An Indian child with Coats plus syndrome due to mutations in STN1

Abstract

The role of the CTC1–STN1–TEN1 (CST) complex in Coats plus syndrome (CP), as well as other telomeropathy‐phenotypes and disorders of genome instability is well documented. We report an Indian child with a clinical diagnosis of CP who presented to us with retinal exudates, extensive cerebral calcification, developmental delay and severe anemia consequent upon chronic gastrointestinal (GI) bleeding. Whole exome sequencing revealed compound heterozygous variants in STN1 as the probable genetic cause leading to CP in the present case. Of the two variants, the nonsense variant c.397C>T (p.Arg133*) was a truncating variant leading to loss of full protein length whereas the second variant c.985G>C (p.Ala329Pro) was novel and neither reported in ExAC, 1KGP or gnomAD. The deleteriousness of the novel variant was explored through molecular dynamics simulation analysis where p.Ala329Pro mutation affected C‐terminal domain interaction between STN1 and TEN1 complex. Hormonal therapy using ethinyl estradiol and norethisterone was apparently associated with a clinically useful, although poorly sustained, decrease in blood transfusion requirement in the proband.

Novel compound heterozygous STN1 variants are associated with Coats Plus syndrome

“…The diagnosis of CP was effectively confirmed with the identification of biallelic rare variants in STN1. The only other STN1-CP cases reported to date are two unrelated patients, each born to consanguineous Palestinian parents, found to harbour homozygous STN1 variants; c.404G>C; p.(Arg135Thr), and c.469G>T; p.(Asp157Tyr), in exons 5 and 6 of STN1, respectively (Simon et al, 2016); and an Indian child with c.397C>T (p.Arg133*) and c.985G>C (p.Ala329Pro) in exons 5 and 10, respectively (Passi et al, 2020). Further biological analysis such as telomere length by flow-FISH would be important in supporting our claim.…”

“…CP has been associated with mutations in any of CTC1 (Anderson et al, 2012;Polvi et al, 2012), POT1 (Takai et al, 2016) and, in three cases, STN1 (Simon et al, 2016;Passi et al, 2020). The identification of biallelic mutations in CTC1 in individuals with CP has focussed attention on the CST (CTC1-STN1-TEN1) complex as a cause of human disease.…”

Telomeres and Cancer

“…A reduction in CTC1 or STN1 produces lengthened G-overhangs as the C-strand fill-in becomes faulty [136,177,191]. STN1mutationlike CTC1 mutation can cause CPS [179,192,193]. Depletion of human CTC1 or STN1 increases multi-telomeric signals, telomere instabilities, and chromosome breakage [191] and can result in impairing C-strand fill-in, leading to excessively long G-overhangs [125,134,136,143].…”

Coats Plus Syndrome Presenting in an Adult

“…Of the 30 cases of CPS in the literature, 2 –23 only 3 presented in patients older than 18 years; those patients were 19 years old, 21 years old, and 23 years old. 21 –23 We report a 38-year-old woman with a complex medical history and fluorescein angiographic evidence of severe bilateral retinal capillary nonperfusion with retinal arteriolitis who had genetic testing that confirmed the diagnosis of CPS.…”