A Novel Heterozygous Pathogenic Variation in CYCS Gene Cause Autosomal Dominant Non-Syndromic Thrombocytopenia 4 in a Large Chinese Family

Abstract

Aim: To determine the etiology of a Chinese family with thrombocytopenia by analyzing the clinical features and genetic variation. Methods: Clinical profiles and genomic DNA extracts of the family members were collected for the study. Whole exome sequencing and Sanger sequencing was used to detect the associated genetic variation and verify the family co-segregation respectively. Bioinformatics analysis assessed the pathogenicity of missense mutations. Results: The study reported a 3-generation pedigree including eight family members with thrombocytopenia. The platelet counts of the patients were varied, ranging from 38 to 110 × 10⁹/L (reference range: 150-450 x 10⁹/L). The mean volumes and morphology of the sampled platelet were both normal. The bleeding abnormality and mitochondriopathy were not observed in all the patients. Clinical signs of thrombocytopenia were mild. A novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified in CYCS gene associated with autosomal dominant thrombocytopenia. Conclusion: We report the first large family with autosomal dominant non-syndromic thrombocytopenia 4 in a Chinese family, a novel heterozygous missense variant c.79C > T (p.His27Tyr) was identified. The whole exome sequencing is an efficient tool for screening the variants specifically associated with the disease. The finding enriches the mutation spectrum of CYCS gene and laid a foundation for future studies on the correlation between genotype and phenotype.

Keywords: CYCS gene; cytochrome c; mutation; platelet counts; thrombocytopenia.

FIGURE 1

(A) Familial pedigree of CYCS-mutated thrombocytopenia. The red arrow indicates the proband. (B) Optical microscopy of bone marrow cells from the proband showed the number of platelets were reduced. The red arrow on the left (Ba) showed a single platelet was sporadically visible, and the blue arrow points to promegakaryocytes (Bb), the green arrow points to granular megakaryocytes (Bb), and the yellow arrow points to thromocytogenic megakaryocytes (Bb). (C) Sanger sequencing of CYCS gene c.79C > T (p.His27Tyr) variant in genomic DNA from the family.

FIGURE 2

(A) Conservation of the p. His27Tyr variant across various species. (B) Amino acid and conformation changes of the p.His27Tyr polypeptide wild-type and mutant type. His27 is located in the random coil domain of CYCS by colored green (Ba); Stick models shows the amino acids around His27 and the selected side chains, wild-type His27 forms a hydrogen bond (green dotted line) with Asn32 and Pro45 (colored yellow) respectively (Bb), and the hydrogen bond was lost in mutant type Tyr27 (Bc). (C) Schematic presentation of linear CYCS protein (NM_018947.6) with all variants, red font indicate reported variant in the present study. The dark blue indicates three Ω-loops.