DNA Repair-related photosensitivity syndromes are heterogeneous heritable skin diseases characterized by photosensitivity and defective DNA repair [1]. Defects in the DNA repair systems and the accumulation of all types of damages and mutations in the genome lead to defects in genome instability. For this reason, most patients show more severe symptoms as they age [3]. Patients show different symptoms depending on the gene, the type of mutation, and the disturbed cellular pathway. These clinical characteristics, including photophobia, and neurological symptoms such as hyporeflexia, deafness, seizures, microcephaly, intellectual impairment, skeletal malformations, and susceptibility to different types of skin and non-skin cancers, may be presented. The most common syndromes related to the category of photosensitivity disorders include xeroderma pigmentosum, cerebro-oculo-facio-skeletal (COFS) syndrome, Cockayne syndrome, UV-sensitive syndrome, and trichothiodystrophy [1].

Xeroderma pigmentosum (XP) is a rare genodermatosis with an autosomal recessive (AR) mode of inheritance with an incidence from 2.3 per one million births in Western Europe and almost 1 in 20,000 in Japan to 1 in 250,000 in the USA [2], [3]. XP results from mutations in eight different genes like XPA, XPB (ERCC3), XPC, XPD (ERCC2), XPE (DDB2), XPF (ERCC4), XPG (ERCC5), which are primarily involved in nucleotide excision repair (NER) pathway and XPV(POLH) involved in the DNA repair by translesion synthesis (TLS) [2], [4]. Some patients with mutations in XPB, XPD, XPF, and XPG genes may represent clinical manifestations of Xeroderma pigmentosum and Cockayne syndrome (XP/CS), and in a rare case of XPF mutation, the affected person also had the symptoms of Fanconi anemia (XP/CS/FA) [5], [6]. The hallmarks of XP are photosensitivity, skin pigmentary changes, and the development of various malignant skin cancers such as basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) at an early stage. Patients have a 10–20% increased risk of developing internal cancers such as lung cancer and oral cavity, 40% represent ocular abnormality, and about 20–30% of patients develop neurologic degeneration [6]. De Sanctis-Cacchione syndrome is the most severe form of the XP that represents dwarfism, hypogonadism, mental retardation, and skin-related symptoms [7].

Cockayne syndrome (CS) is a clinical and genotypical spectrum of disorders characterized by growth failure and multisystemic presentations; CS shows a variable age of onset. The most common genetic cause of CSs is biallelic pathogenic variants in ERCC6 or ERCC8. The phenotypic spectrum of CS ranges from the "classic" or "moderate" form (type I); a more severe form with symptoms present at birth (type II); a milder and later-onset (type III), and COFS, the most severe form of CS. COFS syndrome is an AR multiple congenital anomalies characterized by photosensitivity, microcephaly, congenital cataracts and/or microphthalmia, arthrogryposis, severe developmental delay, facial dysmorphism, and postnatal growth retardation [8]. COFS syndrome had been associated with mutations in four genes ERCC6 (CSB), ERCC2 (XPD), ERCC5 (XPG), and ERCC1. The most common cause of COFS is mutations in the XPG and CSB. Only four patients with ERCC2-related COFS have been disclosed so far leading to early childhood death [9], [10], [11].

UV-sensitive syndrome (UVsS) is an extremely rare AR heritable skin disorder characterized by photosensitivity, acute sunburn, and freckles with solar lentigines [12]. In contrast to other heritable photosensitivity disorders, no neurological manifestations, developmental abnormalities, or cancer susceptibility have been associated with UVsS. So far, mutations in three genes in about 20 patients have been associated with UVsS, including homozygous mutations in ERCC6:p.Arg77Ter, ERCC8:p.Trp361Cys and UVSSA (KIAA1530) [13], [14], [15], [16], [17]. Photosensitivity is also observed in other syndromes unrelated to the DNA repair systems, such as congenital erythropoietic porphyria syndromes, erythropoietic protoporphyria, and Kindler epidermolysis bullosa [18], [19], [20].

In this study, we subjected a cohort of 17 Iranian families with heritable photosensitivity syndromes to next-generation sequencing to identify their genetic defect. We expanded the phenotypic and genotypic spectra of heritable photosensitivity syndromes.