Abstract A024 A homozygous start-loss mutation in <i>TERF1</i> causes a syndrome associated with long telomeres

Abstract Introduction The shelterin complex comprising TERF1, TERF2, TIN2, RAP1, TPP1 and POT1 is the main protein structure present on human telomeres. This complex shields chromosome ends from degradation, end-to-end fusions, and modulates the telomerase activity. In humans, the primary shelterin complex-related disease is dyskeratosis congenita, caused by pathogenic variants in TIN2. Here, we report on a patient who harbors homozygous start-loss variants in the TERF1 gene. This is the first reported case of a human living with the absence of TERF1. In mouse models, Terf1 deletion leads to embryonic lethality. Conditional knockout of Terf1 in mouse epithelial and hematopoietic cells led to skin lesions, bone marrow failure, increased cancer occurrence with shortening of telomere length, activation of DNA damage response, and senescence. The consequences of TERF1 deficiency in humans are unknown. Case Presentation and Results A 12-year-old girl was evaluated for skin hypo- and hyperpigmentation, melanonychia, microcephaly, lymphopenia, seizures, and mild speech delay. She was born at term to healthy, non-consanguineous parents of South Asian descent with an uneventful course of pregnancy and delivery. Between the ages of 5-10, she had three episodes of generalized tonic-clonic seizures with no recurrence afterwards. Her head circumference was less than the first percentile (-4.7 SD) with a normal Brain MRI. She had no family history of malignancy, bone marrow failure, dermatological conditions, or genetic disorders. Physical examination revealed hypo- and hyperpigmented macules and patches and multiple café-au-lait macules following the Blaschko line. There is melanonychia on the right big and third toes. A complete blood count test found decreased RBC and WBC counts. Flow cytometry revealed moderate but significantly decreased CD4+ and CD8+ T cell and B cell populations. Chromosomal microarray analysis and Bloom syndrome sister chromatid exchange tests were negative. A trio-whole exome sequencing identified a homozygous variant of uncertain significance, c.1A&amp;gt;G (p.Met1?) in TERF1, indicating a start-loss variant. The genomic sequence adjacent to this variant revealed no in-frame alternative start codons. Both parents were carriers of this variant. To our knowledge, there are no previously reported homozygous cases of TERF1 in the literature or on ClinVar. As her symptoms were consistent with a telomere biology disorder, her blood sample was sent for telomere length testing. Surprisingly, her telomere length was markedly increased and is greater than the 99th percentile across granulocytes, NK cells, and lymphocyte subpopulations. Conclusion To our knowledge, this is the first report of a human with homozygous TERF1 start-loss mutations. This case illustrates that TERF1 deficiency is not lethal in humans but may lead to telomere lengthening, dysfunctional hematopoiesis, and a potential risk of malignancies. This case also represents a unique opportunity to study the compensatory mechanisms that protect telomere integrity in the absence of TERF1. Citation Format: Tanvi Anandampillai, Peter Kannu, Yigal Dror, Irene Lara-Corrales, Yiming Wang. A homozygous start-loss mutation in TERF1 causes a syndrome associated with long telomeres [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A024.