Submission Details

Variants in DKC1 have been reported since the 1990s, when patients exhibiting characteristics of dyskeratosis congenita (DC), or its more severe form, Hoyeraal-Hreidarsson syndrome (HH syndrome) were found to have variants in DKC1. Variants in patients are almost exclusively missense. DKC1-related disorders exist on a spectrum, and affect a range of tissues/organ systems. Children with HH syndrome tend to die in their infant/toddler years, and have classic DC symptoms alongside severe neurological/developmental features.

Summary of Case Level Data: Variants in this gene have been reported in a number of individual probands (and some families with deceased siblings) since 1999, when Knight et al. (PMID: 10583221) described five cases from two families with DKC1-related disorders (only one surviving case from each family). Since then, additional publications have become available to support this genotype-phenotype relationship. Of note, it is unclear at this time why some patients experience mild symptoms, while others are severely affected, even for the same variant. Revesz syndrome, which includes a characteristic eye phenotype in addition to typical DC/HH syndrome features, may also be caused by DKC1 variants. Two publications (Teixeira et al., PMID: 18195234; Allingham, PMID: 18195234) exist at this time supporting this association, but lack the detail necessary to make this conclusion. Future publications may help to elucidate this association.

Experimental Evidence: Non-human model organisms have been used to investigate the impact of disrupting DKC1 gene function. Two studies, He et al. (PMID: 12400016) and Gu et al. (PMID: 18626023) both demonstrated that DKC1 variants can lead to effects in mice (embryonic lethality and cellular growth damage, respectively), however neither model fully captured the phenotype seen in humans with DKC1-related disorders. This could be due to the type of variants used in the study, which eliminated one or more exons, rather than the missense mutations observed in human cases. Scores for experimental evidence were downgraded due to this discrepancy.

In summary, at present there is sufficient genetic evidence to support a definitive classification for this gene-disease relationship. Future recurations may find additional experimental evidence that provides an explanation for the range of severity observed in patients with DKC1 variants.

Variants in DKC1 have been reported since the 1990s, when patients exhibiting characteristics of dyskeratosis congenita (DC), or its more severe form, Hoyeraal-Hreidarsson syndrome (HH syndrome) were found to have variants in DKC1. Variants in patients are almost exclusively missense. DKC1-related disorders exist on a spectrum, and affect a range of tissues/organ systems. Children with HH syndrome tend to die in their infant/toddler years, and have classic DC symptoms alongside severe neurological/developmental features.

Summary of Case Level Data: Variants in this gene have been reported in a number of individual probands (and some families with deceased siblings) since 1999, when Knight et al. (PMID:10583221) described five cases (two families) with DKC1-related disorders (only one surviving case from each family). Since then, additional publications have become available to support this genotype-phenotype relationship. Of note, it is unclear at this time why some patients experience mild symptoms, while others are severely affected, even for the same variant. Revesz syndrome, which includes a characteristic eye phenotype in addition to typical DC/HH syndrome features, may also be caused by DKC1 variants. Two publications (Teixeira et al., PMID:18195234; and Allingham, PMID:18195234) exist at this time supporting this association, but lack the detail necessary to make this conclusion. Future publications may help to elucidate this association.

Experimental Evidence: Non-human model organisms have been used to investigate the impact of disrupting DKC1 gene function. Two studies, He et al. (PMID:12400016) and Gu et al. (PMID:18626023) both demonstrated that DKC1 variants can lead to effects in mice (embryonic lethality and cellular growth damage, respectively), however neither model fully captured the phenotype seen in humans with DKC1-related disorders. This could be due to the type of variants used in the study, which eliminated one or more exons, rather than the missense mutations observed in human cases. Scores for experimental evidence were downgraded due to this discrepancy.

In summary, at present there is sufficient genetic evidence to support a definitive classification for this gene-disease relationship. Future recurations may find additional experimental evidence, that provides an explanation for the range of severity observed in patients with DKC-1 variants.