Table 2.

Genetic etiology of telomere biology disorders

Gene	Protein	Function	Reported consequences of mutation(s)	Inheritancea	Predominant 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