Infantile nystagmus syndrome (INS), formerly called congenital nystagmus is characterized by rhythmic involuntary oscillations of the eyes that are present at birth or during infancy [1]. This syndrome is one of a wide range of symptoms present in afferent visual system disorders or neurological congenital disorders, but can be the main symptom or sign in idiopathic INS that arises independently of any ocular or neurological abnormalities [2,3]. In addition, INS is a genetically heterogeneous disorder for which there are more than 100 causative genes [4]. Thus, identifying the underlying etiology of INS is both difficult and time-consuming in clinical practice. Patients with INS often undergo numerous investigations including electroretinography (ERG), optical coherence tomography (OCT), and magnetic resonance imaging (MRI) of the brain, but these tests can be challenging in early infancy and children [5-8].

The introduction of next-generation sequencing (NGS) has provided more opportunities to evaluate patients with INS [8]. In particular, targeted gene panel sequencing or whole-genome sequencing leads to faster and more-accurate diagnoses in genetically heterogeneous INS. These advances in genetic testing have the potential to change the diagnostic paradigm of patients with INS [5].

This review summarizes the genotypes and phenotypes of INS, and discusses the promise and pitfalls of genetic testing in INS.

The term ‘idiopathic’ INS means that there are no associated visual or neurological disorders associated with INS [1,4]. This has led to speculation that idiopathic INS could be caused by abnormal development of the ocular motor system itself rather than disorders of the afferent visual pathway [2,3]. The nystagmus usually manifests as horizontal conjugate oscillations, with vertical nystagmus not being typical of idiopathic INS [1,4]. The direction of nystagmus changes with eccentric gaze (right-beating during right gaze and left-beating during left gaze) or alternates periodically with time (periodic alternating nystagmus) [9,10]. The nystagmus waveform can be pendular (Fig. 1A) or jerk with increasing exponential slow phases (Fig. 1B). The nystagmus is often accentuated by anxiety, attention, and attempts to fixate an object, while attenuated with eyelid closure or on convergence. Moving the eyes to a particular position within the orbit—called the null point or null zone—decreases the intensity of nystagmus. Some individuals with INS tend to turn their head to close to the null point, resulting in an abnormal head posture (AHP). The presence of AHP is a common reason for parents bringing children in for medical evaluations and treatment. Despite continuous eye oscillations, individuals with idiopathic INS show relatively good visual acuity and no oscillopsia due to the presence of the foveation period, when the eye velocity is at or near zero (Fig. 1B). During this brief period, the image of the target is relatively stationary in the foveal area, leading to good visual acuity without oscillopsia [1]. However, some individuals may complain of oscillopsia when nystagmus is pronounced or when they feel tired.

Idiopathic INS has heterogeneous inheritance, but an X-linked trait is the most common form [11]. GPR143 and FRMD7 (MIM#300628) have been reported as the causative genes of idiopathic INS (Table 1) [11,12]. Pathogenic variants in GPR143 are primarily associated with ocular albinism (OA), where nystagmus manifests as a secondary phenotype due to afferent visual system disorders. However, these variants have also been reported in idiopathic INS families without the classic phenotype of OA [13,14]. Nevertheless, most cases of idiopathic INS with an X-linked trait have been linked to pathogenic variants in FRMD7 at Xq26 [12,15]. It is known that FRMD7 plays an important role during neuronal development, especially in the elongation of axons and dendrites through the interaction with calcium/calmodulin-dependent serine protein kinase (CASK) or by activating Rho GTPase signaling [16,17]. In situ hybridization studies have found FRMD7 mRNA to be strongly expressed in neuronal tissues such as the developing retina, optic stalk, otic vesicle, vestibulocochlear nerve, vestibular nucleus, and cerebellum [9,15,18]. These regions are known to be involved in the motor control of eye movements, suggesting that pathogenic variants in FRMD7 can induce defective axogenesis, dendritogenesis, and neuronal guidance during this process, leading to the development of nystagmus.

More than 100 different pathogenic variants in FRMD7 have been reported in the literature [7,10]. Half of these are missense variants that may destabilize the overall structure of FRMD7, while the other half are predicted to cause gross defects at the protein level due to truncated variants. Although pathogenic variants occur throughout the entire gene without any consistent hot-spots, the missense variant c.875T>C (p.L292P) has been frequently reported in Korean patients with idiopathic INS [7,10,19]. Given that all patients with c.875T>C share two single-nucleotide polymorphisms (rs6637934 and rs5977623) in exon 12 within FRMD7, this variant might arise from the founder effect in the Korean population [10]. Incomplete penetrance has been observed in female carriers, ranged from 30% to 100% [11,20-23]. Although skewed X-inactivation is a possible mechanism underlying the variable penetrance, some studies have revealed that there is no clear causal link between an X-inactivation pattern and the phenotype in INS families with an FRMD7 variant [20,21]. Furthermore, affected females have shown random X-inactivation and female carriers exhibit different methylation patterns for the X chromosome [21,22]. Thus, other factors such as disease-modifying genes or environmental contributions may influence the variable penetrance.

About 25% of individuals with INS have identifiable visual or ocular anomalies such as ocular and oculocutaneous albinism, achromatopsia, Leber congenital amaurosis, or congenital stationary night blindness [1]. Unlike those with idiopathic INS, most of these patients exhibit a wide spectrum of afferent visual system impairments including decreased visual acuity, high refractive errors, iris abnormalities, cataract, and foveal hypoplasia (Fig. 2). Nystagmus associated with visual system disorders has similar characteristics to idiopathic INS, but certain features may provide diagnostic clues. For example, pendular nystagmus with a low amplitude and high frequency can be common in patients with retinal disorders [24]. Several hypotheses such as abnormal development of cortical binocular motion centers and disrupted calibration of neural integrators have been proposed to explain how deficits in the visual system alone could lead to nystagmus with variable waveforms [2-4].

Since many disorders involving the afferent visual systems have INS as one of clinical manifestations, there are numerous causative genes according to their phenotypes (Table 1). The most frequently reported diseases associated with INS are Leber congenital amaurosis, albinism, and PAX6-related phenotypes. Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies that result in severe visual loss. Various phenotypes associated with at least 29 genotypes account for 70% to 80% of individuals, and so more causative genes remain to be identified [25]. The common genes with known pathogenic variants are CEP290, GUCY2D, CRB1, and RPE65, which play important roles in the development and function of the retina [5-8]. Ocular and oculocutaneous albinism are genetically heterogeneous disorders characterized by decreased or absent pigmentation in the eye, hair, and skin [4]. The ophthalmic manifestations associated with albinism are iris transillumination defect, nystagmus, fundus hypopigmentation, and foveal hypoplasia, which result in varying degrees of visual loss. Genes responsible for albinism such as TYR, OCA2, TYPR1, and GPR143 are known to be involved in the biosynthesis of melanin pigment. PAX6 encodes a transcriptional regulator that plays roles in oculogenesis and other developmental processes [26]. Pathogenic variants in PAX6 are associated with a wide range of congenital eye malformations. The classic phenotype is aniridia characterized by congenital absence of the iris, but there are various non-aniridia phenotypes without iris abnormalities including microcornea and foveal hypoplasia [4]. Altered DNA-binding affinity due to PAX6 variants has been known to determine their phenotypes, but other modifier genes and environmental factors may also affect the phenotypes of PAX6 variants [27].

Traditionally, the first step in diagnosing INS is to perform detailed ophthalmic examinations including fundus photography, ERG, OCT, and measurements of visual evoked potential. These tests are useful for the differential diagnosis of INS because certain clinical signs may be of diagnostic value. For example, anterior segment dysgenesis such as aniridia may be associated with PAX6 variants, and the presence of iris transillumination defect will prompt a comprehensive analysis of albinism-related genes [3-8]. However, clinical tests may be inconclusive due to poor cooperation in early infancy or when nystagmus is severe. More than 100 genes have been reported to cause INS, and there is significant overlap in the phenotypical characteristics among the associated disorders [5-8]. Thus, even when specific clinical signs are present, it might still not be possible to differentiate the subtypes of genetically heterogeneous disorders such as Leber congenital amaurosis and albinism [28]. Indeed, each clinical sign did not show a high predictive power for a molecular diagnosis in INS [7]. Consequently, patients with INS often undergo numerous investigations or unnecessary brain imaging before being correctly diagnosed.

The advent of NGS has greatly facilitated molecular diagnoses in genetically heterogeneous disorders, leading to NGS so widely used in clinical practice. Recent studies have found that targeted gene panel sequencing increased the diagnostic yield of INS by revising initial clinical diagnoses. Establishing a molecular diagnosis in INS has significant clinical utility in terms of achieving an accurate final diagnosis [5-8]. This may inform the visual prognosis and genetic counseling to patients with INS. Many clinicians believe that genetic testing will not lead to changes in disease management, but new genetic therapies are now emerging, such as the first FDA-approved gene therapy product (Luxturna) for Leber congenital amaurosis with pathogenic variants in RPE65 [29]. Experimental gene-based strategies for editing the genetic errors in albinism have showing early success in animal models [30]. Furthermore, an accurate molecular diagnosis may lead to additional evaluations and treatments for systemic characteristics associated with INS (Table 2) [6,8,19]. For example, Alstrom syndrome caused by pathogenic variants in ALMS1 is characterized by cone-rod dystrophy, hearing loss, and nystagmus, but may also have systemic manifestations such as endocrine, cardiac, and hepatic disorders. Early interventions for these symptoms can prevent secondary complications. All of these results have allowed development of a new clinical care pathway using NGS as a frontline diagnostic tool for INS (Fig. 3). Such a new pathway would involve genotype-driven tailored investigations, which could help to prevent patients having to undergo unnecessary examinations and treatments [5].

Nevertheless, there are still several limitations in the critical pathway for INS using genetic testing. A key rationale for genetic testing is that a positive result might motivate patients or clinicians to alter their behavior in treating INS. The goal of nystagmus treatment is to restore clear and stable vision. However, this might not be necessary in most individuals with idiopathic INS, since they do not complain of visual loss or oscillopsia due to the presence of foveation periods [10]. For this reason, genetic testing is not always mandatory in individuals with idiopathic INS. Second, there is no standardization among the various options for genetic testing in INS. Although targeted gene panel sequencing has been preferred, there has been considerable variation in the genes included in the panels for INS [5-7]. Moreover, targeted gene panel sequencing has inherent difficulties in detecting copy number variations or deep intronic variants such as FRMD7 c.285-118C>T and GPR 143 c.659-131T>G, which are predicted to activate a cryptic splice donor [18,31]. Third, genetic testing does not always guarantee to identify pathogenic variants, and negative results does not necessarily exclude a clinical condition. Previous studies using targeted gene panel sequencing have achieved a molecular diagnostic yield of 35% to 80%, suggesting that many causative genes are not still known or identified [5-8]. In addition, variants of uncertain significance from genetic testing may require further interventions such as functional investigations to reveal their pathogenicity. Finally, genetic testing is not yet a perfect substitute for clinical ophthalmic examinations, and some investigations would still be relevant depending on the clinical context. For example, OCT helps provide visual prognostic information in INS with foveal hypoplasia. Serial eye-movement recording might be necessary to evaluate the therapeutic response of nystagmus to medical or surgical interventions. In addition, nystagmus can be one of clinical manifestations of various genetic syndrome, chromosomal abnormalities, and central nervous system disorders (Table 2). Thus, a detailed clinical evaluations including developmental milestones, growth parameters, physical examinations and neurological assessment may be more crucial in infants with nystagmus.

Genetic testing in INS has the potential to clarify a clinical diagnosis or identify systemic manifestations that may require early intervention or monitoring. In addition, it would be possible to develop more-specific treatments for INS by identifying the underlying mechanisms via accurate molecular diagnoses. However, genetic testing cannot be a perfect replacement for clinical investigations, with clinical judgment still being needed to determine the most-appropriate method for evaluating INS. The continued improvement and refinement of genetic testing in conjunction with clinical phenotype may help facilitate precision medicine in patients with INS.

None.

No fundings to declare.

Conception and design: EHO. Drafting the article: EHO. Critical revision of the article: JHC. Final approval of the version to be published: JHC.