Dataset Information

Whole exome sequencing identifies MRVI1 as a susceptibility gene for moyamoya syndrome in neurofibromatosis type 1.

ABSTRACT: BACKGROUND AND PURPOSE:Moyamoya angiopathy is a progressive cerebral vasculopathy. The p.R4810K substitution in RNF213 has previously been linked to moyamoya disease in Asian populations. When associated with other medical conditions, such as neurofibromatosis type 1, this vasculopathy is frequently reported as moyamoya syndrome. Intriguingly, most cases of moyamoya-complicated neurofibromatosis type 1 have been described in Caucasians, inverting the population ratio observed in Asians, although prevalence of neurofibromatosis type 1 is constant worldwide. Our aim was to investigate whether, among Caucasians, additive genetic factors may contribute to the occurrence of moyamoya in neurofibromatosis type 1. METHODS:Whole exome sequencing was carried out on an Italian family with moyamoya-complicated neurofibromatosis type 1 to identify putative genetic modifiers independent of the NF1 locus and potentially involved in moyamoya pathogenesis. Results were validated in an unrelated family of German ancestry. RESULTS:We identified the p.P186S substitution (rs35857561) in MRVI1 that segregated with moyamoya syndrome in both the Italian and German family. CONCLUSIONS:The rs35857561 polymorphism in MRVI1 may be a genetic susceptibility factor for moyamoya in European patients with neurofibromatosis type 1. MRVI1 is a functional partner of ITPR1, PRKG1 and GUCY1A3, which are involved in response to nitric oxide. Mutations in GUCY1A3 have been recently linked to a recessive syndromic form of moyamoya with esophageal achalasia.

SUBMITTER: Santoro C

PROVIDER: S-EPMC6042724 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Whole exome sequencing identifies MRVI1 as a susceptibility gene for moyamoya syndrome in neurofibromatosis type 1.

Santoro Claudia C Giugliano Teresa T Kraemer Markus M Torella Annalaura A Schwitalla Jan Claudius JC Cirillo Mario M Melis Daniela D Berlit Peter P Nigro Vincenzo V Perrotta Silverio S Piluso Giulio G

PloS one 20180712 7

<h4>Background and purpose</h4>Moyamoya angiopathy is a progressive cerebral vasculopathy. The p.R4810K substitution in RNF213 has previously been linked to moyamoya disease in Asian populations. When associated with other medical conditions, such as neurofibromatosis type 1, this vasculopathy is frequently reported as moyamoya syndrome. Intriguingly, most cases of moyamoya-complicated neurofibromatosis type 1 have been described in Caucasians, inverting the population ratio observed in Asians, ...[more]

PMID: 30001348

Similar Datasets

Project description:Congenital Zika Syndrome (CZS) is a critical illness with a wide range of severity caused by Zika virus (ZIKV) infection during pregnancy. Life-threatening neurodevelopmental dysfunctions are among the most common phenotypes observed in affected newborns. Risk factors that contribute to susceptibility and response to ZIKV infection may be related to the virus itself, the environment, and maternal genetic background. Nevertheless, the newborn's genetic contribution to the critical illness is still not elucidated. Here, we aimed to identify possible genetic variants as well as relevant biological pathways that might be associated with CZS phenotypes. For this purpose, we performed a whole-exome sequencing in 40 children born to women with confirmed exposure to ZIKV during pregnancy. We investigated the occurrence of rare harmful single-nucleotide variants (SNVs) possibly associated with inborn errors in genes ontologically related to CZS phenotypes. Moreover, an exome-wide association analysis was also performed using a case-control design (29 CZS cases and 11 controls), for both common and rare variants. Five out of the 29 CZS patients harbored known pathogenic variants likely to contribute to mild to severe manifestations observed. Approximately, 30% of affected individuals carried at least one pathogenic or likely pathogenic SNV in genes candidates to play a role in CZS. Our common variant association analysis detected a suggestive protective effect of the rs2076469 in DISP3 gene (p-value: 1.39 x 10-5). The IL12RB2 gene (p-value: 2.18x10-11) also showed an unusual distribution of nonsynonymous rare SNVs in control samples. Finally, genes harboring harmful variants are involved in processes related to CZS phenotypes such as neurological development and immunity. Therefore, both rare and common variations may be likely to contribute as the underlying genetic cause of CZS susceptibility. The variations and pathways identified in this study may also have implications for the development of therapeutic strategies in the future.

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

Whole exome sequencing identifies MRVI1 as a susceptibility gene for moyamoya syndrome in neurofibromatosis type 1.

Publications

Whole exome sequencing identifies MRVI1 as a susceptibility gene for moyamoya syndrome in neurofibromatosis type 1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets