Multimodal phenotyping of foveal hypoplasia in albinism and albino-like conditions: a pediatric case series with adaptive optics insights.

Aim of the present study is to evaluate the relationship between genetic and phenotypic data in a series of patients affected by grade I and II of foveal hypoplasia with stable fixation and good visual acuity using multimodal imaging techniques. All patients underwent complete clinical and instrumental assessment including structural Optical Coherence Tomography (OCT), OCT Angiography and Adaptive Optics (AO) imaging. Central macular thickness (CMT), inner nuclear layer (INL), vessel density in superficial capillary plexus were the main variables evaluated with OCT technology. Cone density, cone spacing, cone regularity, cone dispersion and angular density were the parameters evaluated with AO. Genetic evaluation and trio exome sequencing were performed in all affected individuals. Eight patients (3 males and 5 females) with a mean age of 12.62 years (range 8-18) were enrolled. The mean best corrected visual acuity (BCVA) was 0.18 ± 0.13 logMAR, mean CMT was 291.9 ± 16.6 µm and INL was 26.2 ± 4.6 µm. The absence of a foveal avascular zone (FAZ) was documented by examination of OCT-A in seven patients in the superficial capillary plexus. However, there was a partial FAZ in the deep plexus in patients P5 and P8. Of note, all the patients presented with major retinal vessels clearly crossing the foveal center. All individuals exhibited a grade I or II of foveal hypoplasia. In 5 patients molecular analyses showed an extremely mild form of albinism caused by compound heterozygosity of a TYR pathogenic variant and the hypomorphic p.[Ser192Tyr;Arg402Gln] haplotype. One patient had Waardenburg syndrome type 2A caused by a de novo variant in MITF. Two patients had inconclusive molecular analyses. All the patients displayed abnormalities on OCT-A. Photoreceptor count did not differ from normal subjects according to the current literature, but qualitative analysis of AO imaging showed distinctive features likely related to an abnormal pigment distribution in this subset of individuals. In patients with foveal hypoplasia, genetic and multimodal imaging data, including AO findings, can help understand the physiopathology of the foveal hypoplasia phenotype. This study confirms that cone density and visual function can both be preserved despite the absence of a pit.

Nystagmus and Foveal Hypoplasia in a Carrier of Oculocutaneous Albinism.

We report a 23-year-old female patient with ophthalmic features of albinism, including refractive errors, nystagmus, depigmented fundus, and foveal hypoplasia. She presented for a rhegmatogenous retinal detachment, which was surgically reattached with no complications. Further genetic testing revealed the presence of a heterozygous pathogenic oculocutaneous albinism OCA2 gene mutation, conferring carrier status. To the best of our knowledge, this is the first reported case of typical ocular phenotype of albinism, specifically nystagmus, in a patient who is carrier for oculo-cutaneous albinism. Further research is required to expand the genotype-phenotype relationship in carriers of oculocutaneous albinism. [Ophthalmic Surg Lasers Imaging Retina 2024;55:349-353.].

Crossed VEP asymmetry in a patient with AHR-linked infantile nystagmus and foveal hypoplasia.

INTRODUCTION: Infantile nystagmus and foveal hypoplasia associated with AHR gene defects is a newly recognized and rare disorder. Our aim was to present a patient with a novel biallelic AHR pathogenic variant with electrophysiological evidence of chiasmal misrouting. MATERIALS AND METHODS: Complete ocular examination, fundus imaging, visual evoked potentials (VEP) and full-field electroretinography were performed at initial presentation. Genetic testing was performed by whole exome sequencing. RESULTS: Female patient of 6 years old presented a reduced best corrected visual acuity, an infantile nystagmus and a grade III typical foveal hypoplasia without ocular hypopigmentation. A crossed asymmetry was discovered on pattern onset/offset VEP. Genetic testing put in evidence a novel homozygous variant in AHR: c.2242del, p. (Gln748Lysfs*5). During 11-years follow-up period, BCVA gradually improved. There was no evidence of retinal degeneration. CONCLUSION: AHR gene defects could be associated with infantile nystagmus, foveal hypoplasia and chiasmal misrouting.

Genetic Characteristics and Clinical Manifestations of Foveal Hypoplasia in Familial Exudative Vitreoretinopathy.

PURPOSE: This study aimed to ascertain the occurrence of foveal hypoplasia (FH) in individuals diagnosed with familial exudative vitreoretinopathy (FEVR). DESIGN: Retrospective cohort study. METHODS: In this study, FEVR families and sporadic cases were diagnosed at the Eye and ENT Hospital, Fudan University, between 2017 and 2023. All patients attended routine ophthalmologic examinations and genetic screenings. The classification of FH was determined using optical coherence tomography (OCT) scans. The FH condition was classified into 2 subgroups: group A (FH being limited to the inner layers) and group B (FH affecting the outer layers). A total of 102 eyes from 58 patients were suitable for analysis. RESULTS: Forty-nine mutations in LRP5, FZD4, NDP, TSPAN12, KIF11, CTNNB1, and ZNF408 were examined and detected, with 26 of them being novel. Forty-seven eyes (46.1%) revealed FH. The majority (53.2%) were due to the typical grade 1 FH. Patients with mutations in LRP5 and KIF11 were found to exhibit a higher prevalence of FH (P = .0088). Group B displayed the lowest visual acuity compared with group A (P = .048) and the group without FH (P < .001). The retinal arteriolar angle in group B was significantly smaller than in group A (P = .001) and those without FH (P < .001). CONCLUSIONS: This study offers a new diagnostic approach and expands the spectrum of FEVR mutations. LRP5 and KIF11 were found to be more susceptible to causing FH in patients with FEVR. FEVR eyes with FH exhibited both greater visual impairment and reduced retinal arteriolar angles. The assessment of foveal status in patients with FEVR should be valued.

Nystagmus Characteristics in Albinism: Unveiling the Link to Foveal Hypoplasia and Visual Acuity.

Purpose: The purpose of this study was to describe the association among nystagmus characteristics, foveal hypoplasia, and visual acuity in patients with albinism. Methods: We studied nystagmus recordings of 50 patients with albinism. The nystagmus waveform was decomposed into two types: dominantly pendular and dominantly jerk. We correlated the nystagmus type, amplitude, frequency, and percentage of low velocity (PLOV) to Snellen visual acuity and foveal hypoplasia grades. Results: The grade of foveal hypoplasia and visual acuity showed a strong correlation (r = 0.87, P < 0.0001). Nystagmus type and PLOV had the strongest significant (P < 0.0001) correlation with visual acuity (r = 0.70 and r = -0.56, respectively) and with foveal hypoplasia (r = 0.76 and r = -0.60, respectively). Patients with pendular nystagmus type had the lowest PLOV, and the highest grade of foveal hypoplasia (P < 0.0001). Severe foveal hypoplasia (grade 4), was almost invariably associated with pendular nystagmus (86%). Conclusions: Foveal hypoplasia grade 4 is associated with pendular nystagmus, lower PLOV, and worse visual acuity. Based on these results, nystagmus recordings at a young age may contribute to predicting visual outcomes.

Foveal hypoplasia in parents of patients with albinism.

BACKGROUND: Albinism is a group of genetic disorders characterized by general skin and retinal hypopigmentation. It is in most cases an autosomal recessive condition. Foveal hypoplasia (FH) is one of the main criteria for the diagnosis of albinism. The aim of this study was to analyze the macular profile of the parents of patients with albinism. METHODS: This study included a case series of 27 patients with albinism seen in Rothschild Foundation between April 2017 and February 2020. Spectral-domain optical coherence tomography (SD-OCT) and OCT angiography (OCT-A) were performed in every patient when possible and in every available parents. FH was graded according to Thomas' classification based on OCT. Next generation sequencing-based gene panel testing was performed in parents and children when a FH was detected on OCT in a parent. RESULTS: Twenty-seven patients with albinism were examined. Nine parents had FH based on the OCT B-scan (33%). In parents without FH based on the SD-OCT B-scan (67%), OCT-A showed a reduced avascular zone in the deep vascular plexus in 4 parents. Six parents carried variants that could explain their phenotype, including TYR R402Q hypomorphic alleles. CONCLUSION: This study showed the presence of FH in parents of patients with albinism, and aimed to genetically explain this phenotype.

Expanding the Spectrum of Oculocutaneous Albinism: Does Isolated Foveal Hypoplasia Really Exist?

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.

Novel biallelic AHR splice site mutation cause isolated foveal hypoplasia in Saudi patient: a case report.

CASE DESCRIPTION: A 12-year-old boy with a history of decreased vision and photophobia since he was 1 year old. Comprehensive clinical and molecular approaches were applied to evaluate his condition by which a detailed ophthalmological examination revealed bilateral isolated foveal hypoplasia with the absence of the avascular zone. Novel homozygous aryl hydrocarbon receptor (AHR) splice site mutation NM_001621.4: c.899_908 + 15del (p.?) was identified and segregated within the family members. CONCLUSION: This case represents the first report of autosomal recessive isolated foveal hypoplasia without infantile nystagmus in the literature and the second reported AHR mutation with autosomal recessive isolated foveal hypoplasia post the original cloning paper. Our identified novel splice site AHR mutation supports the pathogenicity of the AHR gene and expands its phenotypic spectrum.

Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study.

PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

The Phenotypic and Mutational Spectrum of the FHONDA Syndrome and Oculocutaneous Albinism: Similarities and Differences.

Purpose: The purpose of this study was to further expand the mutational spectrum of the Foveal Hypoplasia, Optic Nerve Decussation defect, and Anterior segment abnormalities (FHONDA syndrome), to describe the phenotypic spectrum, and to compare it to albinism. Subjects and Methods: We retrospectively collected molecular, ophthalmic, and electrophysiological data of 28 patients molecularly confirmed with FHONDA from the Netherlands (9), Israel (13), France (2), and the United States of America (4). We compared the data to that of 133 Dutch patients with the 3 most common types of albinism in the Netherlands: oculocutaneous albinism type 1 (49), type 2 (41), and ocular albinism (43). Results: Patients with FHONDA had a total of 15 different mutations in SLC38A8, of which 6 were novel. Excluding missing data, all patients had moderate to severe visual impairment (median visual acuity [VA] = 0.7 logMAR, interquartile range [IQR] = 0.6-0.8), nystagmus (28/28), and grade 4 foveal hypoplasia (17/17). Misrouting was present in all nine tested patients. None of the patients had any signs of hypopigmentation of skin and hair. VA in albinism was better (median = 0.5 logMAR, IQR = 0.3-0.7, P 0.006) and the phenotypes were more variable: 14 of 132 without nystagmus, foveal hypoplasia grades 1 to 4, and misrouting absent in 16 of 74. Conclusions: Compared to albinism, the FHONDA syndrome appears to have a more narrow phenotypic spectrum, consisting of nonprogressive moderately to severely reduced VA, nystagmus, severe foveal hypoplasia, and misrouting. The co-occurrence of nystagmus, foveal hypoplasia, and misrouting in the absence of hypopigmentation implies that these abnormalities are not caused by lack of melanin, which has important implications for understanding the pathogenesis of these features.

Association of Birth Weight With Foveolar Thickness in Adulthood: Results From a Population-Based Study.

Purpose: Low birth weight (BW) is associated with alterations of foveal shape development in childhood-leading to an increased retinal thickness of the fovea. The aim of the present study was to assess whether BW has a long-term effect on foveal retinal thickness (RT) and is still present in adulthood. Methods: In the German population-based Gutenberg Health Study (GHS), participants were examined with spectral-domain optical coherence tomography. The association between self-reported BW and RT in the foveolar and perifoveal locations was assessed. Multivariable linear regression analyses with adjustment for potential confounders and grading of foveal hypoplasia were performed. Results: Overall, RT measurements and self-reported BW were available for 2,539 participants (1300 female, mean age 54.5 ± 9.7 years). The absolute foveolar RT was 239.6 ± 25.8 µm, 232.2 ± 20.1 µm and 234.8 ± 21.0 µm, respectively, in the low (<2500 g), normal (2500-4000 g) and high (>4000 g) BW groups (P < 0.001). After adjustment for confounders, an association was observed between lower BW and increased foveolar thickness (B = -0.35 [95% confidence interval {CI}: -0.49; -0.20] µm/100 g; P < 0.001), whereas only a weak association with RT was observed with the nasal (P = 0.010), temporal (P = 0.011), and inferior (P = 0.021) quadrants in the 1 mm distance, with no association in the 2 mm distance to the fovea. Foveal hypoplasia grade 1 was more frequent in the low BW group (6.8%) compared to the normal (0.9%) and high BW group (1.2%). Conclusions: This study provides evidence of an association between lower BW and increased foveolar thickness and foveal hypoplasia, indicating that prenatal growth may affect macular morphology, which in turn may persist until adulthood and predispose to retinal disease later in life.

Genotype-Phenotype of Isolated Foveal Hypoplasia in a Large Cohort: Minor Iris Changes as an Indicator of PAX6 Involvement.

Purpose: Foveal hypoplasia (FVH) is defined as the lack of fovea with a relatively preserved neuroretina, occurring either as an isolated FVH (IFVH) condition or associated with other diseases. This study aimed to systemically molecularly characterize IFVH. Methods: Genetic defects in 33 families with IFVH were analyzed by exome sequencing. Variants in three genes (PAX6, SLC38A8, and AHR) were selected and evaluated with multistep bioinformatic tools. Results: Mutations in the three genes were identified in 69.7% (23/33) of families with IFVH and infantile nystagmus, including 18 families with PAX6 mutations, 5 with SLC38A8 mutations, but none with AHR mutations. Clinical data from 32 patients in the 23 families showed FVH, infantile nystagmus, and full iris. Careful follow-up visits revealed subtle changes in iris in 9 of 14 patients with PAX6 variants. The PAX6 variants of the 18 families (15 missense and one stop-loss) were mostly located in the C-terminal region of the paired box domain. Variants in AHR, SLC38A8, and PAX6 contributed to IFVH in one (2%), 25 (45%), and 30 (53%) families with identified genetic defects (23 families in this study and 33 reported previously), respectively. Conclusions: PAX6 and SLC38A8 mutations are the main cause of IFVH based on our data and a systematic review. IFVH-associated PAX6 variants are mostly missense with a specific location, indicating a specific correlation of these variants with IFVH but not with typical aniridia. Full iris with subtle structural abnormalities is more common in patients with PAX6-associated IFVH, suggesting a potential diagnostic indicator.

Blue Cone Monochromatism with Foveal Hypoplasia Caused by the Concomitant Effect of Variants in OPN1LW/OPN1MW and GPR143 Genes.

Blue cone monochromatism (BCM) is an X-linked recessive cone dysfunction disorder caused by mutations in the OPN1LW/OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength-sensitive cone opsins. Here, we report on the unusual clinical presentation of BCM caused by a novel mutation in the OPN1LW gene in a young man. We describe in detail the phenotype of the proband, and the subclinical morpho-functional anomalies shown by his carrier mother. At a clinical level, the extensive functional evaluation demonstrated in the proband the M/L cone affection and the sparing of S-cone function, distinctive findings of BCM. Interestingly, spectral-domain optical coherence tomography showed the presence of foveal hypoplasia with focal irregularities of the ellipsoid layer in the foveal area, reported to be associated with some cases of cone-rod dystrophy and achromatopsia. At a molecular level, we identified the novel mutation c.427T > C p.(Ser143Pro) in the OPN1LW gene and the common missense mutation c.607T > C (p.Cys203Arg) in the OPN1MW gene. In addition, we discovered the c.768-2_769delAGTT splicing variant in the GPR143 gene. To our knowledge, this is the first case of foveal hypoplasia in a BCM patient and of mild clinical affection in a female carrier caused by the concomitant effect of variants in OPN1LW/OPN1MW and GPR143 genes, thus as the result of the simultaneous action of two independent genetic defects.

Longitudinal genotype-phenotype analysis in 86 patients with PAX6-related aniridia.

Aniridia is most commonly caused by haploinsufficiency of the PAX6 gene, characterized by variable iris and foveal hypoplasia, nystagmus, cataracts, glaucoma, and aniridia-related keratopathy (ARK). Genotype-phenotype correlations have previously been described; however, detailed longitudinal studies of aniridia are less commonly reported. We identified 86 patients from 62 unrelated families with molecularly confirmed heterozygous PAX6 variants from a UK-based single-center ocular genetics service. They were categorized into mutation groups, and a retrospective review of clinical characteristics (ocular and systemic) from baseline to most recent was recorded. One hundred and seventy-two eyes were evaluated, with a mean follow-up period of 16.3 ± 12.7 years. Nystagmus was recorded in 87.2% of the eyes, and foveal hypoplasia was found in 75%. Cataracts were diagnosed in 70.3%, glaucoma in 20.6%, and ARK in 68.6% of eyes. Prevalence, age of diagnosis and surgical intervention, and need for surgical intervention varied among mutation groups. Overall, the missense mutation subgroup had the mildest phenotype, and surgically naive eyes maintained better visual acuity. Systemic evaluation identified type 2 diabetes in 12.8% of the study group, which is twice the UK prevalence. This is the largest longitudinal study of aniridia in the UK, and as such, it can provide insights into prognostic indicators for patients and guiding clinical management of both ocular and systemic features.

Homozygous single nucleotide duplication of SLC38A8 in autosomal recessive foveal hypoplasia: The first Japanese case report.

PURPOSE: To characterize the clinical and genetic features of a Japanese male patient with foveal hypoplasia caused by a homozygous single nucleotide duplication in the SLC38A8 gene. METHODS: We performed a comprehensive ophthalmic examination including full-field electroretinography (FF-ERG) and pattern-reversal visual evoked potentials (PR-VEPs). Whole-exome sequencing (WES) was performed to identify the disease-causing variant; Sanger sequencing was used for confirmation. RESULTS: In the WES analysis, a homozygous single nucleotide duplication (c.995dupG; p.Trp333MetfsTer35) was identified in SLC38A8 of the patient. His unaffected mother carried the variant heterozygously. The patient exhibited hyperopia, congenital nystagmus, low visual acuity, and grade 4 foveal hypoplasia. Slit-lamp examination revealed mild posterior embryotoxon and goniodysgenesis. Fundus examination revealed the absence of foveal hyperpigmentation and foveal avascularity, but there were no retinal degenerative lesions. In the FF-ERG, the amplitudes of rod ERG, standard-flash, and bright-flash ERG were within the normal range; cone-mediated responses also showed nearly normal amplitudes. The PR-VEP findings revealed delayed P100 latencies and decreased amplitudes of the P100 components, but no chiasmal misrouting. CONCLUSIONS: This report is the first report on the clinical and genetic characteristics of SLC38A8-associated foveal hypoplasia in the Japanese population. This is also the first report of normal rod- and cone-mediated responses in a patient with this disorder.

Genetic causes of nystagmus, foveal hypoplasia and subnormal visual acuity- other than albinism.

Background: To describe genetic molecular findings in individuals with congenital nystagmus, foveal hypoplasia, and subnormal vision, with normal ocular pigmentation (absence of diffuse transillumination or transparent retinal pigment typical for albinism).Methods: This is a retrospective, multicenter study of ophthalmic, systemic, and genetic features, as collected from medical records of patients diagnosed with infantile nystagmus and foveal hypoplasia. Ophthalmic findings include best-corrected visual acuity (BCVA), biomicroscopic examination, cycloplegic refraction, retinal examination, macular optical coherence tomography, and electroretinography. Genetic information was retrieved from the participating genetic clinics and included ethnicity and molecular diagnosis.Results: Thirty-one individuals met the inclusion criteria and had a secure molecular diagnosis. Mutations in two genes predominated, constituting 77.4% of all the represented genes: SLC38A8 (45.1%) and PAX6 (32.3%). Seventy-eight percent of the subjects who had a measurable BCVA had moderate and severe visual impairment (range 20/80 to 20/270). Most patients with a mutation in SLC38A8 had mild to moderate astigmatism, while most patients with PAX6 mutation had moderate and severe myopia. Patients in the PAX6 group had variable degrees of anterior segment manifestations.Conclusion: In our cohort, the main causative genes for congenital nystagmus and foveal hypoplasia in normally pigmented eyes were SLC38A8 and PAX6. A mild phenotype in PAX6 mutations may be an under-diagnosed cause of nystagmus and foveal hypoplasia. Reaching an accurate genetic diagnosis is essential for both the patients and their family members. This enables predicting disease prognosis, tailoring correct follow-up, and providing genetic counseling and family planning to affected families.

PAX6 missense variants in two families with isolated foveal hypoplasia and nystagmus: evidence of paternal postzygotic mosaicism.

PAX6 is considered the master regulator of eye development, the majority of variants affecting this gene cause the pan-ocular developmental eye disorder aniridia. Although no genotype-phenotype correlations are clearly established, missense variants affecting the DNA-binding paired domain of PAX6 are usually associated with non-aniridia phenotypes like microphthalmia, coloboma or isolated foveal hypoplasia. In this study, we report two missense heterozygous variants in the paired domain of PAX6 resulting in isolated foveal hypoplasia with nystagmus in two independent families: c.112 C > G; p.(Arg38Gly) and c.214 G > C; p.(Gly72Arg) in exons 5 and 6, respectively. Furthermore, we provide evidence that paternal postzygotic mosaicism is the cause of inheritance, with clinically unaffected fathers and reduced affected allele fraction. This work contributes to increase the phenotypic spectrum caused by PAX6 variants, and to our knowledge, is the first report to describe the presence of postzygotic parental mosaicism causing isolated foveal hypoplasia with nystagmus. These results support the growing evidence that suggest an overestimation of sporadic cases with PAX6 variants, which has strong implications for both genetic counselling and family planning.