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Telomere biology disorders, largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes,  ACD , which encodes the shelterin protein TPP1, is associated with both autosomal dominantly and autosomal recessively inherited telomere biology disorders. TPP1 recruits telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding  ACD  haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in  ACD  (NM_001082486.1)—c.505_507delGAG, p.(Glu169del); and c.619delG, p.(Asp207Thrfs*22)—and a second proband with a heterozygous chromosomal deletion encompassing  ACD : arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one  ACD  allele was insufficient to induce telomere shortening or confer clinical features. Further analyses of lymphoblastoid cell lines showed decreased nascent  ACD  RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous  ACD  c.619delG, p.(Asp207Thrfs*22), or the  ACD -encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one  ACD  allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.

molecular case studies

Identification and characterization of novel <i>ACD</i> variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length

Identification and characterization of novel ACD variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length