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Article Open Access

Intronic hexanucleotide repeat expansion in TYMS in monozygotic twins with congenital progressive universal melanosis

  • Authors:
    • Sunisa Kanchanasutthiyakorn
    • Sakchai Chaiyamahapurk
    • Siraprapa Tongkobpetch
    • Kanokwan Santawong
    • Chalurmpon Srichomthong
    • Tippayakarn Klomchan
    • Chaiyaporn Virochsangaroon
    • Monnat Pongpanich
    • Prateep Warnnissorn
    • Sutatip Pongcharoen
    • Vorasuk Shotelersuk
  • View Affiliations / Copyright

    Affiliations: Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand, Division of Epidemiology, Department of Community Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand, Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand, Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok 10330, Thailand, Division of Pediatric Endocrinology, Department of Pediatrics, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand, Department of Pathology, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand, Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand, Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand
    Copyright: © Kanchanasutthiyakorn et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 138
    |
    Published online on: June 12, 2025
       https://doi.org/10.3892/br.2025.2016
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Abstract

Hyperpigmentation presents a diverse clinical spectrum, largely influenced by genetic factors that remain incompletely understood. The present study describes a case of monozygotic twin girls aged 15 years with congenital progressive universal melanosis (CPUM) born to non‑consanguineous unaffected parents. CPUM represents a novel clinical entity characterized by progressive widespread hyperpigmentation beginning at birth, without other accompanying symptoms. Skin biopsy and histopathological analysis were performed, followed by long‑read whole‑genome sequencing and short tandem repeat analysis. Gene expression was evaluated using reverse transcription‑PCR, and protein levels were assessed by western blotting in cultured skin fibroblasts from the twins and unaffected controls. Long‑read genome sequencing revealed a biallelic GATGGT repeat expansion of 210‑259 repeat units within the third intron of the thymidylate synthase (TYMS) gene in both twins, whereas their parents were heterozygous. Controls (n=236), derived from the in‑house long‑read sequencing database at Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand, carried the GATGGT repeat in the 42‑172 range. No single nucleotide or structural variants or copy number variations were present in both affected individuals and absent in the unaffected parents. RNA and protein levels of TYMS using cultured skin fibroblasts from both twins showed no discernible differences compared with controls. Fibroblasts were used due to their accessibility via skin biopsy and their role in skin pigmentation through paracrine signaling to melanocytes. More relevant cells, such as melanocytes or keratinocytes, may be required to exhibit such changes, as these cells are directly involved in melanin production and skin pigmentation. TYMS is implicated in skin pigmentation in normal physiological process and in disorders manifesting abnormal skin pigmentation, such as dyskeratosis congenita. The present findings imply a connection between the identified repeat expansion in TYMS and CPUM, underscoring the need for further investigations to elucidate its causal association.
View Figures

Figure 1

Patient with congenital progressive
universal melanosis. Hyperpigmentation of skin on (A) face and
neck, (B) hands, (C) abdomen and (D) foot of twin A. (E)
Histopathological results from the lesion shows basal
hyperpigmentation and superficial dermal melanophages. Red arrows
indicate melanocytes, the pigment-producing cells found in the
basal layer of the epidermis. Black arrow indicates melanophage,
which is characterized by large, darkly pigmented granules and is
located in the dermis.

Figure 2

GATGGT repeat expansion in the
TYMS gene. (A) Schematic diagram showing GATGGT repeats
expansion position (chr18, position:666,891-667,632 of intron 3 in
TYMS; hg38 version). (B) Repeat units in affected twins
compared with carrier parents and controls. TYMS, thymidylate
synthase; UTR, untranslated region.

Figure 3

Expression of TYMS mRNA and
protein in fibroblast cells. Mean TYMS (A) mRNA and (B)
protein expression in controls (n=4) and patients (n=2). The signal
intensity was normalized to β-actin. The blots were obtained from
the same PVDF membrane, with TYMS and β-actin detected in
separate experiments. TYMS, thymidylate synthase.
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Copy and paste a formatted citation
Spandidos Publications style
Kanchanasutthiyakorn S, Chaiyamahapurk S, Tongkobpetch S, Santawong K, Srichomthong C, Klomchan T, Virochsangaroon C, Pongpanich M, Warnnissorn P, Pongcharoen S, Pongcharoen S, et al: Intronic hexanucleotide repeat expansion in <em>TYMS</em> in monozygotic twins with congenital progressive universal melanosis. Biomed Rep 23: 138, 2025.
APA
Kanchanasutthiyakorn, S., Chaiyamahapurk, S., Tongkobpetch, S., Santawong, K., Srichomthong, C., Klomchan, T. ... Shotelersuk, V. (2025). Intronic hexanucleotide repeat expansion in <em>TYMS</em> in monozygotic twins with congenital progressive universal melanosis. Biomedical Reports, 23, 138. https://doi.org/10.3892/br.2025.2016
MLA
Kanchanasutthiyakorn, S., Chaiyamahapurk, S., Tongkobpetch, S., Santawong, K., Srichomthong, C., Klomchan, T., Virochsangaroon, C., Pongpanich, M., Warnnissorn, P., Pongcharoen, S., Shotelersuk, V."Intronic hexanucleotide repeat expansion in <em>TYMS</em> in monozygotic twins with congenital progressive universal melanosis". Biomedical Reports 23.2 (2025): 138.
Chicago
Kanchanasutthiyakorn, S., Chaiyamahapurk, S., Tongkobpetch, S., Santawong, K., Srichomthong, C., Klomchan, T., Virochsangaroon, C., Pongpanich, M., Warnnissorn, P., Pongcharoen, S., Shotelersuk, V."Intronic hexanucleotide repeat expansion in <em>TYMS</em> in monozygotic twins with congenital progressive universal melanosis". Biomedical Reports 23, no. 2 (2025): 138. https://doi.org/10.3892/br.2025.2016
Copy and paste a formatted citation
x
Spandidos Publications style
Kanchanasutthiyakorn S, Chaiyamahapurk S, Tongkobpetch S, Santawong K, Srichomthong C, Klomchan T, Virochsangaroon C, Pongpanich M, Warnnissorn P, Pongcharoen S, Pongcharoen S, et al: Intronic hexanucleotide repeat expansion in <em>TYMS</em> in monozygotic twins with congenital progressive universal melanosis. Biomed Rep 23: 138, 2025.
APA
Kanchanasutthiyakorn, S., Chaiyamahapurk, S., Tongkobpetch, S., Santawong, K., Srichomthong, C., Klomchan, T. ... Shotelersuk, V. (2025). Intronic hexanucleotide repeat expansion in <em>TYMS</em> in monozygotic twins with congenital progressive universal melanosis. Biomedical Reports, 23, 138. https://doi.org/10.3892/br.2025.2016
MLA
Kanchanasutthiyakorn, S., Chaiyamahapurk, S., Tongkobpetch, S., Santawong, K., Srichomthong, C., Klomchan, T., Virochsangaroon, C., Pongpanich, M., Warnnissorn, P., Pongcharoen, S., Shotelersuk, V."Intronic hexanucleotide repeat expansion in <em>TYMS</em> in monozygotic twins with congenital progressive universal melanosis". Biomedical Reports 23.2 (2025): 138.
Chicago
Kanchanasutthiyakorn, S., Chaiyamahapurk, S., Tongkobpetch, S., Santawong, K., Srichomthong, C., Klomchan, T., Virochsangaroon, C., Pongpanich, M., Warnnissorn, P., Pongcharoen, S., Shotelersuk, V."Intronic hexanucleotide repeat expansion in <em>TYMS</em> in monozygotic twins with congenital progressive universal melanosis". Biomedical Reports 23, no. 2 (2025): 138. https://doi.org/10.3892/br.2025.2016
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