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Recessive thrombocytopenia likely due to a homozygous pathogenic variant in the FYB gene: case report.

ABSTRACT: BACKGROUND:Inherited thrombocytopenias (IT) are a heterogeneous group of rare diseases characterized by a reduced number of blood platelets. The frequency of IT is probably underestimated because of diagnostic difficulties and because not all the existing forms have as yet been identified, with some patients remaining without a definitive diagnosis. Exome Sequencing has made possible the identification of almost all variants in the coding regions of protein-coding genes, thereby providing the opportunity to identify the disease causing gene in a number of patients with indefinite diagnoses, specifically in consanguineous families. CASE PRESENTATION:Familial thrombocytopenia with small size platelets was present in several members of a highly consanguineous family from Northern Iraq. Genotyping of all affected, their unaffected siblings and parents, followed by exome sequencing revealed a strong candidate loss of function variant in a homozygous state: a frameshift mutation in the FYB gene. The protein encoded by this gene is known to be a cytosolic adaptor molecule expressed by T, natural killer (NK), myeloid cells and platelets, and is involved in platelet activation and controls the expression of interleukin-2. Knock-out mice were reported to show isolated thrombocytopenia. CONCLUSION:Inherited thrombocytopenias differ in their presentation, associated features, and molecular etiologies. An accurate diagnosis is needed to provide appropriate management as well as counseling for the individuals and their family members. Exome sequencing may become a first diagnostic tool to identify the molecular basis of undiagnosed familial IT. In this report, the clinical evaluation combined with the power and efficiency of genomic analysis defined the FYB gene as the possible underlying cause of autosomal recessive thrombocytopenia with small platelet size. This is the first report linking pathogenic variants in FYB and thrombocytopenia in humans.

SUBMITTER: Hamamy H

PROVIDER: S-EPMC4411870 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Recessive thrombocytopenia likely due to a homozygous pathogenic variant in the FYB gene: case report.

Hamamy Hanan H Makrythanasis Periklis P Al-Allawi Nasir N Muhsin Abdulrahman A AA Antonarakis Stylianos E SE

BMC medical genetics 20141217

<h4>Background</h4>Inherited thrombocytopenias (IT) are a heterogeneous group of rare diseases characterized by a reduced number of blood platelets. The frequency of IT is probably underestimated because of diagnostic difficulties and because not all the existing forms have as yet been identified, with some patients remaining without a definitive diagnosis. Exome Sequencing has made possible the identification of almost all variants in the coding regions of protein-coding genes, thereby providin ...[more]

PMID: 25516138

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Project description:Dent disease-1 is a rare X-linked recessive renal tubular disorder caused by pathogenic variants in the chloride voltage-gated channel 5 (CLCN5) gene. It is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal failure. This is the first report of a CLCN5 pathogenic variant in a Dent disease-1 family of Sri Lankan origin, and it highlights the value of genetic evaluation in children with refractory proteinuria.A 2-year-old boy with non-nephrotic range proteinuria was referred for evaluation. His maternally related 24-year-old uncle had been investigated for similar features at the age of 14 years and his renal histology had shown few sclerosed glomeruli. He remained asymptomatic apart from proteinuria. Biochemical investigation of the child showed ?-2 microglobulinuria and hypercalciuria. After providing pre-test counseling and obtaining written informed consent, the child, his mother and maternal uncle underwent genetic testing for confirmation of the clinically suspected diagnosis of Dent disease-1. Both the child and his maternal uncle were found to be hemizygous for a nonsense pathogenic variant in exon 9 of the CLCN5 gene [NM_000084.4; c.1399C>T; rs797044811] which results in a stop codon at residue 467, leading to a truncated non-functional protein [NP_000075.1; p.R467X]. His mother was confirmed to be an unaffected heterozygous carrier for the same variant. Following confirmation of the diagnosis our patient was started on thiazide diuretics and potassium citrate.Even though the typical phenotype of Dent disease-1 often enables a clinical diagnosis to be made, less severe sub-clinical cases may go undiagnosed. The underlying diagnosis may be missed especially in children who are treated for non-minimal change nephrotic syndrome with steroids. This case highlights the need for tubular proteinuria to be considered in the differential diagnosis of children with refractory proteinuria and for appropriate genetic evaluation to be done to confirm the precise underlying diagnosis in such cases.

Dataset Information

Recessive thrombocytopenia likely due to a homozygous pathogenic variant in the FYB gene: case report.

Publications

Recessive thrombocytopenia likely due to a homozygous pathogenic variant in the FYB gene: case report.

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