TBD-related genes/proteins pathogenic changes (associated inheritance patterns) not listed since to date solely reported in childhood-onset disease: Shelterin complex: POT1/POT1 (AR), telomeric accessory factors: CTC1/CTC1 (AR), STN1/STN1 (AR), and DCLRE1B/Apollo (AR).

Phenotypes listed are not comprehensive but meant to highlight the primary clinical manifestations in adult-onset TBDs.

Pathogenic germline variants in all listed genes can occur de novo but are more common in TINF2 and DKC1.

Monoallelic, pathogenic germline POT1 variants resulting in longer telomeres have been associated with cancer predisposition to a range of malignant and benign tumors, particularly familial melanoma.

Skewed X chromosome inactivation may in some cases result in phenotypically affected females heterozygous for pathogenic variants in DKC1.

The first manifestations of AR TBDs are typically seen in childhood but may also occur in young adults.

TINF2 AD occurs frequently de novo and is primarily associated with severe disease in childhood. However, families with TBDs due to inheritance of heterozygous TINF2 pathogenic variants have been reported. BMF in young adults (<40 years) has been reported as well as rare adult TINF2 cases with PF as the primary clinical complication.

RPA1 was recently identified to belong to realm of TBD genes and was reported in 3 pediatric cases with BMF/MDS, immunodeficiency, and post-hematopoietic cell transplant PF, as well as 1 adult case with PF.³³ 

NPMI, MDM4, and TYMS have all recently been proposed to be TBD associated, but data are limited. NPMI: Germline monoallelic variants were reported in 2 individuals with symptoms indicative of a TBD.⁵³ MDM4: A germline missense variant was reported in a family with TBD features and showed in vitro decreased telomere length.⁵⁴ TYMS: heterozygous germline variants in TYMS and ENOSF1 leading to TYMS deficiency were reported in children and young adults (<40 years) with classic mucocutaneous features of DC.⁵⁰ 

hTR, human telomerase RNA.