Value of whole exome sequencing for syndromic retinal dystrophy diagnosis in young patients

Prokudin, Ivan; Liu, Dong; He, Sijie; Guo, Yiran; Goodwin, Linda; Wilson, Meredith; Rose, Loreto; Tian, Lifeng; Chen, Yulan; Liang, Jinlong; Keating, Brendan J.; Xu, Xun; Jamieson, Robyn V; Hákonarson, Hákon

doi:10.1111/ceo.12391

Cited by 6 publications

(5 citation statements)

References 22 publications

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“…In fact, a pattern of agalactosylated and asialo‐fucosylated structures, indicative of a N‐glycan maturation defect, was found in serum proteins of these patients . Intermittent congenital neutropenia is a hallmark of this disease (detected in 168/224 VPS13B‐CDG patients) . One patient had leukopenia without neutropenia while another had pancytopenia .…”

Section: The Immunological Impact Of Glycosylation Defects—an Update mentioning

confidence: 94%

CDG and immune response: From bedside to bench and back

Pascoal

Francisco

Ferro

et al. 2019

J of Inher Metab Disea

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Glycosylation is an essential biological process that adds structural and functional diversity to cells and molecules, participating in physiological processes such as immunity. The immune response is driven and modulated by protein‐attached glycans that mediate cell‐cell interactions, pathogen recognition and cell activation. Therefore, abnormal glycosylation can be associated with deranged immune responses. Within human diseases presenting immunological defects are congenital disorders of glycosylation (CDG), a family of around 130 rare and complex genetic diseases. In this review, we have identified 23 CDG with immunological involvement, characterized by an increased propensity to—often life‐threatening—infection. Inflammatory and autoimmune complications were found in 7 CDG types. CDG natural history(ies) and the mechanisms behind the immunological anomalies are still poorly understood. However, in some cases, alterations in pathogen recognition and intracellular signaling (eg, TGF‐β1, NFAT, and NF‐κB) have been suggested. Targeted therapies to restore immune defects are only available for PGM3‐CDG and SLC35C1‐CDG. Fostering research on glycoimmunology may elucidate the involved pathophysiological mechanisms and open new therapeutic avenues, thus improving CDG patients' quality of life.

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Section: The Immunological Impact Of Glycosylation Defects—an Update mentioning

confidence: 94%

CDG and immune response: From bedside to bench and back

Pascoal

Francisco

Ferro

et al. 2019

J of Inher Metab Disea

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“…In a third family of Lebanese origin, whole exome sequencing revealed a 1 bp deletion (c.11327delA) leading to a frameshift mutation in VPS13B in two affected siblings. The 7‐year‐old girl and her 4‐year‐old brother presented with developmental delay, postnatal onset microcephaly, characteristic facial gestalt, and pigmentary retinopathy (Prokudin et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Finnish Mediterranean (Bugiani et al, 2008;Douzgou & Petersen, 2011) Amish (Falk et al, 2004) Irish travelers (Murphy, Flanagan, Dunne, & Lynch, 2007) Our patient to a frameshift mutation in VPS13B in two affected siblings. The 7-yearold girl and her 4-year-old brother presented with developmental delay, postnatal onset microcephaly, characteristic facial gestalt, and pigmentary retinopathy (Prokudin et al, 2015).…”

Section: T a B L E 1 Different Genotypes And Associated Clinical Phenmentioning

confidence: 99%

A novel homozygous nonsense mutation of VPS13B associated with previously unreported features of Cohen syndrome

Koehler

Schuelke

Hell

et al. 2019

American J of Med Genetics Pt A

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Cohen syndrome (CS) is a rare autosomal recessive disorder associated with mutations in the vacuolar protein sorting 13 homolog B (VPS13B; formerly COH1) gene. The core clinical phenotype comprises a characteristic facial gestalt, marked developmental delay, and myopia. Additional, nonobligatory features include obesity, microcephaly, short stature, muscular hypotonia, scoliosis, narrow hands and feet, progressive retinopathy, as well as neutropenia. Here we report a novel homozygous nonsense mutation in the VPS13B gene and previously undescribed clinical features in a 19‐year‐old woman with developmental delay, intellectual disability, and a particular facial appearance. The patient showed several features consistent with CS. In addition, the parents observed congenital alacrima and anhidrosis persisting until onset of puberty. The diagnosis was not established based on the clinical phenotype. We performed whole‐genome sequencing and identified a novel homozygous nonsense mutation c.62T>G (NM_152564.4), p.(Leu21*) in the VPS13B gene. Our findings extended the previously reported phenotype of CS. We conclude that transient, prepubertal alacrima and anhidrosis are part of the phenotypic spectrum of CS associated with a novel homozygous nonsense mutation in the VPS13B gene.

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“…However, difficulty in distinguishing between causal and coincidental obesity in unique cases necessitates replication of these results in additional patients. WES has also discovered novel mutations and/or structural variants for syndromic obesity in previously implicated genes and revealed clinical heterogeneity in several obesity syndromes . For example, in a study of individuals with atypical Alström syndrome, novel ALMS1 mutations were identified using WES secondary to a negative classical genetic test of ALMS1 mutational hotspots .…”

Section: Established Strategiesmentioning

confidence: 99%

Established and emerging strategies to crack the genetic code of obesity

2018

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Tremendous progress has been made in the genetic elucidation of obesity over the past two decades, driven largely by technological, methodological and organizational innovations. Current strategies for identifying obesity-predisposing loci/genes, including cytogenetics, linkage analysis, homozygosity mapping, admixture mapping, candidate gene studies, genome-wide association studies, custom genotyping arrays, whole-exome sequencing and targeted exome sequencing, have achieved differing levels of success, and the identified loci in aggregate explain only a modest fraction of the estimated heritability of obesity. This review outlines the successes and limitations of these approaches and proposes novel strategies, including the use of exceptionally large sample sizes, the study of diverse ethnic groups and deep phenotypes and the application of innovative methods and study designs, to identify the remaining obesity-predisposing genes. The use of both established and emerging strategies has the potential to crack the genetic code of obesity in the not-too-distant future. The resulting knowledge is likely to yield improvements in obesity prediction, prevention and care.

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Value of whole exome sequencing for syndromic retinal dystrophy diagnosis in young patients

Cited by 6 publications

References 22 publications

CDG and immune response: From bedside to bench and back

CDG and immune response: From bedside to bench and back

A novel homozygous nonsense mutation of VPS13B associated with previously unreported features of Cohen syndrome

Established and emerging strategies to crack the genetic code of obesity

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