A number sign (#) is used with this entry because of evidence that autosomal dominant dyskeratosis congenita-6 (DKCA6) and autosomal recessive dyskeratosis congenita-7 (DKCB7) are caused by heterozygous or compound heterozygous mutation, respectively, in the ACD gene (609377) on chromosome 16q22. One family with each disorder has been reported.

Dyskeratosis congenita (DKC) is a multisystem disorder caused by defective telomere maintenance. Features are variable and include bone marrow failure, nail dysplasia, oral leukoplakia, and increased risk of cancer (summary by Kocak et al., 2014).

For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).

Dyskeratosis Congenita 6, Autosomal Dominant

Guo et al. (2014) reported a white family in which 3 women in 3 subsequent generations had progressive bone marrow failure. The 18-year-old proband presented at age 8 with progressive pancytopenia and severe aplastic anemia and became transfusion-dependent. Her 33-year-old mother had mild asymptomatic bone marrow failure with a hypocellular bone marrow. The maternal grandmother was diagnosed with aplastic anemia and oral carcinoma at age 55; she died at age 61. Laboratory studies showed that all had shortened telomeres. None had additional features.

Dyskeratosis Congenita 7, Autosomal Recessive

Kocak et al. (2014) reported a male infant born at 29 weeks' gestation with intrauterine growth retardation. He was one of identical twin boys; the other twin died at age 4 months from complications of pertussis infection. During the first year of life, the proband was noted to have developmental delay, microcephaly, oral leukoplakia, nail dystrophy, esophageal stenosis, and cerebellar hypoplasia. He then developed progressive bone marrow failure necessitating hematopoietic stem cell transplantation at age 3 years. Laboratory studies showed extremely shortened telomeres (much less than first percentile in length). The proband's older sister had no clinical features of DKC, but had very short telomeres. Both parents were healthy, although the father had very short telomeres, prematurely gray hair, and minor dental abnormalities.

The transmission pattern of DKCA6 in the family reported by Guo et al. (2014) was consistent with autosomal dominant inheritance.

The transmission pattern of DKCB7 in the family reported by Kocak et al. (2014) was consistent with autosomal recessive inheritance.

Dyskeratosis Congenita 6, Autosomal Dominant

In 3 female members in 3 subsequent generations of a family with DKCA6, Guo et al. (2014) identified a heterozygous in-frame 3-bp deletion in the ACD gene (K170del; 609377.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Lys170 localizes to the surface of the TPP1 protein (encoded by the ACD gene) known as the TEL patch, known to be vital for binding to telomerase (see 602322). Transfection of the mutant protein into 293T cells showed that it localized properly onto telomeres similar to wildtype, but was unable to recruit telomerase to the telomeres. The findings indicated that this defect in TPP1 renders telomerase unable to maintain telomeres during development and hematopoiesis, leading to short telomeres and progressive bone marrow failure.

Dyskeratosis Congenita 7, Autosomal Recessive

In a boy with DKCB7, Kocak et al. (2014) identified compound heterozygous mutations in the ACD gene: K170del and P491T (609377.0002). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The patient's father and sister, who had short telomeres, were heterozygous for the K170del mutation; the patient's mother, who was unaffected, was heterozygous for the missense mutation. In vitro functional expression assays in HeLa cells showed that the K170del mutant compromised telomerase recruitment to telomeres and reduced telomerase enzymatic processivity compared to wildtype. The P491T mutant efficiently colocalized with the RNA component of telomerase (TR; 602322) on telomeres and did not interfere with telomerase interaction with TPP1 (encoded by ACD) or processivity, but it did cause a modest (2-fold) reduction in TIN2 (604319) association. Kocak et al. (2014) concluded that the detrimental effect of the P491T mutation was modest compared to that of the K170del mutation.