Introduction: UV-sensitive syndrome and Cockayne syndrome (CS) are rare autosomal recessive and transcription-coupled nucleotide excision repair disorders with different clinical manifestations, although some types are allelic. Case Presentation: We report on a patient who passed away at 15 years old with a progeroid-like appearance, cachexia, hearing loss, and dental anomalies, which led us to the diagnosis of Cockayne-like progeroid syndromes. Our clinical exome sequencing including all the known genes of progeroid syndromes revealed a homozygous stop-gain variant in the UVSSA gene. Conclusion: Although truncating variants in the UVSSA are known to cause UVsS3, their association with CS has not yet been defined. This case might be the first report of a CS-like phenotype caused by a defective UVSSA.

Established Facts

  • Prior research has identified the UVSSA gene as a critical player in transcription-coupled nucleotide excision repair.

  • Nucleotide excision repair genes cause UV-sensitive syndrome (UVsS), Cockayne syndrome (CS), and other related syndromes.

  • Pathogenic variants of this gene have previously been linked to UVsS.

Novel Insights

  • Our study presents a novel phenotype observed in a patient with a CS-like phenotype, which is thought to be associated with the UVSSA gene. This phenotype has not previously been reported to be associated with pathogenic variants in this gene.

  • Our report expands the spectrum of phenotypic manifestations attributed to pathogenic variants in the UVSSA gene and highlights the importance of further investigation into the gene’s diverse roles.

  • This novel insight opens avenues for future research aimed at unravelling the underlying molecular mechanisms of allelic disorders of nucleotide excision repair genes.

UV-sensitive syndrome (UVsS) and Cockayne syndrome (CS) are rare disorders that are associated with transcription-coupled nucleotide excision repair (TC-NER) defects. Although the disorders are similarly associated with DNA damage recognition, their clinical manifestations markedly differ.

CS is a rare autosomal recessive disorder characterized by neurological abnormalities, growth and development deficits, hearing loss, and premature aging features. It is categorized into three clinical subtypes according to the severity of clinical findings: (1) classic or moderate, (2) severe, and (3) a milder, later-onset form. CS is caused by biallelic pathogenic variants in the ERCC8/CSA or ERCC6/CSB gene [1, 2]. In patients with pathogenic variants in the ERCC3, ERCC4, and ERCC5 genes, features of CS and xeroderma pigmentosum (XP), another syndrome associated with TC-NER disorder, can be seen together (XP/CS).

XP is a rare autosomal recessive nucleotide excision repair (NER) disorder characterized by extreme skin photosensitivity, variable central and peripheral nervous system abnormalities, and increased risk of malignancies, especially sunlight-induced cutaneous neoplasms. Biallelic pathogenic variants in the DDB2, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, POLH, XPA, or XPC genes are known to cause the genetic etiology. Since some of these genes are known to be associated with other TC-NER disorders with similar cutaneous findings, XP is considered in the differential diagnosis.

In a markedly different manifestation to CS, patients affected with UVsS experience photosensitivity, dry skin, and dyspigmentation without neurodegeneration, premature aging, or cancer predisposition. UVsS is caused by biallelic pathogenic variants in the ERCC6 (UVsS1), ERCC8 (UVsS2), and UVSSA (UVsS3) genes. Although CS and UVsS1/2 allelic disorders can occur with the same type of mutation, CS associated with the UVSSA gene has not yet been described in the literature. This report presents a patient with a CS-like phenotype with a novel homozygous truncating variant in the UVSSA gene and a novel heterozygous truncating variant in the XPA gene.

A fourth-degree consanguineous family (42-year-old father and 40-year-old mother) applied to our clinic for genetic counseling after having two affected children with different clinical findings and no healthy children. The mother had two pregnancies. The now 23-year-old girl from the first pregnancy had congenital contractures and distal limb deformities. She was clinically and genetically diagnosed by our clinic as having arthrogryposis due to a homozygous c.470G>T variant in the MYLPF gene.

Their second child, the proband of this paper, passed away at 15 years old. The clinical history incorporated into our study was gathered from the family members and the patient’s medical records. Phenotyping, crucial for our analysis, was conducted utilizing photographs provided by the family. She was the second pregnancy born to a 21-year-old mother and 23-year-old father. Oligohydramnios was reported, but delivery was at term. Her birth weight was 3,300 g, and her birth length was 52 cm. The birth OFC could not be obtained. The newborn hearing screening showed severe bilateral hearing loss, and the patient underwent cochlear implants. Her neurologic gross and fine motor development was reported as normal by her parents. According to their observations, she held her head independently before 3 months and could sit without support at the same time as her peers. She walked at age 1. She developed single words after speech therapy and could recognize written words in her early school years. Failure to thrive was obvious by the early school years, especially after approximately the age of 6; a growth chart could not be obtained. Cachexia was progressive and resistant to supplemental therapies. Hair thinning and baldness started in early childhood. Scoliosis was noted at age 11. While her dental eruption occurred within the expected timeline, the information received from the family pointed to the presence of structural dental abnormalities and excessive tooth decay. Thelarche was noted at age twelve. The patient had multiple medical visits due to headaches and fevers. According to the family, the cause of death was a cardiac arrest that occurred during a hospital admission for these symptoms. Since no autopsy was performed, the cause of death is attributed to complications related to general frailty associated with the disorder, ultimately resulting in a cardiac arrest. Notes from physical examinations performed by different clinics before her death and our examination of the photograph (aged 11) of the patient shown in Figure 1 identified a cachectic appearance, decreased adipose tissue, thin and fragile hair, a triangular face, deep-set eyes, a narrow and prominent nose bridge, dental decay, a high palate, and prominent, anteverted ears, and nevus-like lesions on the chest and neck. The phenotypic and clinical findings led us to consider a diagnosis of a progeroid syndrome, primarily the mild-to-moderate form of CS compatible with one major (postnatal growth failure) and three minor (characteristic physical appearance, sensorineural hearing loss, and dental anomalies) criteria [3, 4]. Before the patient’s death, a DNA sample was isolated in a different institution and was delivered to our clinic by the family. Clinical exome sequencing (CES) was undertaken from this DNA sample.

Fig. 1.

Facial image of the patient at age 11: cachectic appearance, triangular facies, decreased facial adipose tissue, facial freckles, thin and fragile hair, a triangular face, deep-set eyes, a narrow and prominent nose bridge, and prominent ears, nevus-like lesions on the chest and neck.

Fig. 1.

Facial image of the patient at age 11: cachectic appearance, triangular facies, decreased facial adipose tissue, facial freckles, thin and fragile hair, a triangular face, deep-set eyes, a narrow and prominent nose bridge, and prominent ears, nevus-like lesions on the chest and neck.

Close modal

CES including all known genes of progeroid syndromes (XPA, ERCC3, XPC, ERCC2, DDB2, ERCC4, ERCC5, ERCC6, ERCC8, POLH, and UVSSA) was performed using the SOPHiA™ Genetics CESv_2 kit on the Illumina NextSeq 500 platform. CES analysis revealed the novel homozygous NM_020894.4: c.55C>T (p.Arg19Ter) variant in the UVSSA gene and a heterozygous c.682C>T (p.Arg228Ter) variant in the XPA gene. Both variants were interpreted as pathogenic as they were frameshift variants expected to result in premature termination of the protein, according to the American College of Medical Genetics and Genomics 2015 criteria [14]. The variant in the UVSSA gene was found to be heterozygous in the patient’s healthy parents and the sister with arthrogryposis, who did not have progeroid findings. The variant in the XPA gene was found to be heterozygous in the mother, while the father and sister were normal for this variant. CES results validation and a family study were performed using Sanger sequencing. Written informed consent was obtained from the parents for all the tests, as well as to publish this case report and accompanying images.

This study reports a novel homozygous truncating variant in the UVSSA gene, the fifth reported pathogenic variant in this gene. Previously reported variants were (NM_020894.4) c.367A>T (p.Lys123*) in 3 Japanese patients, c.94T>C (p.Cys32Arg) in 1 Japanese patient, c.87delG (p.ILe31Phefs*9) in 1 Israeli patient and 1 Iranian patient, and c.1040G>A (p.Try347*) in 9 Pakistani patients. The phenotypes of all reported patients – regardless of their different ethnicities – were similar, including photosensitivity, telangiectasia, freckles, and dry skin [5‒8].

This study presents the first report of a Turkish patient with a homozygous UVSSA variant creating a wider phenotype than UVsS – including failure to thrive, hearing loss, premature aging, dental abnormalities, dysmorphic facies, baldness, and scoliosis – which overlaps with CS. Although CS is an allelic disease with ERCC6-related UVsS, no UV-stimulated scaffold protein A (UVSSA)-related CS has yet been identified.

NER is one of the three excision repair mechanisms that repair single-stranded DNA after damage occurs. Other mechanisms are base excision repair and DNA mismatch repair. NER will take one of two subpathways depending on the location of the damage: transcription-coupled-NER, which removes the lesion from an actively transcribed DNA strand, and global genome-NER, which repairs the damage to both untranscribed and transcribed DNA. UVSSA plays a role in stabilizing excision repair cross-complementing, group 6 (ERCC6) by forming a complex with ubiquitin-specific protease 7 (USP7) in TC-NER [8‒10] and has been shown to restore RNA polymerase II after UV irradiation. It has also been shown that UVSSA co-immunoprecipitates with ERCC8 regardless of whether or not there is UV radiation (but not with RNA polymerase II or ERCC6) [9]. In one study, Nardo et al. [15] described a UVsS patient with an ERCC8mutation whose cells were hypersensitive to UV radiation but not to oxidative DNA damage. The literature also contains several supportive findings that suggest either tolerating or not tolerating oxidative lesions is a possible molecular explanation for the clinical difference between UVsS and CS [5, 11‒13]. Zhang et al. [8] showed that other genes might cause the CS phenotype by sequencing TCR-deficient CS cell lines with no mutations in the ERCC6 and ERCC8 genes but with single-nucleotide variants in the UVSSA gene. Our case might provide support for the notion that UVSSAmutations cause a CS-like phenotype. This cannot be proven as we required further information that we could not obtain since cellular research was halted by the death of the patient. It should also be remembered that this patient had a heterozygous mutation in the XPA gene. Biallelic pathogenic variants in the XPA gene cause XP, which is an allelic disorder with CS. To date, no digenic or triallelic mechanism has been identified, but one may be possible.

In conclusion, homozygous UVSSAvariants that truncate the protein might be a new cause of a CS-like phenotype. Further studies are needed to support these findings and the hypothesis.

We would like to thank the family for their cooperation in this study.

Written informed consent was obtained from the parent/legal guardian of the patient for publication of the details of their medical case and any accompanying images. Ethical approval was not required for this study in accordance with local/national guidelines.

The authors have no conflicts of interest to declare.

There was no funding relevant to this study.

All authors participated in assessing the patient and acquisition, analysis, and interpretation of data for the work. Y.B. wrote the manuscript. G.K. provided critical feedback and supervised the writing of the manuscript.

The raw data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to patient privacy.

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