ORPHA: 1775, 3322; DO: 0070024;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.12 | Dyskeratosis congenita, autosomal recessive 6 | 616353 | Autosomal recessive | 3 | PARN | 604212 |
A number sign (#) is used with this entry because of evidence that autosomal recessive dyskeratosis congenita-6 (DKCB6) is caused by homozygous or compound heterozygous mutation in the PARN gene (604212) on chromosome 16p13.
Autosomal recessive dyskeratosis congenita-6 is a bone marrow failure disorder associated with abnormal skin pigmentation, nail dystrophy, oral leukoplakia, microcephaly, and developmental delay (summary by Tummala et al., 2015).
For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).
Tummala et al. (2015) reported 4 children from 3 unrelated families with dyskeratosis congenita. Two of the families were of Pakistani origin. Clinical features included abnormal skin pigmentation, leukoplakia, nail dystrophy, bone marrow failure, intrauterine growth retardation, developmental delay, microcephaly, and cerebellar hypoplasia. More variable features included sparse hair and dental caries. Blood samples available from 3 of the patients showed shortened telomeres.
Clinical Variability
Dhanraj et al. (2015) reported a 21-year-old woman with a severe form of DKCB6 and neurologic impairment consistent with a diagnosis of Hoyeraal-Hreidarsson syndrome (see 305000). She had global developmental delay apparent since infancy, profound mental retardation with absent speech, hypertonia, seizures, and hypomyelination of the central nervous system. She also had severe bone marrow failure with pancytopenia. Craniofacial abnormalities included microcephaly, midface hypoplasia, and low-set ears. Additional features included scoliosis, short stature, thin hair, and constipation. Genetic analysis of the patient identified compound heterozygous mutations in the PARN gene (604212.0009 and 604212.0010). Patient cells showed deficiencies in trimming of specific small nucleolar RNAs (snoRNAs), abnormal ribosomal assembly, abnormally adenylated TERC (602322), and short telomeres (less than the first percentile of controls). The patient had severe bone marrow failure with decreased numbers of CD34+ hematopoietic progenitor cells; patient fibroblasts also showed growth defects. One of the mutant alleles carried an intragenic deletion that was inherited from the mother, who had a mental illness requiring admission to a psychiatric ward.
The transmission pattern of DKCB6 in the families reported by Tummala et al. (2015) was consistent with autosomal recessive inheritance.
In 4 children from 3 unrelated families with autosomal recessive DKCB6, Tummala et al. (2015) identified homozygous or compound heterozygous mutations in the PARN gene (604212.0001-604212.0004). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Studies of 1 patient's cells (A383V; 604212.0001) showed reduced deadenylation activity, early DNA damage response with abnormal nuclear p53 (TP53; 191170) expression, cell cycle arrest, and reduced cell viability upon UV treatment. The patient cells showed decreased expression of genes involved in telomere maintenance.
Dhanraj, S., Gunja, S. M. R., Deveau, A. P., Nissbeck, M., Boonyawat, B., Coombs, A. J., Renieri, A., Mucciolo, M., Marozza, A., Buoni, S., Turner, L., Li, H., and 9 others. Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN). J. Med. Genet. 52: 738-748, 2015. [PubMed: 26342108] [Full Text: https://doi.org/10.1136/jmedgenet-2015-103292]
Tummala, H., Walne, A., Collopy, L., Cardoso, S., de la Fuente, J., Lawson, S., Powell, J., Cooper, N., Foster, A., Mohammed, S., Plagnol, V., Vulliamy, T., Dokal, I. Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. J. Clin. Invest. 125: 2151-2160, 2015. [PubMed: 25893599] [Full Text: https://doi.org/10.1172/JCI78963]