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

Abstract

Background:

Dyskeratosis congenita (DC) is a rare inheritable disorder characterized by bone marrow failure and mucocutaneous triad (reticular skin pigmentation, nail dystrophy, and oral leukoplakia). Dyskeratosis congenita 1 (DKC1) is responsible for 4.6% of the DC with an X-linked inheritance pattern. Almost 70 DKC1 variations causing DC have been reported in the Human Gene Mutation Database.

Results:

Here we described a 14-year-old boy in a Chinese family with a phenotype of abnormal skin pigmentation on the neck, oral leukoplakia, and nail dysplasia in his hands and feet. Genetic analysis and sequencing revealed hemizygosity for a recurrent missense mutation c.1156G > A (p.Ala386Thr) in DKC1 gene. The heterozygous mutation (c.1156G > A) from his mother and wild-type sequence from his father were obtained in the same site of DKC1. This mutation was determined as disease causing based on silico software, but the pathological phenotypes of the proband were milder than previously reported at this position (HGMDCM060959). Homology modeling revealed that the altered amino acid was located near the PUA domain, which might affect the affinity for RNA binding.

Conclusion:

This DKC1 mutation (c.1156G > A, p.Ala386Thr) was first reported in a Chinese family with mucocutaneous triad phenotype. Our study reveals the pathogenesis of DKC1 c.1156G > A mutation to DC with a benign phenotype, which expands the disease variation database, the understanding of genotype–phenotype correlations, and facilitates the clinical diagnosis of DC in China.

Introduction

Dyskeratosis congenita (DC) is a rare inheritable disorder characterized by bone marrow failure and mucocutaneous triad (skin pigmentation, dystrophy nails, oral leukoplakia) (1). So far, several genes have been identified to be associated with DC, including dyskeratosis congenita 1 (DKC1), CTS telomere maintenance complex component 1 (CTC1), regulator of telomere elongation helicase 1 (RTEL1), TERF 1-interacting nuclear factor 2 (TINF2), telomerase RNA component (TERC), telomerase reverse transcriptase (TERT), adrenocortical dysplasia homolog (ACD), NHP2 ribonucleoprotein (NHP2), NOP 10 ribonucleoprotein (NOP10), poly(A)-specific ribonuclease (PARN), nuclear assembly factor 1 (NAF1), and WD repeat containing antisense to TP53 (TCAB1), and DKC1 is responsible for 4.6% of the DC (2, 3). Almost 70 dyskeratosis congenita 1 (DKC1) variations causing DC have been reported in the Human Gene Mutation Database (HGMD¹); the gene encoding a nucleolar protein is called dyskerin, which is involved in both ribosome biogenesis (4) and telomere maintenance (5). Here, we found a DC patient in a Chinese family. The clinical data of the patient and literature review of DC are described.

Case Presentation

Clinical Manifestations and Family History

Three affected males (III-6, IV-2, and IV-3) and 14 unaffected individuals are involved in this family and are recruited from Shanxi Province, China (Figure 1G). The proband IV-2 is a 14-year-old boy with abnormal skin pigmentation on the neck (Figure 1A), oral leukoplakia (Figure 1B), and nail dysplasia on his hands and feet (Figures 1C–F). III-6 presents with similar phenotypes. II-2, II-3, III-2, and III-5 are mutation carriers without any mild signs of congenital dyskeratosis.

FIGURE 1

Sequencing Analysis of the Patient and His Family

Whole-exome sequencing (WES) data were functionally annotated and filtered using cloud-based rare disease NGS analysis platform,² based on the Ensembl (GRCh37/hg19), dbSNP, EVS, 1000 genome, ExAC, and GnomAD databases. Exonic sequence alterations and intronic variants at exon–intron boundaries, with unknown frequency or minor allele frequency (MAF) < 1% and not present in the homozygous state in those databases, were retained. Filtering was performed for variants in genes associated with DC. Then the only DC-related gene mutation DKC1 mutation (c.1156G > A, p.Ala386Thr) was identified.

Peripheral blood samples were collected from this family, which includes three individuals (III-2, III-3, and IV-2); a recurrent DKC1 hemizygous mutation (c.1156G > A) in exon 12 was confirmed in the proband (IV-2) by using Sanger sequencing (Figure 1H). Furthermore, a heterozygous mutation (c.1156G > A) in his mother (III-2) and a wild-type sequence in his father (III-3) were obtained on the same site of DKC1 (Figure 1H). The original contributions presented in the study are publicly available. These data can be found here: ClinVar Wizard Submission ID: SUB11097305; Accession: SCV002097631.

Pathogenicity Prediction of Variant

The effect of the missense variant was computationally analyzed by four prediction programs: Mutation Taster, SIFT, PolyPhen-2, and PROVEAN. The outcomes are summarized in Table 1.

Molecular Analysis

Evolutionary conservation of amino acid residue showed that the impaired amino acid residues Ala386 were highly conserved in different species (Figure 1J). The eukaryotic DKC1 protein presents three well-characterized domains: DKCLD (amino acids 49–106), TruB_N (amino acids 107–247), and PUA (amino acids 297–371) besides nuclear and nucleolar localization signals (amino acids 11–20; 446–458) (6, 7). Bioinformatic and biochemical assessment on the effect of the altered amino acid on the functions of DKC1 shows that the missense mutation was concentrated near the PUA domain (Figures 1I,K), which is crucial for the RNA binding of telomerase (7). DKC1 mutations concentrated in or near the PUA domain decrease the affinity for RNA binding (6). In conclusion, the recurrent DKC1 pathogenic variant was identified by WES and Sanger sequencing in a Chinese DC family.

Discussion

Here, we report a case of DC in a Chinese pedigree with a mutation c.1156G > A (p.Ala386Thr) in DKC1. The affected amino acids are located near the PUA kinase domain from the linear structure, indicating that the mutation might result in defect on the affinity for RNA binding (6). Evolutionary conservation analysis of amino acid residue showed that the amino acid residue Ala386 is highly conserved among DKC1 protein from different species, indicating that the mutation is likely pathological.

We have reviewed articles describing cases of DC using the Human Gene Mutation Database and NCBI—PubMed, with the search term “dyskeratosis congenita” from January 1998 to November 2021 (Table 2). Among the studies, we identified 74 variations in DKC1 with 85 individuals for analysis. Most publications were case reports so that the clinical data were not comprehensive. There were 87.5% male patients, 12.5% female patients, and 29 patients without gender description in the patients, indicating that males were the dominant patients of DC.

We find that the clinical symptoms of these DC patients are varied, but skin pigmentation, nail dystrophy, mucosal leukoplakia, and bone marrow failure are the most classic symptoms in patients. In this analysis, the incidence of skin pigmentation, nail dystrophy, and mucosal leucoplakia are nearly 86.58, 78.048, and 64.63%, respectively. Moreover, apart from the mucocutaneous triad, anemia can be another routine clinical sign of DC. Missense mutation is the most common mutation type among all the variations and shows higher incidence of the typical clinical symptoms of DC, but only one patient with c.194G > C (p.R65K) had mild symptoms such as pulmonary symptoms (20). The patient with mutation of small indel (c.166_167invCT) only suffer from thrombocytopenia and anemia (18). The patients with mutations of regulatory (c.-142C > G or c.-141C > G) only suffer from short telomere or pulmonary fibrosis (22, 24).

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). The incidence of the mucocutaneous triad (skin pigmentation, nail dystrophy, and mucosal leukoplakia), bone marrow failure, thrombocytopenia, and telomere shortening in Asia are similar to that of non-Asia (Table 3; 1, 3, 4, 7–12, 14, 16–24, 26, 28–35, 38–42, 45, 46). However, the DC-Asians are more likely to develop anemia instead of pulmonary fibrosis than non-Asians apart from the mucocutaneous triad (Table 3; 1, 3, 4, 7–12, 14, 16–24, 26, 28–35, 38–42, 45, 46). Unfortunately, the patient involved in our study did not present with anemia; the reason could be due to the lower incidence (35.7%) of anemia in Asian DC population.

The DKC1 variation of c.1156G > A (p.Ala386Thr) was also reported from a DCR216-family in 2006 (4). The patient presents both the features of classic DC and Hoyeraal Hreidarsson (HH) syndrome, including intrauterine growth retardation, developmental delay, microcephaly, cerebellar hypoplasia, immunodeficiency, or bone marrow failure (4). However, the patient involved in our study only presents with benign phenotype of the mucocutaneous triad without any other abnormality, which provides more information on the mutation phenotype spectrum of DC. A similar case occurs for the DKC1 c.1226C > G (p.P409R) mutation. This mutation was first identified in the patient with the features of liver cirrhosis, frequent caries, low platelets, gray hair, and tongue cancer in 2013 (1). However, the patient with the same mutation was reported from China in 2020 presenting fewer symptoms of reticulate interspersed pigmentation with hypopigmented macules on the neck, fingernail ridging and longitudinal splitting, and mucosal leukoplakia on the tongue (7). Those results demonstrate that there is no specific relationship between the genotype and phenotype.

Our findings indicate DKC1 missense mutation c.1156G > A leads to a benign phenotype, which expands the disease variation database, the understanding of genotype–phenotype correlations, and facilitates the clinical diagnosis of DC in China. However, the mechanism of DKC1 mutation resulting in DC should be investigated further.

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