Wiskott–Aldrich syndrome in a child presenting with macrothrombocytopenia

Bastida, José María; Rey, Mónica del; Revilla, Nuria; Benito, Rocí­o; Pérez-Andrés, Martín; González, Berta; Riesco, Susana; Janusz, Kamila; Padilla, José; Benito-Sendin, Ana Hortal; Bueno, David; Blanco, E; Hernández-Rivas, Maria; Vicente, Vicente; Rivera, José; González-Porras, Ramon; Lozano, Marı́a Luisa

doi:10.1080/09537104.2016.1246715

Cited by 18 publications

(17 citation statements)

References 14 publications

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“…Remarkably, in this project 3 young children had their molecular diagnosis confirmed as having either CHS or WAS defects, and 1 of the WAS patients (Case 66) atypically presented with macrothrombocytopenia of uncertain phenotype. 32 …”

Section: Discussionmentioning

confidence: 99%

Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders

et al. 2017

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Inherited platelet disorders are a heterogeneous group of rare diseases, caused by inherited defects in platelet production and/or function. Their genetic diagnosis would benefit clinical care, prognosis and preventative treatments. Until recently, this diagnosis has usually been performed via Sanger sequencing of a limited number of candidate genes. High-throughput sequencing is revolutionizing the genetic diagnosis of diseases, including bleeding disorders. We have designed a novel high-throughput sequencing platform to investigate the unknown molecular pathology in a cohort of 82 patients with inherited platelet disorders. Thirty-four (41.5%) patients presented with a phenotype strongly indicative of a particular type of platelet disorder. The other patients had clinical bleeding indicative of platelet dysfunction, but with no identifiable features. The high-throughput sequencing test enabled a molecular diagnosis in 70% of these patients. This sensitivity increased to 90% among patients suspected of having a defined platelet disorder. We found 57 different candidate variants in 28 genes, of which 70% had not previously been described. Following consensus guidelines, we qualified 68.4% and 26.3% of the candidate variants as being pathogenic and likely pathogenic, respectively. In addition to establishing definitive diagnoses of well-known inherited platelet disorders, high-throughput sequencing also identified rarer disorders such as sitosterolemia, filamin and actinin deficiencies, and G protein-coupled receptor defects. This included disease-causing variants in DIAPH1 (n=2) and RASGRP2 (n=3). Our study reinforces the feasibility of introducing high-throughput sequencing technology into the mainstream laboratory for the genetic diagnostic practice in inherited platelet disorders.

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Section: Discussionmentioning

confidence: 99%

Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders

et al. 2017

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“…Given the syndromic macrothrombocytopenia, the patient's DNA was screened for molecular variants in 71 candidate genes related to inherited platelet disorders (IPDs) by use of an established high‐throughput sequencing (HTS) platform (MiSeq; Illumina, San Diego, CA, USA) and accompanying variant analysis . Serum PS and cholesterol levels were quantified with gas–liquid chromatography (GLC) .…”

Section: Methodsmentioning

confidence: 99%

Two novel variants of the ABCG5 gene cause xanthelasmas and macrothrombocytopenia: a brief review of hematologic abnormalities of sitosterolemia

Bastida

Benito

Janusz

et al. 2017

Journal of Thrombosis and Haemostasis

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Background Sitosterolemia (STSL) is a recessive inherited disorder caused by pathogenic variants in the ABCG5 and ABCG8 genes. Increased levels of plasma plant sterols (PSs) usually result in xanthomas and premature coronary atherosclerosis, although hematologic abnormalities may occasionally be present. This clinical picture is unfamiliar to many physicians, and patients may be at high risk of misdiagnosis. Objectives To report two novel ABCG5 variants causing STSL in a Spanish patient, and review the clinical and mutational landscape of STSL. Patient/Methods A 46-year-old female was referred to us with lifelong macrothrombocytopenia. She showed familial hypercholesterolemia-related xanthomas. Molecular analysis was performed with high-throughput sequencing. Plasma PS levels were evaluated with gas-liquid chromatography. The STSL landscape was reviewed with respect to specific online databases and all reports published since 1974. Results A blood smear revealed giant platelets and stomatocytes. Novel compound heterozygous variants were detected in exons 7 (c.914C>G) and 13 (c.1890delT) of ABCG5. The patient showed an increased plasma level of sitosterol. These findings support the diagnosis of STSL. In our review, we identified only 25 unrelated STLS patients who presented with hematologic abnormalities including macrothrombocytopenia. It remains unknown why only some patients develop hematologic abnormalities. Conclusions This is the first Spanish STSL patient to be reported and molecularly characterized. The early diagnosis of STLS is strongly supported by the presence of stomatocytes in blood smears. The definitive diagnosis of STSL by measurement of serum PS levels and molecular analyses prompted the use of ezetimibe therapy.

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“…In this case, the patient underwent a successful allogeneic transplantation from an unrelated donor. 57 The application of HTS also helped to identify rare variants in infrequent situations such as STSL. In this context, our group reported novel compound heterozygous variants affecting the ABCG5 gene in a 46-year-old female with lifelong macrothrombocytopenia, stomatocytes, arthritis, and xanthelasmas.…”

Section: Inherited Thrombocytopeniamentioning

confidence: 99%

Molecular Diagnosis of Inherited Coagulation and Bleeding Disorders

Bastida

Benito

Lozano

et al. 2019

Semin Thromb Hemost

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Diagnosis of inherited bleeding disorders (IBDs) remains challenging, especially in the case of inherited platelet disorders, due to the heterogeneity of the clinical and laboratory phenotype, the limited specificity of platelet function tests, and the large number of potential culprit genes. Unraveling the underlying molecular defect provides the definitive diagnosis of IBDs, facilitating prognosis and clinical care, which are especially important for severe clinical syndromes and those that may be associated with an increased risk of malignancy. Until recently, Sanger sequencing of candidate genes has been the only method of molecular diagnosis, but this approach is time-consuming and costly and requires phenotype-based identification of any obvious candidate gene(s). Nowadays, high-throughput sequencing (HTS) allows the simultaneous and rapid investigation of multiple genes at a manageable cost. This HTS technology that includes targeted sequencing of prespecified genes, whole-exome sequencing, or whole-genome sequencing, is revolutionizing the genetic diagnosis of human diseases. Through its extensive implementation in research and clinical practice, HTS is rapidly improving the molecular characterization of IBDs. However, despite the availability of this powerful approach, many patients still do not receive a diagnosis. As IBDs are complex and rare diseases, development of more advanced laboratory assays, improvements in bioinformatic pipelines, and the formation of multidisciplinary teams are encouraged to advance our understanding of IBDs.

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Wiskott–Aldrich syndrome in a child presenting with macrothrombocytopenia

Cited by 18 publications

References 14 publications

Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders

Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders

Two novel variants of the ABCG5 gene cause xanthelasmas and macrothrombocytopenia: a brief review of hematologic abnormalities of sitosterolemia

Molecular Diagnosis of Inherited Coagulation and Bleeding Disorders

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