Genetic analysis in Egyptian patients with Chediak–Higashi syndrome reveals new
            <i>
              <scp>LYST</scp>
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            mutations

Gomaa, Nesrin S.; Lee, J. Y. W.; Sharkawy, A. El; Chazli, Y. F. El; Hassab, Hoda; Doghaim, Noha Nabil; McGrath, John A.; Onoufriadis, Alexandros

doi:10.1111/ced.13937

Cited by 4 publications

(1 citation statement)

References 5 publications

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“…There is no systematic review about biallelic LYST mutations associated with Chediak Higashi syndrome. Nonetheless, mutations seem to be scattered all throughout the gene and are a combination of point/missense mutations, insertion/deletion, or frameshift variants [1,3,5,7,23,28 ▪ ,29,30,31 ▪ ,32–46]. A few reports identify canonical splice-site mutations and association with uniparental isodisomy [47,48].…”

Section: Mutations In Lyst Cause Chediak Higashi Syndromementioning

confidence: 99%

Chediak-Higashi syndrome

Talbert

Malicdan

Introne

2023

Current Opinion in Hematology

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Purpose of reviewChediak-Higashi syndrome is a rare autosomal recessive disorder characterized by congenital immunodeficiency, bleeding diathesis, pyogenic infection, partial oculocutaneous albinism, and progressive neurodegeneration. Treatment is hematopoietic stem cell transplantation or bone marrow transplantation; however, this does not treat the neurologic aspect of the disease. Mutations in the lysosomal trafficking regulator (LYST) gene were identified to be causative of Chediak-Higashi, but despite many analyses, there is little functional information about the LYST protein. This review serves to provide an update on the clinical manifestations and cellular defects of Chediak-Higashi syndrome. Recent findingsMore recent papers expand the neurological spectrum of disease in CHS, to include hereditary spastic paraplegia and parkinsonism. Granule size and distribution in NK cells have been investigated in relation to the location of mutations in LYST. Patients with mutations in the ARM/HEAT domain had markedly enlarged granules, but fewer in number. By contrast, patients with mutations in the BEACH domain had more numerous granules that were normal in size to slightly enlarged, but demonstrated markedly impaired polarization. The role of LYST in autophagosome formation has been highlighted in recent studies; LYST was defined to have a prominent role in autophagosome lysosome reformation for the maintenance of lysosomal homeostasis in neurons, while in retinal pigment epithelium cells, LYST deficiency was shown to lead to phagosome accumulation. SummaryDespite CHS being a rare disease, investigation into LYST provides an understanding of basic vesicular fusion and fission. Understanding of these mechanisms may provide further insight into the function of LYST.

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Section: Mutations In Lyst Cause Chediak Higashi Syndromementioning

confidence: 99%

Chediak-Higashi syndrome

Talbert

Malicdan

Introne

2023

Current Opinion in Hematology

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Clinical Characteristics and Outcomes of 101 Children with Hemophagocytic Lymphohistiocytosis: A Four-Year Single-Center Experience from Egypt

Elsharkawy

Assem

Mikhael

et al. 2020

Pediatric Hematology and Oncology

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Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature

Morimoto,

Nicoli,

Kuptanon

et al. 2023

J Med Genet

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IntroductionChediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterised by partial oculocutaneous albinism, a bleeding diathesis, immunological dysfunction and neurological impairment. Bi-allelic loss-of-function variants inLYSTcause CHS.LYSTencodes the lysosomal trafficking regulator, a highly conserved 429 kDa cytoplasmic protein with an unknown function.MethodsTo further our understanding of the pathogenesis of CHS, we conducted clinical evaluations on individuals with CHS enrolled in our natural history study. Using genomic DNA Sanger sequencing, we identified novel pathogenicLYSTvariants. Additionally, we performed an extensive literature review to curate reportedLYSTvariants and classified these novel and reported variants according to the American College of Medical Genetics/Association for Molecular Pathology variant interpretation guidelines.ResultsOur investigation unveiled 11 novel pathogenicLYSTvariants in eight patients with a clinical diagnosis of CHS, substantiated by the presence of pathognomonic giant intracellular granules. From these novel variants, together with a comprehensive review of the literature, we compiled a total of 147 variants inLYST, including 61 frameshift variants (41%), 44 nonsense variants (30%), 23 missense variants (16%), 13 splice site variants or small genomic deletions for which the coding effect is unknown (9%), 5 in-frame variants (3%) and 1 start-loss variant (1%). Notably, a genotype–phenotype correlation emerged, whereby individuals harbouring at least one missense or in-frame variant generally resulted in milder disease, while those with two nonsense or frameshift variants generally had more severe disease.ConclusionThe identification of novel pathogenicLYSTvariants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS.

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Genetic analysis in Egyptian patients with Chediak–Higashi syndrome reveals new LYST mutations

Abstract: Click https://www.wileyhealthlearning.com/ced.aspx for the corresponding questions to this CME article.

Cited by 4 publications

References 5 publications

Chediak-Higashi syndrome

Chediak-Higashi syndrome

Clinical Characteristics and Outcomes of 101 Children with Hemophagocytic Lymphohistiocytosis: A Four-Year Single-Center Experience from Egypt

Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature

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