Utilizing Whole-Exome Sequencing to Characterize the Phenotypic Variability of Sickle Cell Disease

Alsultan, Abdulrahman; Alsuliman, Ahmed; Aleem, Aamer; Algahtani, Farjah H.; Alfadhel, Majid

doi:10.1089/gtmb.2018.0058

Cited by 12 publications

(7 citation statements)

References 44 publications

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“…The rs750046020 in the MPL gene has been reported as a pathogenic variant associated with thrombocytosis in the Saudi population. 19 The second (rs7755898) observation, associated with CAH, has been included in the National New-Born Screening Program. 18 It is known that mutations in the CYP21A2 gene are associated with more than 95% of the CAH cases, resulting in 21-hydroxylase deficiency (21-OHD).…”

Section: Discussionmentioning

confidence: 99%

Common disease-associated gene variants in a Saudi Arabian population

et al. 2022

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BACKGROUND: Screening programs for the most prevalent conditions occurring in a country is an evidence-based prevention strategy. The burden of autosomal recessive disease variations in Saudi Arabia is high because of the highly consanguineous population. The optimal solution for estimating the carrier frequency of the most prevalent diseases is carrier screening. OBJECTIVES: Identify the most influential recessive alleles associated with disease in the Saudi population. DESIGN: We used clinical whole-exome sequencing data from an in-house familial database to evaluate the most prevalent genetic variations associated with disease in a Saudi population. SETTINGS: King Abdullah International Medical Research Center (KAIMRC) and King Abdulaziz Medical City. METHODS: Whole exome sequencing data obtained from clinical studies of family members, a cohort of 1314 affected and unaffected individuals, were filtered using the in-house pipeline to extract the most prevalent variant in the dataset. MAIN OUTCOME MEASURES: Most prevalent genetic variations associated with disease in the Saudi population. SAMPLE SIZE: 1314 affected and unaffected individuals. RESULTS: We identified 37 autosomal recessive variants and two heterozygous X-linked variants in 35 genes associated with the most prevalent disorders, which included hematologic (32%), endocrine (21%), metabolic (11%) and immunological (10%) diseases. CONCLUSION: This study provides an update of the most frequently occurring alleles, which support future carrier screening programs. LIMITATIONS: Single center that might represent the different regions but may be biased. In addition, most of the families included in the database are part of the proband's genetic identification for specific phenotypes. CONFLICT OF INTEREST: None.

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Section: Discussionmentioning

confidence: 99%

Common disease-associated gene variants in a Saudi Arabian population

et al. 2022

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“…Giantin knock-out or mutant animal models have revealed the cell-type specific function of Giantin (Katayama et al, 2011, 2018; Lan et al, 2016; Bergen et al, 2017; McGee et al, 2017; Stevenson et al, 2017). Moreover, Giantin gene mutations and pathogenic changes in Giantin levels have been reported in various diseases, including sickle cell disease (Alsultan et al, 2018; Amlie-Lefond et al, 2018), bipolar disorder (Kerner et al, 2013), hepatocellular carcinoma (Choi et al, 2017), leukemia (Troadec et al, 2017), pulmonary disease (Raparelli et al, 2018), and post-alcohol recovery (Casey et al, 2018). These various phenotypes might be caused by the expression of Giantin binding partners, including GCP60 (Sohda et al, 2001), RCAN2 (Stevenson et al, 2018), PRMT5 (Sohail et al, 2015), PLK3 (Ruan et al, 2004), Rab6, p115, and Rab1 (Beard et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

The Golgin Protein Giantin Regulates Interconnections Between Golgi Stacks

Satoh

Hayashi-Nishino

Shakuno

et al. 2019

Front. Cell Dev. Biol.

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Golgins are a family of Golgi-localized long coiled-coil proteins. The major golgin function is thought to be the tethering of vesicles, membranes, and cytoskeletal elements to the Golgi. We previously showed that knockdown of one of the longest golgins, Giantin, altered the glycosylation patterns of cell surfaces and the kinetics of cargo transport, suggesting that Giantin maintains correct glycosylation through slowing down transport within the Golgi. Giantin knockdown also altered the sizes and numbers of mini Golgi stacks generated by microtubule de-polymerization, suggesting that it maintains the independence of individual Golgi stacks. Therefore, it is presumed that Golgi stacks lose their independence following Giantin knockdown, allowing easier and possibly increased transport among stacks and abnormal glycosylation. To gain structural insights into the independence of Golgi stacks, we herein performed electron tomography and 3D modeling of Golgi stacks in Giantin knockdown cells. Compared with control cells, Giantin-knockdown cells had fewer and smaller fenestrae within each cisterna. This was supported by data showing that the diffusion rate of Golgi membrane proteins is faster in Giantin-knockdown Golgi, indicating that Giantin knockdown structurally and functionally increases connectivity among Golgi cisternae and stacks. This increased connectivity suggests that contrary to the cis -golgin tether model, Giantin instead inhibits the tether and fusion of nearby Golgi cisternae and stacks, resulting in transport difficulties between stacks that may enable the correct glycosylation of proteins and lipids passing through the Golgi.

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“…In Kuwait, the prevalence of stroke is 1.4% in children [30], and in Shiraz, Iran, it seems to be low among children with SCD. When adults are considered, the stroke prevalence is high in Saudi Arabia's provinces (~7%) [31][32][33][34].…”

Section: Prevalence Of All Strokes In People With Scd Who Do Not Get ...mentioning

confidence: 99%

Pediatric Sickle Cell Disease and Stroke: A Literature Review

Parikh¹,

Goti²,

Yashi³

et al. 2023

Cureus

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Both ischemic and hemorrhagic strokes in children can be a complication of sickle cell disease, which also affects adults. The occurrence is high without any screening or preventative care. This review article found that although transcranial Doppler (TCD) has reduced the prevalence of stroke in pediatric patients, there is still a need for an epidemiological survey to define such screening for adults, the ideal dose of hydroxyurea to reduce the incidence of stroke, and to identify silent cerebral stroke to prevent its complications. Increased hydroxyurea prescription and specific antibiotic and vaccination regimes lowered the occurrence of this condition. In pediatric cases with a time-averaged mean of the maximal velocity greater than 200cm/s, transcranial Doppler screening and preventive chronic transfusion for at least the first year have lowered the occurrence of stroke by up to 10 times. The ideal dose of hydroxyurea is still debatable, but it seems to reduce the risk of the first stroke to a comparable level in the average population. Adult ischemic and hemorrhagic stroke prevention has not yet received the same attention. Though there are fewer studies, sickle cell disease is also more common than age-matched controls in terms of silent cerebral infarction on magnetic resonance imaging (MRI), as well as other neurological problems such as cognitive impairment, seizures, and headaches. Currently, there is no evidence-supported way to prevent ischemic stroke in adults at any age. Also, there is no defined ideal dose of hydroxyurea that can be helpful in preventing strokes. Data also lack a way to identify a silent cerebral infarction, so its complications can be prevented. An additional epidemiological survey may help in the prevention of the condition. The primary aim of this article was to emphasize the importance of information on clinical, neuropsychological, and quantitative MRI assessment of sickle cell patients to understand the epidemiology and etiology of stroke in sickle cell patients to prevent stroke and its related morbidity.

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Utilizing Whole-Exome Sequencing to Characterize the Phenotypic Variability of Sickle Cell Disease

Abstract: WES provided limited information to explain the severity of SCD. Whole genome sequencing, epigenetic studies, and assessment of environmental factors might expand our knowledge of SCD heterogeneity.

Cited by 12 publications

References 44 publications

Common disease-associated gene variants in a Saudi Arabian population

Common disease-associated gene variants in a Saudi Arabian population

The Golgin Protein Giantin Regulates Interconnections Between Golgi Stacks

Pediatric Sickle Cell Disease and Stroke: A Literature Review

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