CD8⁺ T‐cell senescence and skewed lymphocyte subsets in young Dyskeratosis Congenita patients with PARN and DKC1 mutations

Abstract

Background Dyskeratosis congenita (DC) is a syndrome resulting from defective telomere maintenance. Immunodeficiency associated with DC can cause significant morbidity and lead to premature mortality, but the immunological characteristics and molecular hallmark of DC patients, especially young patients, have not been described in detail. Methods We summarize the clinical data of two juvenile patients with DC. Gene mutations were identified by whole‐exome and direct sequencing. Swiss‐PdbViewer was used to predict the pathogenicity of identified mutations. The relative telomere length was determined by QPCR, and a comprehensive analysis of lymphocyte subsets and CD57 expression was performed by flow cytometry. Results Both patients showed typical features of DC without severe infection. In addition, patient 1 (P1) was diagnosed with Hoyeraal‐Hreidarsson syndrome due to cerebellar hypoplasia. Gene sequencing showed P1 had a compound heterozygous mutation (c.204G > T and c.178‐245del) in PARN and P2 had a novel hemizygous mutation in DKC1 (c.1051A > G). Lymphocyte subset analysis showed B and NK cytopenia, an inverted CD4:CD8 ratio, and decreased naïve CD4 and CD8 cells. A significant increase in CD21low B cells and skewed numbers of helper T cells (Th), regulatory T cells (Treg), follicular regulatory T cells (Tfr), and follicular helper T cells (Tfh) were also detected. Short telomere lengths, increased CD57 expression, and an expansion of CD8 effector memory T cells re‐expressing CD45RA (TEMRA) were also found in both patients. Conclusion Unique immunologic abnormalities, CD8 T‐cell senescence, and shortened telomere together as a hallmark occur in young DC patients before progression to severe disease.

A rare homozygous variant in TERT gene causing variable bone marrow failure, fragility fractures, rib anomalies and extremely short telomere lengths with high serum IgE

“…Similar to our results, skewed lymphocyte subsets, cytotoxic T‐cell senescence and strong CD23 expression on B cells were reported in patients with DC caused by mutations in PARN and DKC1 genes 16 . Also, immunoglobulin level abnormalities were reported in several published cases which might be unique to DC in comparison to patients with acquired BMFSs.…”

“…Similar to our results, skewed lymphocyte subsets, cytotoxic T-cell senescence and strong CD23 expression on B cells were reported in patients with DC caused by mutations in PARN and DKC1 genes. 16 Also, immunoglobulin level abnormalities were reported in several published cases Standing height using a portable stadiometer was measured to the nearest millimetre and weight was measured using an electronic scale to the nearest 100 g. Body mass index (BMI) was computed by dividing weight in kilograms by height in metre squares. Subsequently, the height, weight and BMI were converted to Z scores using Egyptian/WHO normative data.…”

Case Report: A Missense Mutation in Dyskeratosis Congenita 1 Leads to a Benign Form of Dyskeratosis Congenita Syndrome With the Mucocutaneous Triad

“…We also found 13 variants of DKC1 in Asia with 100% male ( 7 , 9 , 13 , 20 , 23 , 28 , 32 , 35 , 36 , 40 ), 52 variants in non-Asia with 84.8% male ( 1 , 8 , 10 – 14 , 16 – 19 , 21 , 24 – 26 , 29 , 31 , 33 , 34 , 37 , 38 , 41 , 42 , 44 , 45 ), and 10 variants with unknown nationality ( 3 , 4 , 30 ). Asians develop DC at a younger age than non-Asians, between 4.3 and 46 years old ( 1 , 7 – 12 , 14 , 16 – 24 , 26 , 28 , 29 , 31 – 35 , 38 – 42 ).…”

Construction of m7G subtype classification on heterogeneity of sepsis

“…Through whole exome and sequencing of patients with congenital dyskeratosis (DC), the study found that there were compound heterozygous mutations (c.204 g > T and c.178-245del) in PARN. At the same time, B cells and NK blood cells were also detected to be reduced, the ratio of CD4:CD8 was inverted, and naive CD4 and CD8 cells were reduced ( Zeng et al, 2020 ). However, in sepsis, lymphocytopenia and T-cell depletion are often found to be immunopathological characteristics ( van der Poll et al, 2017 ).…”