De Novo Splice-Site Variant in DKC1 in a Female With Clinical Features of Hoyeraal-Hreidarsson Syndrome.

The dyskerin encoding gene DKC1 plays an important role in telomerase activity and telomere maintenance. Pathogenic variants in DKC1 cause an X-linked multiorgan disease called dyskeratosis congenita (DC), the most severe form of which is Hoyeraal-Hreidarsson syndrome (HHS). HHS due to DKC1 variants has so far only been reported in hemizygous males and is associated with severe neurological impairment and progressive bone marrow failure, often causing lethality in early childhood. Heterozygous carrier females are often phenotypically normal. Here, we report a young adult female carrying a de novo splice-site variant in DKC1 and presenting with clinical features overlapping with HHS, such as intrauterine and postnatal growth retardation, microcephaly, intellectual disability, and recurrent infections, while lacking other typical aspects such as dermatological manifestations, cerebellar hypoplasia, or bone marrow failure. Aberrant splicing was confirmed with an in vitro assay, and further analysis revealed very short telomere lengths in the individual, supporting a causative role of the DKC1 variant. Our observations therefore suggest that heterozygous splice-site variants in DKC1 leading to loss of function might result in a phenotype overlapping with but not being typical for HHS in females, supporting a potential genotype-phenotype correlation.