RTS was first described in 1868 by Auguste Rothmund who reported children from a Bavarian village presenting juvenile cataracts, short stature and skin eruptions (Rothmund, 1868). In 1923, Sydney Thomson described individuals with skin problems similar to those observed by Rothmund, but without juvenile cataracts and the presence of radial ray defects and short stature, naming the disease as “congenital poikiloderma” (Thomson, 1923). In 1957, Taylor postulated that these patients suffered from the same disease, coining the eponym Rothmund-Thomson syndrome (Taylor, 1957; Wang et al., 2001; Larizza et al., 2010).

The typical skin rash starts between 3 and 10 months of age as erythema on the face, associated with some swelling and, less often, blisters, spreads to extremities (extensor areas first, then flexor areas) and buttocks, sparing trunk and abdomen. In the evolution to a chronic phase, different types of lesions can be observed, such as telangiectasias, areas of reticulated hyperpigmentation and hypopigmentation and punctate atrophy, consistent with poikiloderma. In addition, one-third of patients develop hyperkeratosis, with excess accumulation of keratin in regions of the skin. The erythema can get worse after sun exposure. Other ectodermal findings include sparse/brittle/thin hair, sparse eyebrows/eyelashes; dystrophic nails; abnormal teeth (microdontia, abnormal crown formation, short roots, and increased incidence of caries) (Wang et al., 2001; Larizza et al., 2010; Wang and Plon, 2020). Another cardinal feature in RTS are cataracts, which are usually bilateral, juvenile and of rapid progression. Other ocular abnormalities include corneal anomalies, glaucoma, retinal atrophy, iris dysgenesis and strabismus. Individuals with RTS frequently present low birth weight and length that persist in clinical evolution, in some cases accompanied by growth hormone deficiency. Gastrointestinal anomalies are also seen, with feeding problems in infancy, sometimes requiring tube feeding; chronic diarrhea that resolves in early childhood and, occasionally, congenital anomalies, including anal atresia. Skeletal anomalies are characterized particularly by radial ray defects, but often also include patella hypoplasia/aplasia, osteopenia, irregular metaphysis with abnormal trabeculation and joint dislocations. Neurocognitive development is normal in the majority of patients (Wang et al., 2001; Larizza et al., 2010). Increased risk for cancer is a major concern in individuals with RTS, with an estimated prevalence of 30% for osteosarcoma and 5% for skin cancer (squamous cell carcinoma). Osteosarcoma, which could be isolated or multicentric, develops at a median age of 11.5 years, earlier than in non-syndromic cases. Metastatic osteosarcoma is one of the major causes of death in RTS patients, requiring careful clinical management. Other less frequently described tumors include malignant fibrous histiocytoma, basal cell carcinoma, Bowen´s disease, myelodysplasia, acute myeloid leukemia. This increased risk for cancer development is not observed in the heterozygous parents (Wang et al., 2001; Larizza et al., 2010; Wang and Plon, 2020).

Over 100 years after the first description of the disease, Kitao et al. (1999) identified RECQL4 (located on chromosome 8q24.3) as the first gene associated with RTS, but already in this study it was evident that RTS presented locus heterogeneity. Further to this discovery, it was established that while RECQL4 mutations are observed in ca.60% of RTS patients, a further 40% did not have variants identified in this gene, such that the disease was subdivided into RTS type 1 (no variants identified in RECQL4) and type 2 (biallelic variants in RECQL4) (Wang et al., 2003; Larizza et al., 2010; Wang and Plon, 2020). Over the years, it has become evident that there were also clinical differences between the disease subtypes, with RTS type 1 more likely to be associated with bilateral juvenile cataracts, while type 2 RTS is characterized by an increased risk for osteosarcoma and skeletal abnormalities (Wang et al., 2001; 2003; Mehollin-Ray et al., 2008).

Despite the revolution in the diagnosis of rare human genetic disorders afforded by next-generation sequencing techniques, the identification of new RTS genes remained stagnant for almost two decades, until the recent identification of three new genes associated with the disease: ANAPC1 (located on chromosome 2q13), CRIPT (located on chromosome 10q21.3) and DNA2 (located on chromosome 2p21).

In 2019, Ajeawung et al., 2019 evaluated a cohort of ten individuals from seven families, three of them of Amish ancestry, with clinical findings compatible with the diagnosis of RTS type I (mainly poikiloderma, with other ectodermal findings, and juvenile cataracts). Pathogenic/likely pathogenic variants in RECQL4 were ruled out previously by molecular studies. Exome-sequencing was performed in all probands and biallelic variants were identified in ANAPC1, followed by the identification of a single large region of homozygosity on chr2q13-q14.1 in the Amish individuals and low levels of ANAPC1 expression levels in qRT-PCR experiments. A recurrent intronic variant (c.2705–198C>T) in ANAPC1 was identified in all individuals, in a homozygous state in all Amish and in one non-Amish patient, and in compound heterozygosity with a loss-of-function (LoF) variant in the other ones. Three other individuals from two families presenting RTS, but without juvenile cataracts, and negative for variants in RECQL4, were also screened for ANAPC1 variants, but the analysis failed to show causative variants in the gene, suggesting that it could be exclusively associated with RTS type I.

Although the number of individuals evaluated was small, the authors noticed a more complex phenotype in those individuals harboring the intronic variant in trans with a LoF allele, compared to the homozygotes for the intronic variant, with the former more frequently presenting growth compromise requiring growth hormone therapy, as well as a greater involvement and findings in teeth, nails, and endocrine, genital and skeletal systems (Ajeawung et al., 2019). An additional individual, a 14-month-old boy presenting poikiloderma and other ectodermal findings, as well as developmental delay, was reported in 2021 harboring the same intronic variant reported previously by Ajeawung et al. (2019) in trans with a 1.7 Mb microdeletion in 2q13 encompassing, among ten genes in this chromosomal region, ANAPC1 (Zirn et al., 2021).

Interestingly, ANAPC1 mutations account for only 10% of RTS patients, such that ca.30% of patients remained undiagnosed (Wang and Plon, 2020). These results showed that there must be other gene(s) responsible for the clinical features fulfilling the criteria for RTS. Fortunately, four years later, two new genes were described for the syndrome.

Averdunk et al. (2023) evaluated two individuals presenting short stature, feeding difficulties, poikiloderma, sparse hair/eyebrows and eyelashes, developmental delay, facial dysmorphisms, skeletal anomalies (osteopenia, metaphyseal striations, short terminal phalanges) and one of them developed cataracts at the age of 8 years. As they fulfill the clinical criteria established for this disorder (Wang et al., 2001), the patients were diagnosed as RTS. No variants in RECQL4 and ANAPC1 were identified, but both patients harbored homozygous variants in CRIPT. The authors also updated the clinical findings of four previously described individuals harboring variants in CRIPT (Shaheen et al., 2014; Leduc et al., 2016; Akalin et al., 2023). Thus, in the six individuals evaluated, all presented with neurologic involvement with developmental delay, particularly a severe speech compromise, and high prevalence of seizures; growth compromise with short stature and microcephaly; ectodermal findings, such as poikiloderma or hypopigmented/dyspigmented skin patches, sparse/absent hair, eyebrows and eyelashes, and less often, dysplastic nails; ophthalmologic abnormalities, mainly retinal pigmentary changes and one individual with cataracts; skeletal anomalies, mainly osteopenia, metaphyseal striations, short phalanges, scoliosis; recurrent pulmonary infections (leading to a premature death in one of the individuals) and no history of cancer development. The authors concluded that biallelic variants in CRIPT were responsible for a phenotype similar to RTS with neurologic impairment.

Our group was responsible for the discovery of another gene related to RTS (Di Lazzaro Filho et al., 2023). By the analyses of an admixed cohort, a specific cluster of patients displayed clinical symptoms reminiscent of RTS, but with a distinct genetic basis. Six individuals originated from Brazil and a duo of Swiss/Portuguese siblings, exhibited a phenotype marked by widespread poikiloderma, severe growth failure (with growth hormone—GH—deficiency or combined pituitary hormone deficiency), microcephaly and congenital cataracts. Additionally, these individuals exhibited clinical characteristics consistent with RTS, including sparse hair, eyebrows and eyelashes, dystrophic nails, craniofacial dysmorphisms and skeletal anomalies (osteopenia, metaphyseal flaring and short metacarpals/phalanges). Through whole genome sequencing (WGS), we identified compound heterozygosity for an intronic splicing variant in trans with LoF variants in DNA2, resulting in diminished DNA2 protein levels. Remarkably, this intronic variant was shared among all the patients and was also detected in the Portuguese father of the European siblings, suggesting a possible founder effect.

Thus, four different genes have been reported to be responsible for a phenotype typical or reminiscent of RTS. The number of individuals harboring variants in these novel genes is small, which precludes a clear genotype-phenotype correlation at present. However, a comparison between clinical findings observed for RTS patients harboring mutations in each of these genes highlights commonalities and gene-specific discrepancies in clinical presentation (Table 1). As expected, poikiloderma is present in all patients, although DNA2-patients have a more generalized distribution compared to other gene groups. Perhaps more surprising is the finding that both sparse hair/eyebrows/eyelashes and short stature are highly prevalent in all RTS gene groups. Skeletal findings such as short metacarpals/phalanges are also very prevalent, but RECQL4 patients are much more prone to radial ray defects. Moreover, cataracts were almost exclusively seen in individuals harboring variants in ANAPC1 and DNA2, in the former as the classical, juvenile form described in the first reports of RTS, and in the latter, as a congenital form, frequently associated with other ocular anomalies. Interestingly, the ANAPC1 and DNA2 groups share a high prevalence of growth-hormone deficiency. Neurological involvement, as either developmental delay/intellectual disability, or the presence of seizures, were most common in the individuals harboring CRIPT biallelic variants, while microcephaly is most frequent in both CRIPT and DNA2 patients. The presence of osteosarcoma was seen only in individuals harboring biallelic variants in RECQL4, but given that the individuals in each group are still young, a long-term follow-up is required to determine whether the increased risk for cancer development is restricted to the RECQL4 group.

Over the years, several mutant alleles have been cataloged for RTS-related genes. Of these, a large proportion (87/114, or 76%) consist of variants that are either large deletions or are predicted to lead to premature termination codons (PTCs) or splicing defects (Figure 1 and Supplementary Table S1). As these aberrant transcripts are often degraded by quality control mechanisms such as nonsense-mediated mRNA decay (Lindeboom et al., 2019), most are predicted to lead to reduced mRNA and therefore low overall protein levels, such that the location of these mutations in relation to protein domain architecture or catalytic activities must be interpreted with caution. Even within the remaining missense or in-frame insertion/deletion mutations, which only result in localized changes to amino acid sequence, some variants may compromise overall protein stability, for instance by destabilizing protein folding, and their locations must therefore also be cautiously interpreted. However, some variants are particularly informative and will be briefly discussed. For instance, mRNAs containing PTCs within the last exon (exon 21 in the case of RECQL4), are generally spared of nonsense-mediated decay (Lindeboom et al., 2019), suggesting that the two RECQL4 variants c.3523C>T (p. Gln1175*) and c.3599_3600delCG (p.Thr1200Argfs*26), which affect exon 21, may produce essentially full-length proteins, at essentially normal levels. While speculative, this would indicate that the very C-terminal portion of the 1208 amino acid-long RECQL4 protein may have important functions. Another interesting observation is that both missense mutations in CRIPT are cysteine-to-tyrosine mutations. Cysteines often participate in coordination of metal ions, such as in zinc finger domains. Indeed, upon close inspection of a recently published cryo-electron microscopy structure containing CRIPT among many other proteins (PDB: 7DVQ), the affected residues (cysteine 3 and cysteine 76) are part of two different Zn²⁺-coordinating centers in CRIPT, one formed by Cys3, Cys6, Cys83 and Cys86 and the other formed by Cys58, Cys61, Cys73 and Cys76 (Bai et al., 2021).

RECQL4 encodes a member of the RECQ helicase family characterized by the presence of an ATP-dependent DNA helicase domain, with a 3′→5′polarity, first identified in Escherichia coli RecQ (Umezu et al., 1990). These proteins act in different cellular processes such as replication, recombination, repair, telomere maintenance, translation, RNA processing, mitochondrial DNA maintenance and chromosomal segregation, and are therefore important for the maintenance of genome stability (Chu and Hickson, 2009; Croteau et al., 2014; Wang and Plon, 2020; Balajee, 2021).

Uniquely among human RECQ family members, RECQL4 is an essential gene. Interestingly, this essential function is not associated with helicase activity, but has instead been mapped to an N-terminal Sld2-like domain which is crucial for the initiation of DNA replication (Sangrithi et al., 2005; Matsuno et al., 2006; Im et al., 2009; Abe et al., 2011; Croteau et al., 2012a; Collart et al., 2013; Smeets et al., 2014; Castillo-Tandazo et al., 2021). During replication origin firing, RECQL4 is thought to promote the recruitment of the GINS complex and of the leading strand polymerase Polε to the prereplication-complex (pre-RC), in concert with TopBP1, and may also play roles in the subsequent recruitment of AND-1, Mcm10 and the DNA pol α-primase complex (Sangrithi et al., 2005; Matsuno et al., 2006; Im et al., 2009; Xu et al., 2009; Shin et al., 2019). Shin et al. (2019) demonstrated that direct tethering of RECQL4 to the pre-RC generated replication stress and the accumulation of single-stranded DNA (ssDNA) due to increased DNA synthesis in early S phase, suggesting that RECQL4 also regulates the temporal control of late replication origin firing and protects against replication stress.

In addition, RECQL4 is thought to function in the maintenance of telomeres (Ghosh et al., 2009; 2012; Croteau et al., 2012a; Ferrarelli et al., 2013), which is evidenced by telomere abnormalities in RECQL4-mutated patient cells, such as telomere fragility and segmental exchanges between telomeric sister chromatids (Ghosh et al., 2012), as well as an increase in replication stress markers, such as 53BP1 bodies, localizing to telomeric structures in these cells (Ghosh et al., 2012). During S phase, the localization of RECQL4 to telomeres is increased, and it has been shown to interact directly with both telomeric DNA and telosome proteins (Ghosh et al., 2012). While the molecular roles of RECQL4 at telomeres are insufficiently understood, there is evidence that it can resolve telomeric D-loops, in particular those containing lesions such as 8-oxodG or thymine glycol, with the help of TRF1, TRF2 and POT1 (Ghosh et al., 2009; Ghosh et al., 2012; Ferrarelli et al., 2013).

RECQL4 has also been implicated in the replication and protection of the mitochondrial genome (Croteau et al., 2012b; Chi et al., 2012; De et al., 2012; Gupta et al., 2014). In this context, RECQL4 is thought to associate with p53 and serve as an accessory factor that stabilizes the interaction between subunits of the mitochondrial DNA polymerase Polγ, thus promoting the processivity of the PolγA/B2 holoenzyme (Gupta et al., 2014). Loss of both RECQL4 and p53 was shown to cause a decrease in the replication fidelity of mitochondrial genetic material, resulting in polymorphisms and somatic mutations (Gupta et al., 2014), although how this can be reconciled with the lack of clear mitochondria-related clinical symptoms in RTS patients is unclear.

The RECQL4 helicase domain has been shown to participate in the resection of DNA double-stranded breaks (DSB) during the repair of these lesions through homologous recombination (HR) (Xu and Liu, 2009; Croteau et al., 2012a; Lu et al., 2016), via a physical interaction of RECQL4 with the MRN (MRE11-RAD50-NBS1) complex and CtIP, responsible for initiating the resection of DSBs (Lu et al., 2016). RECQL4 also interacts with XPA, an important protein in nucleotide excision repair (NER), and this interaction is enhanced after UV-irradiation (Fan and Luo, 2008). However, since UV hypersensitivity is not a characteristic of RTS, the role of RECQL4 in NER should be secondary and needs further study (Fan and Luo, 2008). RECQL4 also interacts with proteins involved in base excision repair (BER), such as APE1 and FEN1, colocalizing after treatment with H₂O₂ and stimulating their apurinic endonuclease and incision activity, respectively (Schurman et al., 2009). Furthermore, RTS patients accumulate more XRCC1 foci and have difficulty responding normally to oxidative stress, indicating that RECQL4-deficient cells show an increased amount of oxidative damage (Schurman et al., 2009). Woo et al. (2006) also showed that RECQL4 accumulates in nucleoli after treatment with H₂O₂ and streptonigrin, interacting with PARP-1, a protein important in DNA damage signaling (Chiarugi, 2002; Huang et al., 2022). This nucleolar localization of RECQL4 is PARP-1 dependent, as it is abolished after the use of PARP-1 inhibitor. Interestingly, the C-terminal portion of RECQL4 is targeted by PARP-1 (Woo et al., 2006).

Therefore, despite being extensively studied, the precise biochemical role of RECQL4 in DNA replication, DNA repair and how defects in its activity lead to the clinical presentations of RTS still lacks characterization.

ANAPC1 encodes the largest subunit of the anaphase-promoting complex/cyclosome (APC/C), which is an E3 ubiquitin ligase that targets proteins for degradation by the proteasome. Its main functions are in the control of the cell cycle, both during mitosis and in the G1/S transition (Melloy, 2020).

At the end of mitosis and during G1, the APC/C is bound to the co-activator Cdh1 and high APC/C^Cdh1 complex activity is required to maintain cells in G1 and allow the licensing of new replication origins in preparation for the next S phase (Harper et al., 2007; Sigl et al., 2009; Eguren et al., 2011; Cappell et al., 2016; Schrock et al., 2020). APC/C^Cdh1 inactivation is a crucial step during the transition between the G1 and S phases and is considered the “point of no return” for the onset of S phase (Cappell et al., 2016). Furthermore, the absence of Cdh1 leads to incomplete DNA replication (Greil et al., 2016), probably due to dysregulation in dNTP levels and a consequent decrease in replication fork speed (Garzón et al., 2017).

APC/C^Cdh1 has also been shown to have non-canonical functions in response to DNA damage, and the loss of Cdh1 increases genome instability and sensitivity to DNA damaging agents (Engelbert et al., 2008; Lafranchi et al., 2014). In G2, APC/C^Cdh1 prevents the initiation of mitosis after DNA damage via degradation of the mitotic cyclins A and B (Sudo et al., 2001; Peters, 2006; Bassermann et al., 2008). In G1, APC/C^Cdh1 interacts with CtIP, targeting it for degradation and restricting DNA end resection and HR efficiency, while in G2 and after DNA damage, this activity is regulated by the SKP2-SCF complex to promote HR under these conditions (Lafranchi et al., 2014; Li et al., 2020).

APC/C can also be activated by Cdc20, which occurs during mitosis and ensures the progression from metaphase to anaphase, by promoting the degradation of securin, Pds1, and cyclin B, which allows the separation of sister chromatids and segregation of chromosomes to opposite poles of the cell during anaphase (Peters, 2006; Harper et al., 2007). In this context, APC/C^Cdc20 is essential for correct chromosome segregation and cell division, and the inhibition of this complex causes a delay in progression through mitosis, with cells arrested in metaphase (Zeng et al., 2010).

While the importance of the APC/C complex, and therefore of the ANAPC1 gene, in cell cycle progression and regulation of target protein levels in different cell cycle stages is well-established, how the loss of these functions may contribute to the phenotype of RTS patients is still unknown.

Like RECQL4, the DNA2 gene is embryonic lethal, which has made it difficult to elucidate its functions. DNA2 has two catalytic activities contained in distinct active sites: an ATP-dependent helicase domain with 3′→5′polarity and an endonuclease domain (Budd and Campbell, 1995; Bae et al., 1998; Liao et al., 2008).

Due to these capabilities, DNA2 has been implicated in multiple DNA replication and repair mechanism. In budding yeast, DNA2 was shown to participate in the maturation of Okazaki fragments during lagging strand replication (Kang et al., 2010), although there is little evidence for a similar activity in humans (Duxin et al., 2012). During lagging strand replication, the yeast Pif1 helicase, together with the Polδ (delta) subunit, Pol32, unwind previously synthesized Okazaki fragments. If these fragments are short (<30 nt), they are readily cleaved by the canonical flap endonuclease FEN1 (Kang et al., 2010; Hudson and Rass, 2021). However, if longer flaps (>30 nt) are generated, these are covered by RPA, inhibiting the action of Fen1 and requiring DNA2 to incise the flap and remove a large portion of the ssDNA region, allowing Fen1 to process the resulting short flap (Bae and Seo, 2000; Bae et al., 2001; Rossi et al., 2018; Kahli et al., 2019). In the absence of DNA2, these RPA-covered flaps are thought to activate DNA damage signaling via Mec1 (ATR), which likely accounts for the lethality of DNA2 mutants (Budd et al., 2011; Rossi et al., 2018). Although DNA2 also contains a helicase domain, its functions are less clear, given that DNA2 often associates with other helicases such as WRN (RECQL2) and/or BLM (RECQL3) (Masuda-Sasa et al., 2006).

DNA2 is also important during replication fork reversal (Neelsen and Lopes, 2015; Hudson and Rass, 2021), which is a process by which DNA replication forks are remodeled to allow their restart after their progression has been blocked (Zellweger et al., 2015). DNA2 is recruited to stalled replication forks and is required for controlled nucleolytic degradation of reversed replication forks, in concert with WRN, which promotes replication restart and prevents the aberrant processing of replication intermediates by other pathways (Hu et al., 2012; Neelsen and Lopes, 2015; Thangavel et al., 2015; Hudson and Rass, 2021).

DNA2 also plays a role in the replication of repetitive regions of the genome, such as centromeres and telomeres, requiring both of its functions (helicase and endonuclease) for the resolution of structures formed in these regions, and thus facilitating replication fork progression (Choe et al., 2002; Lin et al., 2013; Li et al., 2018). At telomeres, DNA2 has been proposed to process G4 quadruplex structures formed in the G-rich strand (Masuda-Sasa et al., 2008; Lin et al., 2013), C-rich ssDNA (Markiewicz-Potoczny et al., 2018), and to promote de novo telomere addition by telomerase (Choe et al., 2002). At centromeres, it has been proposed that DNA2 is also involved in resolving G4 structures and stem loops formed due to the repetitive nature of the centromeric DNA, perhaps in a similar fashion to its proposed role in flap processing during Okazaki fragment maturation in concert with FEN1 (Tishkoff et al., 1997; Li et al., 2018).

Perhaps the most well-established role of DNA2, at least in human cells, is its involvement in the repair of DSBs via homologous recombination (Zhu et al., 2008; Di Lazzaro Filho et al., 2023). In this process, the initial resection of the DSB regions is performed by the MRN complex, which degrades only a few nucleotides (short resection) (Zhu et al., 2008), activated by the CtIP protein. Subsequently, DNA2 combines with WRN or BLM (RECQL3) to perform long-range resection, which can also be performed in a redundant fashion by the exonuclease EXO1 (Budd et al., 2005; Mimitou and Symington, 2009; Nimonkar et al., 2011; Ranjha et al., 2018).

As with RECQL4 and ANAPC1, it is unclear which of these multiple functions of DNA2 could be most relevant for RTS pathology.

CRIPT (cysteine-rich interactor of PDZ three) is a well-conserved protein, being present from plants to animals and is expressed in several tissues (Niethammer et al., 1998), with highest expression in the hippocampus, moderately in the striatum and cortex and in smaller amounts in the midbrain (Niethammer et al., 1998). CRIPT is known for binding to the third domain of PSD-95 (PDZ3) (Niethammer et al., 1998), which localizes in specific cell-cell binding sites at synapses in the mammalian nervous system and is involved in cellular localization of proteins and in establishing cell polarity (Ehlers et al., 1996). By identifying activities for sub-membranous protein complexes, PDZ domains serve as a signaling mechanism for a variety of pathways as receptor-mediated, transport channel-mediated and cytoskeleton-associated molecules, binding to specific C-terminal regions of other proteins (Ponting et al., 1997). Both CRIPT and PSD-95 co-localize in excitatory synapses and dendritic spines, interacting with the tubulin portion of the cytoskeleton (Niethammer et al., 1998), with CRIPT being the bridge between PSD-95 and the microtubules, given that PSD-95 lacks this ability (Passafaro et al., 1999).

CRIPT is also involved in mRNA processing, by stabilizing U12 small nuclear ribonucleoprotein (snRNP) within the minor spliceosome complex (Bai et al., 2021). U12-introns are rare regions in the genome, which require a splicing machinery different from the machinery used in the removal of introns of the U2-type (more abundant) (Burge et al., 1998). This machinery is called U12-dependent or minor spliceosome and is believed to be evolutionarily ancient, given that U12-introns are present from cnidarians to mammals and plants, being absent in C. elegans and yeast (Wu et al., 1996; Dietrich et al., 1997; Burge et al., 1998).

Cells from CRIPT patients exhibit high expression of senescence markers (p53/p16/p21), confirmed by the ß-galactosidase activity test. Even so, no significant increase was observed in cell sensitivity to various genotoxic agents, such as ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate (Averdunk et al., 2023), precluding the identification of a role for CRIPT in DNA repair.

How these varied functions of CRIPT relate to the clinical presentation of RTS patients is currently unknown.