Table 2.

Genetic etiology of telomere biology disorders

GeneProteinFunctionReported consequences of mutation(s)InheritanceaPredominant phenotype(s)Frequency in NCI cohort1 Approximate frequency in TBDs
ACD TPP1 Shelterin component, telomerase recruitment, activity and processivity Impaired telomerase recruitment to telomeres AD AA 1% Very rare 
AR HH 0.5% Very rare 
CTC1 CTC1 Telomere capping CST complex/C-strand fill in, telomere replication Impaired telomere replication, fragile telomeres AR DC, CP 3% Main cause of CP, very rare for DC 
DKC1 Dyskerin Telomerase enzyme complex/telomerase assembly, TERC stability Reduced TERC stability and telomerase activity XLRb,c DC, HH, PF 16% of total, 22% of males Common in males 
DCLRE1B Apollo DNA cross-link repair, interacts with TRF2 at telomeres Chromosome instability but normal telomere length AR DC, HH 0% Very rare 
MDM4 MDM4 Telomere associated regulation of p53 p53 activation and short telomeres AD AA, HNSCC N/Ad Very rare 
NAF1 NAF1 Telomerase biogenesis, TERC stability Reduced TERC stability and telomerase activity AD PF, LD, MDS 0% Very rare 
NHP2 NHP2 Telomerase biogenesis, TERC stability Reduced TERC stability and telomerase activity AR DC 0% Very rare 
NOP10 NOP10 Telomerase biogenesis, TERC stability Reduced TERC stability and telomerase activity AR DC 0% Very rare 
NPM1 NPM1 rRNA modification No telomere biology association AD DC 0% Very rare 
PARN PARN TERC (hTR) maturation and stability Reduced TERC stability and telomerase activity AD PF 2% Common 
AR DC, HH 2% Very rare 
POT1 POT1 Shelterin complex component, interaction with CST complex, negative telomerase regulation, telomere protection from DDR Defective telomerase regulation, dysfunctional telomere replication AR CP 0% Very rare 
RTEL1 RTEL1 Telomeric DNA replication/repair, t-loop stability and unwinding, prevention of telomere loss during cell division Impaired telomere replication/stability AD PF, AA, LD, DC 14.5% Common 
AR DC, HH 7.5% Rare 
RPA1 RPA1 Binds ssDNA to prevent secondary structure formation Increased ssDNA binding affinity and increased telomere unfolding AD DC 0% Very rare 
STN1 STN1 CST complex/C-strand fill in, telomere replication Impaired telomere replication AR CP 0% Very rare 
TERC Encodes hTR RNA Telomerase enzyme
complex/telomere elongation 		Reduction of telomerase activity ADb DC, AA, PF, LD, MDS, AML 15% Common 
TERT hTERT Telomerase enzyme complex/telomere elongation/telomerase recruitment Reduction telomerase recruitment, processivity, and/or activity ADb DC, AA, PF, LD, MDS, AML 23.5% Common 
AR HH 1% Very rare 
TINF2 TIN2 Shelterin protein complex/telomerase regulation, sister telomere cohesion, telomere protection from DDR, telomere recruitment Multifactorial disruption of telomere maintenance AD DC, HH, RS, PF 12.5% Common 
USB1 USB1 snRNA maturation No telomere biology associatione AR PN, RTS N/A N/A 
WRAP53 TCAB1 Associated with telomerase complex/telomerase trafficking through Cajal bodies and recruitment Impaired telomerase trafficking though Cajal body and recruitment to telomeres AR DC, HH 1.5% Very rare 
ZCCHC8 ZCCHC8 TERT maturation Impaired telomerase function AD PF 0% Very rare 
GeneProteinFunctionReported consequences of mutation(s)InheritanceaPredominant phenotype(s)Frequency in NCI cohort1 Approximate frequency in TBDs
ACD TPP1 Shelterin component, telomerase recruitment, activity and processivity Impaired telomerase recruitment to telomeres AD AA 1% Very rare 
AR HH 0.5% Very rare 
CTC1 CTC1 Telomere capping CST complex/C-strand fill in, telomere replication Impaired telomere replication, fragile telomeres AR DC, CP 3% Main cause of CP, very rare for DC 
DKC1 Dyskerin Telomerase enzyme complex/telomerase assembly, TERC stability Reduced TERC stability and telomerase activity XLRb,c DC, HH, PF 16% of total, 22% of males Common in males 
DCLRE1B Apollo DNA cross-link repair, interacts with TRF2 at telomeres Chromosome instability but normal telomere length AR DC, HH 0% Very rare 
MDM4 MDM4 Telomere associated regulation of p53 p53 activation and short telomeres AD AA, HNSCC N/Ad Very rare 
NAF1 NAF1 Telomerase biogenesis, TERC stability Reduced TERC stability and telomerase activity AD PF, LD, MDS 0% Very rare 
NHP2 NHP2 Telomerase biogenesis, TERC stability Reduced TERC stability and telomerase activity AR DC 0% Very rare 
NOP10 NOP10 Telomerase biogenesis, TERC stability Reduced TERC stability and telomerase activity AR DC 0% Very rare 
NPM1 NPM1 rRNA modification No telomere biology association AD DC 0% Very rare 
PARN PARN TERC (hTR) maturation and stability Reduced TERC stability and telomerase activity AD PF 2% Common 
AR DC, HH 2% Very rare 
POT1 POT1 Shelterin complex component, interaction with CST complex, negative telomerase regulation, telomere protection from DDR Defective telomerase regulation, dysfunctional telomere replication AR CP 0% Very rare 
RTEL1 RTEL1 Telomeric DNA replication/repair, t-loop stability and unwinding, prevention of telomere loss during cell division Impaired telomere replication/stability AD PF, AA, LD, DC 14.5% Common 
AR DC, HH 7.5% Rare 
RPA1 RPA1 Binds ssDNA to prevent secondary structure formation Increased ssDNA binding affinity and increased telomere unfolding AD DC 0% Very rare 
STN1 STN1 CST complex/C-strand fill in, telomere replication Impaired telomere replication AR CP 0% Very rare 
TERC Encodes hTR RNA Telomerase enzyme
complex/telomere elongation 		Reduction of telomerase activity ADb DC, AA, PF, LD, MDS, AML 15% Common 
TERT hTERT Telomerase enzyme complex/telomere elongation/telomerase recruitment Reduction telomerase recruitment, processivity, and/or activity ADb DC, AA, PF, LD, MDS, AML 23.5% Common 
AR HH 1% Very rare 
TINF2 TIN2 Shelterin protein complex/telomerase regulation, sister telomere cohesion, telomere protection from DDR, telomere recruitment Multifactorial disruption of telomere maintenance AD DC, HH, RS, PF 12.5% Common 
USB1 USB1 snRNA maturation No telomere biology associatione AR PN, RTS N/A N/A 
WRAP53 TCAB1 Associated with telomerase complex/telomerase trafficking through Cajal bodies and recruitment Impaired telomerase trafficking though Cajal body and recruitment to telomeres AR DC, HH 1.5% Very rare 
ZCCHC8 ZCCHC8 TERT maturation Impaired telomerase function AD PF 0% Very rare 

Germline pathogenic variants in these genes have been reported in patients with classic DC and/or those with overlapping medical problems without the classic mucocutaneous triad, hence the TBD designation. The approximate frequency in TBDs is estimated based on reports in the literature and the author's experience; it is not intended to be quantitative because of ascertainment biases of the different published studies. The approximate frequency for common is 10% to 20%, for rare, <10%, and for very rare, <1%.

a

All listed gene mutations can occur de novo, but it is frequently reported in TINF2.50,51

b

Somatic reversion of mutations in blood-derived DNA have been reported.

c

Skewed X chromosome inactivation may result in phenotypically affected females.

d

TBD-associated variants in MDM4 were first discovered in the NCI cohort, but the patients were not included due to the inclusion criteria of Niewisch et al.4,35

e

USB1 is only listed because some phenotypes overlap, but the reported patients' phenotypes are more consistent with poikiloderma with neutropenia (PN) and/or Rothmund-Thomson syndrome (RTS).

AA, aplastic anaemia; CP, Coats plus; DDR, DNA damage response; HNSCC, head and neck squamous cell carcinoma; LD, liver disease; N/A, not applicable.

Adapted with permission from Niewisch and Savage.1 

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