, there are many monogenic causes of FSGS with variable presentation from nephrotic syndrome with histological features of primary podocytopathy to more modest degrees of proteinuria with limited evidence of podocyte foot process injury. It is likely that genetic causes are largely underdiagnosed, as the role and the timing of genetic testing in FSGS is not established and genetic counseling, testing options, and interpretation of genotype in the context of phenotype may be outside the scope of practice for both nephrologists and geneticists. Yet most clinicians believe that a genetic diagnosis can lead to targeted therapy, limit the use of high-dose corticosteroids as a therapeutic trial, and allow the prediction of the natural history and risk for recurrence in the transplanted kidney. In this manuscript, we emphasize that genetic FSGS is not monolithic in its presentation, opine on the importance of genetic testing and provide an algorithmic approach to deployment of genetic testing in a timely fashion when faced with a patient with FSGS.
Collapse
Affiliation(s)
- Meenakshi Sambharia
- Division of Nephrology, Department of Internal MedicineUniversity of IowaIowa CityIowaUSA
| | - Prerna Rastogi
- Department of PathologyUniversity of IowaIowa CityIowaUSA
| | - Christie P. Thomas
- Division of Nephrology, Department of Internal MedicineUniversity of IowaIowa CityIowaUSA,Department of PediatricsUniversity of IowaIowa CityIowaUSA,The Iowa Institute of Human GeneticsUniversity of IowaIowa CityIowaUSA,Medical ServiceVeterans Affairs Medical CenterIowa CityIowaUSA
| |
Collapse
|
|
4
|
König JC, Karsay R, Gerß J, Schlingmann KP, Dahmer-Heath M, Telgmann AK, Kollmann S, Ariceta G, Gillion V, Bockenhauer D, Bertholet-Thomas A, Mastrangelo A, Boyer O, Lilien M, Decramer S, Schanstra J, Pohl M, Schild R, Weber S, Hoefele J, Drube J, Cetiner M, Hansen M, Thumfart J, Tönshoff B, Habbig S, Liebau MC, Bald M, Bergmann C, Pennekamp P, Konrad M. Refining Kidney Survival in 383 Genetically Characterized Patients With Nephronophthisis. Kidney Int Rep 2022; 7:2016-2028. [PMID: 36090483 PMCID: PMC9459005 DOI: 10.1016/j.ekir.2022.05.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 05/30/2022] [Indexed: 11/26/2022] Open
Abstract
Introduction Nephronophthisis (NPH) comprises a group of rare disorders accounting for up to 10% of end-stage kidney disease (ESKD) in children. Prediction of kidney prognosis poses a major challenge. We assessed differences in kidney survival, impact of variant type, and the association of clinical characteristics with declining kidney function. Methods Data was obtained from 3 independent sources, namely the network for early onset cystic kidney diseases clinical registry (n = 105), an online survey sent out to the European Reference Network for Rare Kidney Diseases (n = 60), and a literature search (n = 218). Results A total of 383 individuals were available for analysis: 116 NPHP1, 101 NPHP3, 81 NPHP4 and 85 NPHP11/TMEM67 patients. Kidney survival differed between the 4 cohorts with a highly variable median age at onset of ESKD as follows: NPHP3, 4.0 years (interquartile range 0.3–12.0); NPHP1, 13.5 years (interquartile range 10.5–16.5); NPHP4, 16.0 years (interquartile range 11.0–25.0); and NPHP11/TMEM67, 19.0 years (interquartile range 8.7–28.0). Kidney survival was significantly associated with the underlying variant type for NPHP1, NPHP3, and NPHP4. Multivariate analysis for the NPHP1 cohort revealed growth retardation (hazard ratio 3.5) and angiotensin-converting enzyme inhibitor (ACEI) treatment (hazard ratio 2.8) as 2 independent factors associated with an earlier onset of ESKD, whereas arterial hypertension was linked to an accelerated glomerular filtration rate (GFR) decline. Conclusion The presented data will enable clinicians to better estimate kidney prognosis of distinct patients with NPH and thereby allow personalized counseling.
Collapse
|
|
5
|
Najafi M, Riedhammer KM, Rad A, Torbati PN, Berutti R, Schüle I, Schroda S, Meitinger T, Ćomić J, Bojd SS, Baranzehi T, Shojaei A, Azarfar A, Khazaei MR, Köttgen A, Backofen R, Karimiani EG, Hoefele J, Schmidts M. High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases. Front Pediatr 2022; 10:974840. [PMID: 36245711 PMCID: PMC9555279 DOI: 10.3389/fped.2022.974840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/11/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Steroid resistant nephrotic syndrome (SRNS) represents a significant renal disease burden in childhood and adolescence. In contrast to steroid sensitive nephrotic syndrome (SSNS), renal outcomes are significantly poorer in SRNS. Over the past decade, extensive genetic heterogeneity has become evident while disease-causing variants are still only identified in 30% of cases in previously reported studies with proportion and type of variants identified differing depending on the age of onset and ethnical background of probands. A genetic diagnosis however can have implications regarding clinical management, including kidney transplantation, extrarenal disease manifestations, and, in some cases, even causal therapy. Genetic diagnostics therefore play an important role for the clinical care of SRNS affected individuals. METHODOLOGY AND RESULTS Here, we performed NPHS2 Sanger sequencing and subsequent exome sequencing in 30 consanguineous Iranian families with a child affected by SRNS with a mean age of onset of 16 months. We identified disease-causing variants and one variant of uncertain significance in 22 families (73%), including variants in NPHS1 (30%), followed by NPHS2 (20%), WT1 (7%) as well as in NUP205, COQ6, ARHGDIA, SGPL1, and NPHP1 in single cases. Eight of these variants have not previously been reported as disease-causing, including four NPHS1 variants and one variant in NPHS2, ARHGDIA, SGPL1, and NPHP1 each. CONCLUSION In line with previous studies in non-Iranian subjects, we most frequently identified disease-causing variants in NPHS1 and NPHS2. While Sanger sequencing of NPHS2 can be considered as first diagnostic step in non-congenital cases, the genetic heterogeneity underlying SRNS renders next-generation sequencing based diagnostics as the most efficient genetic screening method. In accordance with the mainly autosomal recessive inheritance pattern, diagnostic yield can be significantly higher in consanguineous than in outbred populations.
Collapse
Affiliation(s)
- Maryam Najafi
- Genome Research Division, Human Genetics Department, Radboud University Medical Center, Nijmegen, Netherlands.,Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Freiburg, Germany
| | - Korbinian M Riedhammer
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.,Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Aboulfazl Rad
- Genome Research Division, Human Genetics Department, Radboud University Medical Center, Nijmegen, Netherlands.,Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | | | - Riccardo Berutti
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Isabel Schüle
- Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Freiburg, Germany
| | - Sophie Schroda
- Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Freiburg, Germany
| | - Thomas Meitinger
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Jasmina Ćomić
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.,Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Simin Sadeghi Bojd
- Children and Adolescents Health Research Center, Research Institute of Cellular and Molecular Science in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Tayebeh Baranzehi
- Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran
| | - Azadeh Shojaei
- Department of Medical Genetics and Molecular Biology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Anoush Azarfar
- Pediatric Nephrology, Kidney Transplantation Complications Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmood Reza Khazaei
- Department of Pediatrics, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran
| | - Anna Köttgen
- Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.,Center for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany
| | - Rolf Backofen
- Center for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany.,Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany
| | - Ehsan Ghayoor Karimiani
- Next Generation Genetic Polyclinic, Mashhad, Iran.,Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's University, London, United Kingdom
| | - Julia Hoefele
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Miriam Schmidts
- Genome Research Division, Human Genetics Department, Radboud University Medical Center, Nijmegen, Netherlands.,Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Freiburg, Germany.,Center for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany
| |
Collapse
|
|
6
|
Mason AE, Saleem MA, Bierzynska A. A critical re-analysis of cases of post-transplantation recurrence in genetic nephrotic syndrome. Pediatr Nephrol 2021; 36:3757-3769. [PMID: 34031708 PMCID: PMC8497325 DOI: 10.1007/s00467-021-05134-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 04/29/2021] [Accepted: 05/12/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND Genetic defects in podocyte proteins account for up to 30% of steroid-resistant nephrotic syndrome (SRNS) in the paediatric population. Most children with genetic SRNS are resistant to immunosuppression and at high risk of progression to stage 5 chronic kidney disease. Kidney transplantation is often the treatment of choice. The possibility of post-transplantation disease recurrence in genetic SRNS remains controversial, and poses fundamental questions about disease biology. METHODS We critically evaluated the published cases of post-transplantation recurrence in genetic patients, particularly testing 'mutations' against the most recent population variant databases, in order to clarify the diagnoses, and compare the clinical courses and responses to therapy. RESULTS Biallelic pathogenic variants in NPHS1 leading to a complete absence of nephrin were the most commonly reported and best understood instance of nephrotic syndrome occurring post-transplantation. This is an immune-mediated process driven by antibody production against the novel nephrin protein in the allograft. We also identified a number of plausible reported cases of post-transplantation recurrence involving pathogenic variants in NPHS2 (8 patients, biallelic), one in WT1 (monoallelic) and one in NUP93 (biallelic). However, the mechanism for recurrence in these cases remains unclear. Other instances of recurrence in genetic disease were difficult to interpret due to differing clinical criteria, inclusion of patients without true pathogenic variants or the influence of other factors on renal outcome. CONCLUSIONS Overall, post-transplantation recurrence remains very rare in patients with genetic SRNS. It appears to occur later after transplantation than in other patients and usually responds well to plasmapheresis with a good renal outcome.
Collapse
Affiliation(s)
- Anna E Mason
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Moin A Saleem
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK.
| | - Agnieszka Bierzynska
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| |
Collapse
|
|
7
|
Zhou J, Yang Z, Yang CS, Lin H. Paraneoplastic focal segmental glomerulosclerosis associated with gastrointestinal stromal tumor with cutaneous metastasis: A case report. World J Clin Cases 2021; 9:8120-8126. [PMID: 34621870 PMCID: PMC8462187 DOI: 10.12998/wjcc.v9.i27.8120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 07/25/2021] [Accepted: 08/05/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumor (GIST) with cutaneous metastasis is very rare. As a result, cutaneous GISTs have not been well characterized. Focal segmental glomerulosclerosis (FSGS) is also a rare symptom among paraneoplastic nephritic syndromes (PNS).
CASE SUMMARY In this case report, we describe a patient with cutaneous metastatic GIST accompanied by nephrotic syndrome occurring as a malignancy-associated PNS, for whom symptomatic treatment was ineffective, but clinical remission was achieved after surgery. Moreover, the patient has a missense mutation in NPHP4, which can explain the occurrences of GIST and FSGS in this patient and indicates that the association is not random.
CONCLUSION This is the first reported case of a GIST with cutaneous metastasis accompanied by nephrotic syndrome manifesting as a PNS.
Collapse
Affiliation(s)
- Jun Zhou
- Department of Nephrology and Rheumatology, Haikou People’s Hospital Affiliated to Xiangya School of Medicine of Central South University, Haikou 570208, Hainan Province, China
| | - Zhen Yang
- Department of Nephrology and Rheumatology, Haikou People’s Hospital Affiliated to Xiangya School of Medicine of Central South University, Haikou 570208, Hainan Province, China
| | - Cui-Shun Yang
- Department of Nephrology and Rheumatology, Haikou People’s Hospital Affiliated to Xiangya School of Medicine of Central South University, Haikou 570208, Hainan Province, China
| | - Hua Lin
- Department of Nursing, Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou 570208, Hainan Province, China
| |
Collapse
|
|
8
|
A girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis. CEN Case Rep 2021; 11:116-119. [PMID: 34435324 DOI: 10.1007/s13730-021-00640-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/20/2021] [Indexed: 10/20/2022] Open
Abstract
Mutations in the ciliary gene TTC21B, NPHP4, and CRB2 cause familial focal and segmental glomerulosclerosis (FSGS). We report a girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis. The patient had mental retardation, postaxial polydactyly, and ataxic breathing, and was diagnosed as having compound heterozygous CC2D2A missense mutations at age 5. Retrospectively, azotemia at 1 year and proteinuria at 5 years were recorded but not investigated. At age 6, she was referred to the pediatric nephrology service because of hypertension, pretibial pitting edema, heavy proteinuria, and hematuria. eGFR was 66 ml/min/1.73 m2, total protein 5.3 g/dl, albumin 2.4 g/dl, and cholesterol 317 mg/dl. Ultrasonography showed normal-sized kidneys with a cyst in the right. Losartan was started. On renal biopsy, 8 out of 24 glomeruli were globally sclerosed, and three showed segmental sclerosis and/or hyalinosis with no immune deposits. Mild tubular dilatation, tubular atrophy, and interstitial fibrosis were observed. On electron microscopy, glomeruli showed focal foot process effacement with no electron dense deposits. Since losartan did not exert an obvious effect, treatment with prednisolone was tried. Urine protein decreased from 6.6 to 3.7 g/gCr. Prednisolone was discontinued after 10 days, however, because she developed duodenal ulcer perforation that necessitated omentoplasty. Subsequently, she was treated with losartan only. Her renal function deteriorated and peritoneal dialysis was initiated 8 months later. FSGS in this patient could be primary glomerular associated with CC2D2A mutation, rather than the consequences of tubulointerstitial fibrosis.
Collapse
|
|
9
|
Akira M, Suzuki H, Ikeda A, Iwasaki M, Honda D, Takahara H, Rinno H, Tomita S, Suzuki Y. Atypical histological abnormalities in an adult patient with nephronophthisis harboring NPHP1 deletion: a case report. BMC Nephrol 2021; 22:261. [PMID: 34246230 PMCID: PMC8272369 DOI: 10.1186/s12882-021-02466-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 07/01/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Nephronophthisis (NPHP) is a chronic tubular interstitial disorder that exhibits an autosomal recessive genetic form and causes progressive renal failure in children. Patients with NPHP rarely show urinary abnormalities, edema, or hypertension. Thus, NPHP is often detected only when renal failure becomes advanced. NPHP can be divided into three types based on the age of end-stage renal failure, i.e., infant type (approximately 5 years old), juvenile type (approximately 13-14 years old), and adolescent type (approximately 19 years old). Here, we report a case of NPHP diagnosed by genetic analysis at 26 years of age with atypical histological abnormalities. CASE PRESENTATION A 26-year-old woman showed no growth disorders or urinary abnormalities in annual school physical examinations. However, at a check-up at 26 years old, she exhibited renal dysfunction (eGFR 26 mL/min/1.73 m2). Urine tests indicated low specific gravity of urine, but not proteinuria or microscopic hematuria. Urinary β2-microglobulin was high (805 μg/L), and renal biopsy was performed for definitive diagnosis. Histological findings showed no significant findings in glomeruli. However, moderate fibrosis was observed in the interstitial area, and moderate atrophy was observed in the tubules. There were no significant findings in immunofluorescence analysis, and no electron dense deposits were detected by electron microscopy. Although cyst-like expansion of the tubules was unclear, tubular atrophy was dominantly found in the distal tubule by cytokeratin 7 staining. Genetic analysis of the NPHP1 gene showed complete deletion of this gene, leading to a definitive diagnosis of NPHP. CONCLUSIONS NPHP is not merely a pediatric disease and is relatively high incidence in patients with adult onset end-stage of renal disease. In this case, typical histological abnormalities, such as cyst-like expansion of the tubular lesion, were not observed, and diagnosis was achieved by genetic analysis of the NPHP1 gene, which is responsible for the onset of NPHP. In patients with renal failure with tubular interstitial disease dominantly in the distal tubules, it is necessary to discriminate NPHP, even in adult cases.
Collapse
Affiliation(s)
- Maiko Akira
- Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba, 279-0021, Japan
| | - Hitoshi Suzuki
- Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba, 279-0021, Japan.
| | - Arisa Ikeda
- Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba, 279-0021, Japan
| | - Masako Iwasaki
- Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba, 279-0021, Japan
| | - Daisuke Honda
- Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba, 279-0021, Japan
| | - Hisatsugu Takahara
- Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba, 279-0021, Japan
| | - Hisaki Rinno
- Department of Nephrology, Juntendo University Urayasu Hospital, 2-1-1 Tomioka, Urayasu-shi, Chiba, 279-0021, Japan
| | - Shigeki Tomita
- Department of Pathology, Juntendo University Urayasu Hospital, Chiba, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| |
Collapse
|
|
10
|
Mason AE, Sen ES, Bierzynska A, Colby E, Afzal M, Dorval G, Koziell AB, Williams M, Boyer O, Welsh GI, Saleem MA, on behalf of the UK RaDaR/NephroS Study. Response to First Course of Intensified Immunosuppression in Genetically Stratified Steroid Resistant Nephrotic Syndrome. Clin J Am Soc Nephrol 2020; 15:983-994. [PMID: 32317330 PMCID: PMC7341765 DOI: 10.2215/cjn.13371019] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 03/18/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND OBJECTIVES Intensified immunosuppression in steroid-resistant nephrotic syndrome is broadly applied, with disparate outcomes. This review of patients from the United Kingdom National Study of Nephrotic Syndrome cohort aimed to improve disease stratification by determining, in comprehensively genetically screened patients with steroid-resistant nephrotic syndrome, if there is an association between response to initial intensified immunosuppression and disease progression and/or post-transplant recurrence. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Pediatric patients with steroid-resistant nephrotic syndrome were recruited via the UK National Registry of Rare Kidney Diseases. All patients were whole-genome sequenced, whole-exome sequenced, or steroid-resistant nephrotic syndrome gene-panel sequenced. Complete response or partial response within 6 months of starting intensified immunosuppression was ascertained using laboratory data. Response to intensified immunosuppression and outcomes were analyzed according to genetic testing results, pattern of steroid resistance, and first biopsy findings. RESULTS Of 271 patients, 178 (92 males, median onset age 4.7 years) received intensified immunosuppression with response available. A total of 4% of patients with monogenic disease showed complete response, compared with 25% of genetic-testing-negative patients (P=0.02). None of the former recurred post-transplantation. In genetic-testing-negative patients, 97% with complete response to first intensified immunosuppression did not progress, whereas 44% of nonresponders developed kidney failure with 73% recurrence post-transplant. Secondary steroid resistance had a higher complete response rate than primary/presumed resistance (43% versus 23%; P=0.001). The highest complete response rate in secondary steroid resistance was to rituximab (64%). Biopsy results showed no correlation with intensified immunosuppression response or outcome. CONCLUSIONS Patients with monogenic steroid-resistant nephrotic syndrome had a poor therapeutic response and no post-transplant recurrence. In genetic-testing-negative patients, there was an association between response to first intensified immunosuppression and long-term outcome. Patients with complete response rarely progressed to kidney failure, whereas nonresponders had poor kidney survival and a high post-transplant recurrence rate. Patients with secondary steroid resistance were more likely to respond, particularly to rituximab.
Collapse
Affiliation(s)
- Anna E. Mason
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Ethan S. Sen
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Agnieszka Bierzynska
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Elizabeth Colby
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Maryam Afzal
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Guillaume Dorval
- Department of Pediatric Nephrology, Reference Center for Hereditary Kidney Diseases, Necker Hospital, Assistance Publique—Hôpitaux de Paris, Paris, France
| | - Ania B. Koziell
- Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
| | - Maggie Williams
- Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, Bristol, United Kingdom
| | - Olivia Boyer
- Department of Pediatric Nephrology, Reference Center for Hereditary Kidney Diseases, Necker Hospital, Assistance Publique—Hôpitaux de Paris, Paris, France
| | - Gavin I. Welsh
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - Moin A. Saleem
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
| | - on behalf of the UK RaDaR/NephroS Study
- Bristol Renal, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Department of Pediatric Nephrology, Reference Center for Hereditary Kidney Diseases, Necker Hospital, Assistance Publique—Hôpitaux de Paris, Paris, France
- Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
- Bristol Genetics Laboratory, Pathology Sciences, Southmead Hospital, Bristol, United Kingdom
| |
Collapse
|
|
11
|
Hudson R, Patel C, Hawley CM, O'Shea S, Snelling P, Ho G, Holman K, Bennetts B, Crawford J, Francis L, Simons C, Mallett A. Adult-Diagnosed Nonsyndromic Nephronophthisis in Australian Families Caused by Biallelic NPHP4 Variants. Am J Kidney Dis 2019; 76:282-287. [PMID: 31810733 DOI: 10.1053/j.ajkd.2019.08.031] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 08/29/2019] [Indexed: 11/11/2022]
Abstract
There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults. We identified 2 families with presumed adult-diagnosed nonsyndromic NPHP and negative diagnostic genetic testing results from our Renal Genetics Clinic. Both had 2 affected siblings without extrarenal phenotypes. After informed consent, research whole-genome sequencing was undertaken. Biallelic NPHP4 variants were identified in trans and clinically confirmed in all 4 affected individuals, confirming a genetic diagnosis. Participant 1 of the first family (F1P1) had kidney failure diagnosed at 19 years of age. An affected younger sibling (F1P2) reached kidney failure at age 15 years after kidney biopsy suggested NPHP. Pathogenic variants detected in NPHP4 in this family were NM_015102.4:c.3766C>T (p.Gln1256*) and a 31-kb deletion affecting exons 12 to 16. In the second family, F2P3 reached kidney failure at age 27 years having undergone kidney biopsy suggesting NPHP. An affected younger sibling (F2P4) has chronic kidney disease stage 4 at age 39 years. The NPHP4 variants detected were NM_015102.4:c.1998_1999del (p.Tyr667Phefs*23) and c.3646G>T (p.Asp1216Tyr). The latter variant was initially missed in diagnostic sequencing due to inadequate NPHP4 coverage (94.3% exonic coverage). With these reports, we identify NPHP4 as an appreciable genetic cause for adult-diagnosed nonsyndromic NPHP that should be considered by adult nephrologists.
Collapse
Affiliation(s)
- Rebecca Hudson
- Department of Renal Medicine, Royal Brisbane and Women's Hospital, Herston, QLD
| | - Chirag Patel
- Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD; KidGen Collaborative, Australian Genomics Health Alliance, Parkville, VIC
| | - Carmel M Hawley
- Department of Nephrology, Princess Alexandra Hospital, Woolloongabba, QLD; Translational Research Institute, Brisbane, Queensland; Australasian Kidney Trials Network, The University of Queensland, Queensland
| | | | - Paul Snelling
- KidGen Collaborative, Australian Genomics Health Alliance, Parkville, VIC; Department of Nephrology, Royal Prince Alfred Hospital, Camperdown, NSW
| | - Gladys Ho
- KidGen Collaborative, Australian Genomics Health Alliance, Parkville, VIC; Department of Molecular Genetics, Children's Hospital at Westmead, Westmead, NSW; Discipline of Genetic Medicine and Discipline of Child & Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW
| | - Katherine Holman
- KidGen Collaborative, Australian Genomics Health Alliance, Parkville, VIC; Department of Molecular Genetics, Children's Hospital at Westmead, Westmead, NSW
| | - Bruce Bennetts
- KidGen Collaborative, Australian Genomics Health Alliance, Parkville, VIC; Department of Molecular Genetics, Children's Hospital at Westmead, Westmead, NSW; Discipline of Genetic Medicine and Discipline of Child & Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW
| | - Joanna Crawford
- KidGen Collaborative, Australian Genomics Health Alliance, Parkville, VIC; Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD
| | - Leo Francis
- Department of Anatomical Pathology, Pathology Queensland, Herston, QLD
| | - Cas Simons
- KidGen Collaborative, Australian Genomics Health Alliance, Parkville, VIC; Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD; Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, Parkville, Melbourne, VIC
| | - Andrew Mallett
- Department of Renal Medicine, Royal Brisbane and Women's Hospital, Herston, QLD; KidGen Collaborative, Australian Genomics Health Alliance, Parkville, VIC; Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD; Department of Anatomical Pathology, Pathology Queensland, Herston, QLD; Faculty of Medicine, The University of Queensland, Herston, QLD, Australia.
| |
Collapse
|
|
12
|
Wang M, Chun J, Genovese G, Knob AU, Benjamin A, Wilkins MS, Friedman DJ, Appel GB, Lifton RP, Mane S, Pollak MR. Contributions of Rare Gene Variants to Familial and Sporadic FSGS. J Am Soc Nephrol 2019; 30:1625-1640. [PMID: 31308072 PMCID: PMC6727251 DOI: 10.1681/asn.2019020152] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 04/25/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Over the past two decades, the importance of genetic factors in the development of FSGS has become increasingly clear. However, despite many known monogenic causes of FSGS, single gene defects explain only 30% of cases. METHODS To investigate mutations underlying FSGS, we sequenced 662 whole exomes from individuals with sporadic or familial FSGS. After quality control, we analyzed the exome data from 363 unrelated family units with sporadic or familial FSGS and compared this to data from 363 ancestry-matched controls. We used rare variant burden tests to evaluate known disease-associated genes and potential new genes. RESULTS We validated several FSGS-associated genes that show a marked enrichment of deleterious rare variants among the cases. However, for some genes previously reported as FSGS related, we identified rare variants at similar or higher frequencies in controls. After excluding such genes, 122 of 363 cases (33.6%) had rare variants in known disease-associated genes, but 30 of 363 controls (8.3%) also harbored rare variants that would be classified as "causal" if detected in cases; applying American College of Medical Genetics filtering guidelines (to reduce the rate of false-positive claims that a variant is disease related) yielded rates of 24.2% in cases and 5.5% in controls. Highly ranked new genes include SCAF1, SETD2, and LY9. Network analysis showed that top-ranked new genes were located closer than a random set of genes to known FSGS genes. CONCLUSIONS Although our analysis validated many known FSGS-causing genes, we detected a nontrivial number of purported "disease-causing" variants in controls, implying that filtering is inadequate to allow clinical diagnosis and decision making. Genetic diagnosis in patients with FSGS is complicated by the nontrivial rate of variants in known FSGS genes among people without kidney disease.
Collapse
Affiliation(s)
- Minxian Wang
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Justin Chun
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Division of Nephrology, Department of Medicine, University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada
| | - Giulio Genovese
- Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Andrea U Knob
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Ava Benjamin
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Maris S Wilkins
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - David J Friedman
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Gerald B Appel
- Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York
| | - Richard P Lifton
- Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York; and
| | - Shrikant Mane
- Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
| | - Martin R Pollak
- Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts
| |
Collapse
|
|
13
|
Thomas CP, Mansilla MA, Sompallae R, Mason SO, Nishimura CJ, Kimble MJ, Campbell CA, Kwitek AE, Darbro BW, Stewart ZA, Smith RJH. Screening of Living Kidney Donors for Genetic Diseases Using a Comprehensive Genetic Testing Strategy. Am J Transplant 2017; 17:401-410. [PMID: 27434427 PMCID: PMC5297870 DOI: 10.1111/ajt.13970] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 06/20/2016] [Accepted: 07/12/2016] [Indexed: 01/25/2023]
Abstract
Related living kidney donors (LKDs) are at higher risk of end-stage renal disease (ESRD) compared with unrelated LKDs. A genetic panel was developed to screen 115 genes associated with renal diseases. We used this panel to screen six negative controls, four transplant candidates with presumed genetic renal disease and six related LKDs. After removing common variants, pathogenicity was predicted using six algorithms to score genetic variants based on conservation and function. All variants were evaluated in the context of patient phenotype and clinical data. We identified causal variants in three of the four transplant candidates. Two patients with a family history of autosomal dominant polycystic kidney disease segregated variants in PKD1. These findings excluded genetic risk in three of four relatives accepted as potential LKDs. A third patient with an atypical history for Alport syndrome had a splice site mutation in COL4A5. This pathogenic variant was excluded in a sibling accepted as an LKD. In another patient with a strong family history of ESRD, a negative genetic screen combined with negative comparative genomic hybridization in the recipient facilitated counseling of the related donor. This genetic renal disease panel will allow rapid, efficient and cost-effective evaluation of related LKDs.
Collapse
Affiliation(s)
- C. P. Thomas
- Department of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA,Department of PediatricsCarver College of MedicineUniversity of IowaIowa CityIA,VA Medical CenterIowa CityIA
| | - M. A. Mansilla
- Iowa Institute of Human GeneticsCarver College of MedicineUniversity of IowaIowa CityIA
| | - R. Sompallae
- Iowa Institute of Human GeneticsCarver College of MedicineUniversity of IowaIowa CityIA
| | - S. O. Mason
- Iowa Institute of Human GeneticsCarver College of MedicineUniversity of IowaIowa CityIA
| | - C. J. Nishimura
- Iowa Institute of Human GeneticsCarver College of MedicineUniversity of IowaIowa CityIA
| | - M. J. Kimble
- Iowa Institute of Human GeneticsCarver College of MedicineUniversity of IowaIowa CityIA
| | - C. A. Campbell
- Department of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA,Iowa Institute of Human GeneticsCarver College of MedicineUniversity of IowaIowa CityIA
| | - A. E. Kwitek
- Iowa Institute of Human GeneticsCarver College of MedicineUniversity of IowaIowa CityIA,Department of PharmacologyCarver College of MedicineUniversity of IowaIowa CityIA
| | - B. W. Darbro
- Department of PediatricsCarver College of MedicineUniversity of IowaIowa CityIA,Interdisciplinary Program in GeneticsUniversity of IowaIowa CityIA,The Holden Comprehensive Cancer CenterUniversity of IowaIowa CityIA
| | - Z. A. Stewart
- Department of SurgeryDivision of Transplant SurgeryCarver College of MedicineUniversity of IowaIowa CityIA
| | - R. J. H. Smith
- Department of Internal MedicineCarver College of MedicineUniversity of IowaIowa CityIA,Department of PediatricsCarver College of MedicineUniversity of IowaIowa CityIA,Iowa Institute of Human GeneticsCarver College of MedicineUniversity of IowaIowa CityIA,Interdisciplinary Program in GeneticsUniversity of IowaIowa CityIA,Department of OtorhinolaryngologyCarver College of MedicineUniversity of IowaIowa CityIA
| |
Collapse
|
|
14
|
Gast C, Pengelly RJ, Lyon M, Bunyan DJ, Seaby EG, Graham N, Venkat-Raman G, Ennis S. Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant 2015; 31:961-70. [PMID: 26346198 DOI: 10.1093/ndt/gfv325] [Citation(s) in RCA: 178] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 08/12/2015] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Multiple genes underlying focal segmental glomerulosclerosis (FSGS) and/or steroid-resistant nephrotic syndrome (SRNS) have been identified, with the recent inclusion of collagen IV mutations responsible for Alport disease (AD) or thin basement membrane nephropathy (TBMN). We aimed to investigate the distribution of gene mutations in adult patients with primary FSGS/SRNS by targeted next generation sequencing (NGS). METHODS Eighty-one adults from 76 families were recruited; 24 families had a history of renal disease. A targeted NGS panel was designed and applied, covering 39 genes implicated in FSGS/SRNS including COL4A3-5. RESULTS Confirmed pathogenic mutations were found in 10 patients (6 with family history) from 9 families (diagnostic rate 12%). Probably pathogenic mutations were identified in an additional six patients (combined diagnostic rate 20%). Definitely pathogenic mutations were identified in 22% of patients with family history and 10% without. Mutations in COL4A3-5 were present in eight patients from six families, representing 56% of definitely pathogenic mutations, and establishing a diagnosis of AD in six patients and TBMN in two patients. Collagen mutations were identified in 38% of families with familial FSGS, and 3% with sporadic FSGS, with over half the mutations occurring in COL4A5. Patients with collagen mutations were younger at presentation and more likely to have family history, haematuria and glomerular basement membrane abnormalities. CONCLUSIONS We show that collagen IV mutations, including COL4A5, frequently underlie FSGS and should be considered, particularly with a positive family history. Targeted NGS improves diagnostic efficiency by investigating many candidate genes in parallel.
Collapse
Affiliation(s)
- Christine Gast
- Wessex Kidney Centre, Portsmouth Hospitals NHS Trust, Portsmouth, UK Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Reuben J Pengelly
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Matthew Lyon
- Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
| | - David J Bunyan
- Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK
| | - Eleanor G Seaby
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
| | - Nikki Graham
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
| | | | - Sarah Ennis
- Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton, Southampton, UK
| |
Collapse
|
|
15
|
Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies. Kidney Int 2013; 85:880-7. [PMID: 24257694 PMCID: PMC3972265 DOI: 10.1038/ki.2013.450] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Revised: 08/27/2013] [Accepted: 08/29/2013] [Indexed: 01/05/2023]
Abstract
Rare single-gene disorders cause chronic disease. However, half of the
6,000 recessive single gene causes of disease are still unknown. Because
recessive disease genes can illuminate, at least in part, disease
pathomechanism, their identification offers direct opportunities for improved
clinical management and potentially treatment. Rare diseases comprise the
majority of chronic kidney disease (CKD) in children but are notoriously
difficult to diagnose. Whole exome resequencing facilitates identification of
recessive disease genes. However, its utility is impeded by the large number of
genetic variants detected. We here overcome this limitation by combining
homozygosity mapping with whole exome resequencing in 10 sib pairs with a
nephronophthisis-related ciliopathy, which represents the most frequent genetic
cause of CKD in the first three decades of life. In 7 of 10 sib-ships with a
histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy
we detect the causative gene. In six sib-ships we identify mutations of known
nephronophthisis-related ciliopathy genes, while in two additional sib-ships we
found mutations in the known CKD-causing genes SLC4A1 and
AGXT as phenocopies of nephronophthisis-related ciliopathy.
Thus whole exome resequencing establishes an efficient, non-invasive approach
towards early detection and causation-based diagnosis of rare kidney diseases.
This approach can be extended to other rare recessive disorders, thereby
providing accurate diagnosis and facilitating the study of disease
mechanisms.
Collapse
|
|
16
|
Al-Romaih KI, Genovese G, Al-Mojalli H, Al-Othman S, Al-Manea H, Al-Suleiman M, Al-Jondubi M, Atallah N, Al-Rodhyan M, Weins A, Pollak MR, Adra CN. Genetic diagnosis in consanguineous families with kidney disease by homozygosity mapping coupled with whole-exome sequencing. Am J Kidney Dis 2011; 58:186-95. [PMID: 21658830 PMCID: PMC3291334 DOI: 10.1053/j.ajkd.2011.01.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2010] [Accepted: 01/12/2011] [Indexed: 12/30/2022]
Abstract
BACKGROUND Accurate diagnosis of the primary cause of an individual's kidney disease can be essential for proper management. Some kidney diseases have overlapping histopathologic features despite being caused by defects in different genes. In this report, we describe 2 consanguineous Saudi Arabian families in which individuals presented with kidney failure and mixed clinical and histologic features initially believed to be consistent with focal segmental glomerulosclerosis. STUDY DESIGN Case series. SETTING & PARTICIPANTS We studied members of 2 apparently unrelated families from Saudi Arabia with kidney disease. MEASUREMENTS Whole-genome single-nucleotide polymorphism analysis followed by targeted isolation and sequencing of exons using genomic DNA samples from affected members of these families, followed by additional focused genotyping and sequence analysis. RESULTS The 2 apparently unrelated families shared a region of homozygosity on chromosome 2q13. Exome sequence from affected individuals lacked sequence reads from the NPHP1 gene, which is located within this homozygous region. Additional polymerase chain reaction-based genotyping confirmed that affected individuals had NPHP1 deletions, rather than defects in a known focal segmental glomerulosclerosis-associated gene. LIMITATIONS The methods used here may not result in a clear genetic diagnosis in many cases of apparent familial kidney disease. CONCLUSIONS This analysis shows the power of new high-throughput genotyping and sequencing technologies to aid in the rapid genetic diagnosis of individuals with an inherited form of kidney disease. We believe it is likely that such tools may become useful clinical genetic tools and alter the manner in which diagnoses are made in nephrology.
Collapse
Affiliation(s)
- Khaldoun I. Al-Romaih
- Stem Cell Therapy Program, Medicine and Pathology, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
- Nephrology Division, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
| | - Giulio Genovese
- Nephrology Division, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Hamad Al-Mojalli
- Department of Pediatrics, Medicine and Pathology, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Saleh Al-Othman
- Stem Cell Therapy Program, Medicine and Pathology, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Hadeel Al-Manea
- Department of Laboratory, Medicine and Pathology, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
| | | | | | - Nourah Atallah
- Stem Cell Therapy Program, Medicine and Pathology, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Maha Al-Rodhyan
- Stem Cell Therapy Program, Medicine and Pathology, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
| | - Astrid Weins
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Martin R. Pollak
- Nephrology Division, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Chaker N. Adra
- Stem Cell Therapy Program, Medicine and Pathology, King Faisal Specialist Hospital & Research Centre, Riyadh, 11211, Kingdom of Saudi Arabia
- Transplantation Center, Children's Hospital Boston & Brigham and Women's Hospital, Boston, MA 02215 USA
| |
Collapse
|
|
17
|
Zhao C, Malicki J. Nephrocystins and MKS proteins interact with IFT particle and facilitate transport of selected ciliary cargos. EMBO J 2011; 30:2532-44. [PMID: 21602787 DOI: 10.1038/emboj.2011.165] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2010] [Accepted: 04/19/2011] [Indexed: 01/16/2023] Open
Abstract
Cilia are required for the development and function of many organs. Efficient transport of protein cargo along ciliary axoneme is necessary to sustain these processes. Despite its importance, the mode of interaction between the intraflagellar ciliary transport (IFT) mechanism and its cargo proteins remains poorly understood. Our studies demonstrate that IFT particle components, and a Meckel-Gruber syndrome 1 (MKS1)-related, B9 domain protein, B9d2, bind each other and contribute to the ciliary localization of Inversin (Nephrocystin 2). B9d2, Inversin, and Nephrocystin 5 support, in turn, the transport of a cargo protein, Opsin, but not another photoreceptor ciliary transmembrane protein, Peripherin. Interestingly, the components of this mechanism also contribute to the formation of planar cell polarity in mechanosensory epithelia. These studies reveal a molecular mechanism that mediates the transport of selected ciliary cargos and is of fundamental importance for the differentiation and survival of sensory cells.
Collapse
Affiliation(s)
- Chengtian Zhao
- Division of Craniofacial and Molecular Genetics, and Program in Genetics, Sackler School of Graduate Biomedical Studies, Tufts University, Boston, MA, USA
| | | |
Collapse
|