Mutations and Phenotypes of Unclassifiable Inherited Bone Marrow Failure Syndromes

Study Overview
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Brief Summary
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Inherited bone marrow failure syndromes (IBMFSs) are a diverse collection of genetic illnesses characterized by various degrees of peripheral cytopenias due to defective single-lineage or multi-lineage hematopoiesis, it can manifest itself at birth or later in life.

Detailed Description
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Studying the genetic etiology underlying unclassifiable IBMFSs with bone fragility fractures should be useful for clarifying the undiagnosed pathophysiological mechanisms and other accessory factors to improve the diagnosis, follow-up, prognosis, and management of these patients as well as prevent future complications. Moreover, early diagnosis of risk factors of unusual presentations of IBMFSs will be a useful tool for better treatment strategy. In addition, along with typical IBMFSs, novel clinical entities must be included in an overall molecular portrait of IBMF disorders. As a result, comprehensive genetic analysis will be effective in establishing an accurate genetic diagnosis at medical evaluation.

Official Title
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Identification of The Novel Mutations and A Comprehensive Analysis of The Phenotype and Genetic Etiology Underlying Unclassifiable Inherited Bone Marrow Failure Syndromes With Bone Fragility Fractures

Conditions
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Inherited BMF Syndrome

Intervention / Treatment
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* Genetic: The whole-exome sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed a two-generational family with IBMFSs presented with signs and symptoms of bone fragility fractures and admitted or treated in Hematology Division at Internal Medicine Departments of various university hospitals will be screened for enrollment in this study. The investigators will invite the entire family for testing for IBMFSs mutations, and three additional family members consented to participate in this study. Exclusion Criteria: • Patients will be diagnosed with paroxysmal nocturnal hemoglobinuria Patients will be diagnosed with de novo myelodysplastic syndrome IBMFSs-patients will refuse to consent to this study. Serologic evidence of recent virus infection as hepatitis A (HAV), HBV, HCV, HEV, cytomegalovirus (CMV), Epstein-Barr virus (EBV), or positive test for HIV. IBMFSs patients with severe systemic diseases (such as cardiovascular, renal, and hepatic disease) or surgical/medical conditions that might interfere with follow-up instructions. IBMFs patients with psychiatric disorders or a history of drug abuse,
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Genetic: The whole-exome sequencing|Exome sequencing will be performed at the Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan and will be analyzed at Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Japan.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Progression of pancytopenia | Progression of pancytopenia severity | Two year after diagnosis | 
| Number of Participants with Fragility Fractures | occurrence of the Fragility Fractures | Two year after diagnosis | 
| Number of Participants with Malignancy transformation | Occurrence of hematological or solid malignancy | Two year after diagnosis |