A novel biallelic missense mutation (c.470A>T) in the STN1 gene is responsible for Coats Plus Syndrome.

This case report describes a diagnosis of Coats plus syndrome in an otherwise visually asymptomatic Chinese female aged 22 years who presented for a complete ophthalmologic examination to identify any potential retinal abnormalities.

POLA2 encodes the accessory subunit of DNA polymerase α (polα)/primase, which is crucial for telomere C-strand fill-in. Incomplete fill-in of the C-rich telomeric strand after DNA replication has been proposed as a mechanism for Coats plus syndrome, a phenotype within the broader spectrum of telomere biology disorders (TBD). Coats plus syndrome has so far been associated with pathogenic variants in POT1, CTC1, and STN1. Here we report the findings of biallelic deleterious rare variants in POLA2 gene detected by whole genome sequencing and segregation analysis in five young adults from two unrelated families. All five individuals displayed abnormally short telomeres and a clinical phenotype suggesting a TBD disorder with Coats plus features including retinal and gastrointestinal telangiectasias. Our results suggest POLA2 as a novel autosomal recessive gene for a TBD with Coats plus features.

Telomeres protect the ends of chromosomes but shorten following cell division in the absence of telomerase activity. When telomeres become critically short or damaged, a DNA damage response is activated. Telomeres then become dysfunctional and trigger cellular senescence or death. Telomere shortening occurs with ageing and may contribute to associated maladies such as infertility, neurodegeneration, cancer, lung dysfunction and haematopoiesis disorders. Telomere dysfunction (sometimes without shortening) is associated with various diseases, known as telomere biology disorders (also known as telomeropathies). Telomere biology disorders include dyskeratosis congenita, Høyeraal-Hreidarsson syndrome, Coats plus syndrome and Revesz syndrome. Although mouse models have been invaluable in advancing telomere research, full recapitulation of human telomere-related diseases in mice has been challenging, owing to key differences between the species. In this Review, we discuss telomere protection, maintenance and damage. We highlight the differences between human and mouse telomere biology that may contribute to discrepancies between human diseases and mouse models. Finally, we discuss recent efforts to generate new 'humanized' mouse models to better model human telomere biology. A better understanding of the limitations of mouse telomere models will pave the road for more human-like models and further our understanding of telomere biology disorders, which will contribute towards the development of new therapies.

Coats plus syndrome (CPS) is a rare telomere biology disorder (TBD) linked to mutations in the CTC1-STN1-TEN1 complex and characterized by cerebroretinal microangiopathy, bone marrow failure, and liver disease, often progressing to hepatopulmonary syndrome (HPS). The case is a 16-year-old boy clinically diagnosed with CPS at age 7. He developed exertional dyspnea at 14 with 93% of resting oxygen saturation (SpO2), 70 mmHg of partial pressure of oxygen (PaO2), and 22.9 mmHg of alveolar-arterial oxygen difference (A-aDO2) under room air, prompting home oxygen therapy (HOT). Imaging and liver biopsy showed significant collateral circulation and portal vein fibrosis and dilation without cirrhosis or pulmonary fibrosis. HPS was diagnosed by positive microbubble contrast echocardiography and 15.7% of shunt fraction in pulmonary ventilation-perfusion scintigraphy. Due to the rapid progression of HPS, he underwent living-donor LT. The postoperative disease course was good, except for acute liver rejection, and the patient was discharged on postoperative day 40. One month after transplantation, echocardiography showed a negative bubble study, pulmonary scintigraphy revealed an improved shunt fraction of 10.2%, resting SpO2 under room air was 100%, and he is doing well without the recurrence of HPS. Historically, LT for HPS patients with TBDs was avoided because of uncertain prognosis and potential disease progression in other organs. However, early-stage LT in TBDs may be preferable and reduce the complexity of LT. Before irreversible changes in intrapulmonary blood vessels occur, early hypoxemia monitoring and regular imaging are essential to ensure timely LT for HPS.