Simultaneous Sequencing of 24 Genes Associated with Steroid-Resistant Nephrotic Syndrome

McCarthy, Hugh; Bierżyńska, Agnieszka; Wherlock, Matthew; Ognjanović, Miloš; Kerecuk, Larissa; Hegde, Shivaram; Feather, Sally; Gilbert, Rodney D.; Krischock, Leah; Jones, Caroline; Sinha, Manish D.; Webb, Nicholas J.A.; Christian, Martin; Williams, Margaret M.; Marks, Stephen D.; Koziell, Ania; Welsh, Gavin I.; Saleem, Moin A.

doi:10.2215/cjn.07200712

Cited by 158 publications

(107 citation statements)

References 31 publications

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“…We performed whole exome sequencing using an Illumina platform on 187 SRNS cases as an extension of previous analysis of a cohort of childhood SRNS 1 . Cases lacking mutations in the known 53 nephrotic genes were analysed further in particular those with congenital nephrotic syndrome which is generally autosomal recessive and a developmental disorder.…”

Section: Discussionmentioning

confidence: 99%

MAGI2 Mutations Cause Congenital Nephrotic Syndrome

Bierżyńska¹,

Soderquest

Dean

et al. 2016

JASN

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Steroid–resistant nephrotic syndrome (SRNS), a heterogeneous disorder of the renal glomerular filtration barrier, results in impairment of glomerular permselectivity. Inheritance of genetic SRNS may be autosomal dominant or recessive, with a subset of autosomal recessive SRNS presenting as congenital nephrotic syndrome (CNS). Mutations in 53 genes are associated with human SRNS, but these mutations explain ≤30% of patients with hereditary cases and only 20% of patients with sporadic cases. The proteins encoded by these genes are expressed in podocytes, and malfunction of these proteins leads to a universal end point of podocyte injury, glomerular filtration barrier disruption, and SRNS. Here, we identified novel disease–causing mutations in membrane–associated guanylate kinase, WW, and PDZ domain–containing 2 (MAGI2) through whole-exome sequencing of a deeply phenotyped cohort of patients with congenital, childhood–onset SRNS. Although MAGI2 has been shown to interact with nephrin and regulate podocyte cytoskeleton and slit diaphragm dynamics, MAGI2 mutations have not been described in human SRNS. We detected two unique frameshift mutations and one duplication in three patients (two families); two siblings shared the same homozygous frameshift mutation, whereas one individual with sporadic SRNS exhibited compound heterozygosity. Two mutations were predicted to introduce premature stop codons, and one was predicted to result in read through of the normal translational termination codon. Immunohistochemistry in kidney sections from these patients revealed that mutations resulted in lack of or diminished podocyte MAGI2 expression. Our data support the finding that mutations in the MAGI2 gene are causal for congenital SRNS.

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Section: Discussionmentioning

confidence: 99%

MAGI2 Mutations Cause Congenital Nephrotic Syndrome

Bierżyńska¹,

Soderquest

Dean

et al. 2016

JASN

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“…It is known that NGS-based methods are less accurate to detect indel mutations than point mutations. 17 Importantly, simple visual inspection of the NGS reads using IGV very clearly showed these two mutations, suggesting that, even if a few indels are missed by the variant caller, they will be caught by simple careful visual analysis of the reads by using IGV, which thus, must be performed for all patients with no identified mutation. Another problem thought to be unique to certain NGS methods is contiguous runs of the same base pair called homopolymer repeats.…”

Section: Discussionmentioning

confidence: 99%

“…It has recently been shown to be efficient in diagnostic screening of human diseases, 15 including renal diseases, such as autosomal dominant polycystic kidney disease 16 and steroid-resistant nephrotic syndrome. 17 Here, we used multiplex PCR, amplicon quantification, library barcoding, and sample pooling followed by NGS for mutation analysis of three type IV collagen genes in a large series of patients affected with AS or BFH.…”

mentioning

confidence: 99%

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Morinière¹,

Dahan

Hilbert

et al. 2014

Journal of the American Society of Nephrology

132

131

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Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%-5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the webbased sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.

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“…The gene coding for podocin, NPHS2, located on chromosome 1q25-31, has been the focus of many studies of recurrent FSGS because it is one of the most common genetic causes of primary disease [16,17]. Podocin is a slit-diaphragm protein that interacts with nephrin [19,20]. Patients who are homozygous for a mutation represent the most common genetic cause of familial autosomal recessive steroid-resistant nephrotic syndrome (SRNS).…”

Section: Pathogenesismentioning

confidence: 99%

Recurrent focal segmental glomerulosclerosis after kidney transplantation

2015

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Focal segmental glomerulosclerosis (FSGS) is an important cause of glomerular disease in children and adolescents and nearly 50 % of affected patients will progress to endstage kidney disease over a 5 to 10-year period. Unfortunately, there is no established treatment for disease in the native kidney. Moreover, up to 55 % of patients develop recurrent disease after receiving a kidney transplant, with a substantially higher risk in patients who have already experienced recurrent disease in a prior transplant. A number of clinical and laboratory factors have been identified as risk factors for this complication. In addition, new investigations into podocyte biology and circulating permeability factors have shed light on the cause of recurrent the disease. While a number of novel therapeutic agents have been applied in the management of this problem, there still is no proven treatment. In this review, we summarize recent advances in the epidemiology, pathophysiology, and treatment of recurrent FSGS in pediatric patients who have received a kidney transplant.

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Simultaneous Sequencing of 24 Genes Associated with Steroid-Resistant Nephrotic Syndrome

Cited by 158 publications

References 31 publications

MAGI2 Mutations Cause Congenital Nephrotic Syndrome

MAGI2 Mutations Cause Congenital Nephrotic Syndrome

Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing

Recurrent focal segmental glomerulosclerosis after kidney transplantation

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