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Parental Whole-Exome Sequencing Enables Sialidosis Type II Diagnosis due to an NEU1 Missense Mutation as an Underlying Cause of Nephrotic Syndrome in the Child.

ABSTRACT: Introduction:Monogenetic renal diseases, including recessively inherited nephrotic syndromes, represent a significant health burden despite being rare conditions. Precise diagnosis, including identification of the underlying molecular cause, is especially difficult in low-income countries and/or if affected individuals are unavailable for biochemical testing. Whole-exome sequencing (WES) has opened up novel diagnostic perspectives for these settings. However, sometimes the DNA of affected individuals is not suitable for WES due to low amounts or degradation. Methods:We report on the use of parental WES with implementation of specific stepwise variant filtering to identify the underlying molecular cause of the childhood-onset nephrotic syndrome as nephrosialidosis resulting from a mutation in NEU1. Results:Sequencing both parents enabled a nephrosialidosis diagnosis in the deceased child. To date, only 16 other cases of nephrosialidosis have been reported in the literature, with only 1 genetically confirmed case. After we reviewed the clinical information of all reported cases, we found that most patients presented with proteinuria, which started at between 2 and 3 years of age. Renal pathology showed mainly focal segmental glomerulosclerosis (FSGS)with vacuolated cells, and steroid treatment was always unsuccessful. Hepatomegaly was present in nearly all cases, whereas corneal clouding and a cherry red spot on the macula was observed in only approximately 50% of cases. Fourteen of 16 previously reported cases were no longer alive at the time of reporting. Conclusions:Our findings demonstrate the power of parental WES to diagnose rare genetic diseases, such as childhood-onset nephrotic syndrome. We further provide a comprehensive overview of the clinical course of nephrosialidosis and raise awareness of this ultra-rare condition as an underlying cause of FSGS.

SUBMITTER: Maroofian R

PROVIDER: S-EPMC6224678 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Parental Whole-Exome Sequencing Enables Sialidosis Type II Diagnosis due to an <i>NEU1</i> Missense Mutation as an Underlying Cause of Nephrotic Syndrome in the Child.

Maroofian Reza R Schuele Isabel I Najafi Maryam M Bakey Zeineb Z Rad Abolfazl A Antony Dinu D Habibi Haleh H Schmidts Miriam M

Kidney international reports 20180729 6

<h4>Introduction</h4>Monogenetic renal diseases, including recessively inherited nephrotic syndromes, represent a significant health burden despite being rare conditions. Precise diagnosis, including identification of the underlying molecular cause, is especially difficult in low-income countries and/or if affected individuals are unavailable for biochemical testing. Whole-exome sequencing (WES) has opened up novel diagnostic perspectives for these settings. However, sometimes the DNA of affecte ...[more]

PMID: 30450471

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Project description:BACKGROUND AND OBJECTIVES:Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. RESULTS:In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. CONCLUSIONS:Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

Dataset Information

Parental Whole-Exome Sequencing Enables Sialidosis Type II Diagnosis due to an NEU1 Missense Mutation as an Underlying Cause of Nephrotic Syndrome in the Child.

Publications

Parental Whole-Exome Sequencing Enables Sialidosis Type II Diagnosis due to an <i>NEU1</i> Missense Mutation as an Underlying Cause of Nephrotic Syndrome in the Child.

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