Clinical and genetic analysis of a child with X-linked Hoyeraal-Hreidarsson syndrome due to variant of DKC1 gene and a literature review.
10.3760/cma.j.cn511374-20241207-00641
- Author:
Yuhui YOU
1
,
2
;
Dongqing HAN
;
Wenjing LIU
;
Zhaohong YUAN
Author Information
1. Department of Pediatrics Primary Care and Rehabilitation, The Affiliated Hospital of Jining Medical University, Jining, Shandong 272029, China. yuanzhh2002@
2. com.
- Publication Type:English Abstract
- MeSH:
Humans;
Infant;
Male;
Cell Cycle Proteins/genetics*;
Dyskeratosis Congenita/genetics*;
Exome Sequencing;
Fetal Growth Retardation/genetics*;
Intellectual Disability/genetics*;
Microcephaly/genetics*;
Mutation;
Nuclear Proteins/genetics*;
X-Linked Intellectual Disability/genetics*
- From:
Chinese Journal of Medical Genetics
2025;42(10):1212-1218
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To explore the clinical features and genetic etiology of a child with Hoyeraal-Hreidarsson syndrome (HHS).
METHODS:A child with HHS diagnosed at the Affiliated Hospital of Jining Medical University due to "developmental delay and anaemia" on April 27, 2024 was selected as the study subject. Clinical data of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Whole-exome sequencing was carried out, and candidate variant was verified by Sanger sequencing of his family members and bioinformatics analysis using CASAVA v1.8.2. The pathogenicity of the candidate variant was rated according to the Standards and Guidelines for the Interpretation of Sequence Variants released by the American College of Medical Genetics and Genomics (ACMG). Relevant literature on HHS cases reported in China was reviewed to analyze the clinical and genetic characteristics. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2024-10-C003).
RESULTS:The child, a 7-month-old boy, had mainly manifested with growth retardation, developmental delay, microcephaly, cerebellar hypoplasia, immunodeficiency and bone marrow failure. Routine blood test indicated pancytopenia. The immunological workup showed reduction of B cells, NK cells and immunoglobulins. Cranial MRI demonstrated the volume of bilateral cerebellar hemispheres and brainstem and corpus callosum was small. Whole-exome sequencing revealed that he has harbored a hemizygous c.103_105del (p.Glu35del) variant of the DKC1 gene. Sanger sequencing showed that his mother and two sisters have carried the same variant. Based on the ACMG guidelines, the variant was predicted to be likely pathogenic (PM1+PM4+PS4_Supporting+PM2_Supporting). Four relevant literature were retrieved, which has involved 8 HHS cases. Together with the patient from this study, they have consisted of 8 males and 1 females. The most common symptoms of the 9 patients were blood system abnormalities and developmental delay. All patients had shown cerebellar dysplasia and anemia/erythrocytopenia. Among them, 3 cases have harbored TINF2 gene variants, and 6 cases had harbored DKC1 gene variants. The c.103_105del variant has not been reported in China previously.
CONCLUSION:The hemizygous c.103_105del (p.Glu35del) variant of the DKC1 gene probably underlay the disease in this child. Above finding has expanded the mutational and phenotypic spectra of the DKC1 gene, and has facilitated early diagnosis of HHS in this child.
