Biallelic variants in FRA10AC1 have been identified as the cause of a neurodevelopmental disorder with growth retardation, dysmorphic features and corpus callosum abnormalities (MIM: # 620113). Ten patients from 6 unrelated families have been described to date with variable disease manifestations (Table 1) ranging from mild intellectual disability without motor delay to profound global delay associated with multiple congenital anomalies [5,6,7]. In this report, we describe a new patient and highlight the broad clinical manifestations and multisystem involvement associated with FRA10AC1 variants.

Our patient had severe motor and cognitive delay, dysmorphic facies, hypotonia, and delayed speech, which were observed in all described patients. However, his growth showed improvement over time, indicating that growth retardation seems not to be a constant finding. In addition, the patient had behavioral problems, which were noted before in a single patient [5]. Although brain imaging findings were available for only 6/10 patients, corpus callosum abnormalities were strikingly observed in all of them. Similarly, our patient had hypogenesis of the corpus callosum, and we were able to show a small cyst in the caudate lobe of the basal ganglia.

Multiple congenital anomalies have been reported in patients harboring FRA10AC1 variants [5,6,7]. Skeletal anomalies, congenital heart defects, and skin manifestations were found in 8/10 (80%), 5/10 (50%), and 3/10 (30%) of patients, respectively. Our patient did not have any skeletal or heart defects; however, he had a café au lait patch on the arm and a hypopigmented patch on the knee. In addition, the patient had fused kidneys at the midline of the pelvis. Similarly, one of the patients reported by von Elsner et al. [5] had a caudally located left kidney and increased cortical signal in both kidneys. Visual problems have been observed before in 4/10 patients [6, 7], however our patients showed cone dystrophy that appears to be the cause of the visual problems that have been reported before. Therefore, ophthalmological examination of patients with FRA10AC1 variants is highly recommended. Other rare reported findings were seizures (2 patients), growth hormone deficiency (2 patients), sensorineural hearing loss (1 patient), cleft palate (1 patient), and hypospadias (1 patient).

The facial features (high forehead, long palpebral fissures, and bulbous nose) seen in our patient have been present in all individuals reported, suggesting that FRA10AC1-related neurodevelopmental disorder may be a recognizable syndromic disorder. Banka et al. [7] suggested that the facial dysmorphism was overlapping with Kabuki facial features but lacking the eversion of the lateral third of the lower eyelid. In our patient, the long palpebral fissures became less prominent with age. In addition, triangular  face and a pointed chin were noted to evolve with age [5, 6].

So far, six different variants have been described in patients with FRA10AC1-related disorder (Fig. 1H). These variants were 2 nonsense p.(Arg110Ter) and p.(Arg161Ter), 2 intragenic deletions (deletion of exons 1–2 and deletion of exons 1–3), 1 frameshift p.(Ser188PhefsTer6), and 1 in-frame deletion variant p.(Glu165del). None of these variants recurred in more than one family, though the majority of reported families were from Saudi Arabia (3 families) and Egypt (2 families). In this study, we identified the first splice variant (c.465+1G>A) in the gene, raising the total number of reported variants to 7. Functional characterization of this variant using the patient’s mRNA confirmed that it is associated with skipping of exon 7 and early protein truncation.

We are aware that it is early to comment on phenotype-genotype correlations based on the small number of patients reported to date (n = 11, including our patient). However, the three sibs harboring the in-frame deletion variant p.(Glu165del), which was confirmed to affect the FRA10AC1 stability but not its subcellular localization, had a milder phenotype in comparison to patients with loss-of-function variants [5,6,7]. None of the three sibs had skin, renal, ocular, or heart anomalies. In addition, they had mild intellectual disability with or without mild motor delay [5]. In contrast, patients with loss-of-function variants have more severe motor and cognitive delay and multiple congenital anomalies, as evident in our patient and those described before [5,6,7]. The identification of more patients with FRA10AC1 variants in the future would greatly help to confirm this observation.

In conclusion, we reported a new patient with FRA10AC1-related disorder. Our patient shared the core clinical features of the disorder and had, in addition, kidney and ocular manifestations, which we suggest as an expansion of the multisystem involvement associated with the disorder. Phenotype-genotype correlations might exist as loss-of-function variants appear to be associated with a more severe cognitive and motor delay and multiple congenital anomalies. The diverse clinical phenotypes associated with pathogenic variants in FRA10AC1 underscore the critical role of this gene in the neurodevelopmental pathways.