Dyskeratosis Congenita with Pigmentary Mosaicism and Hematopoietic Trisomy 9 in a Female Associated with a de novo DKC1 Variant and Markedly Skewed X Chromosome Inactivation
Pathogenic germline variants (PGVs) in dyskerin pseudouridine synthase 1 (DKC1) cause X-linked recessive dyskeratosis congenita (DC), a telomere biology disorder. Females with heterozygous DKC1 PGVs rarely exhibit DC phenotypes due to favorable X chromosome inactivation (XCI). We report a female with classic DC, pigmentary mosaicism and bone marrow failure associated with a novel de novo DKC1 variant (c.190 G > C, p.Val64Leu) with reduced expression of DKC1 and TERC along with downregulated signatures associated with aberrant telomere biology and ribosome function. Markedly skewed XCI was detected with expression of the mutated allele in skin fibroblasts and wild-type DKC1 expression in the bone marrow. We hypothesize that selective pressure in the bone marrow favored wild type expressing cells which acquired a trisomy 9 but were unable to resume normal hematopoiesis. This study demonstrates DKC1 c. 190 G > C as a likely PGV causing classic DC and highlights the molecular and clinical complexities associated with skewed XCI.
Authors
- Maryam Rafati (ORCID: https://orcid.org/0000-0001-7118-3412)
- Tianna Zhao (ORCID: https://orcid.org/0000-0002-7821-7168)
- Esther Lieberman
- Consuelo Salas‐Labadía (ORCID: https://orcid.org/0000-0002-3301-7357)
- Sara Frı́as (ORCID: https://orcid.org/0000-0002-3097-6368)
- Kristine M. Jones (ORCID: https://orcid.org/0000-0003-1584-8920)
- Burak Altintas (ORCID: https://orcid.org/0000-0001-5968-4812)
- Chad Highfill
- Angélica Monsiváis
- Belynda Hicks
- Logan P Zeigler
- Benilde García-de-Teresa
- Bertha Molina
- Lisa J. McReynolds
- Neelam Giri
- Difei Wang
- Komal Jain
- Mauricio Rojas
- Leda Torres
- Ulises Juárez-Figueroa
- Sharon A. Savage
- Raymond Caylor
- Jia Liu (ORCID: https://orcid.org/0009-0006-8111-2910)
- Weiyin Zhou
- María de la Luz Orozco-Covarrubias
- Moisés Fiesco-Roa
- Silvia Sánchez
Institutions
- National Institutes of Health (US)
- Secretaria de Salud (MX)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Instituto Nacional de Pediatria (MX)
- Greenwood Genetic Center (US)
- Centro Universitario Patria (MX)
- Instituto Nacional de Cancerología (MX)
- National Institutes of Health Clinical Center (US)
- Division of Cancer Epidemiology and Genetics
- Universidad Nacional Autónoma de México (MX)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2026-06-09
- DOI
- https://doi.org/10.1038/s41525-026-00587-8
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- National Cancer Institute
- Division of Cancer Epidemiology and Genetics, National Cancer Institute