Ocular albinism (OA1) is a rare X-linked recessive disorder caused by alterations of the GPR143 gene. Typically, only males are classically affected, whereas heterozygous carrier females are not clinically affected due to random X chromosome inactivation. We report two cases of female patients presenting with clinical features typical of OA1, caused in one case by the presence of a homozygous pathogenic variant in a consanguineous context, and in the other case by X-inactivation bias, with the heterozygous pathogenic variant – bearing chromosome being active in nearly 100% of cells. The phenotype of these two female patients is undistinguishable from that of males with OA1. These data indicate that ocular albinism caused by loss of function of the GPR143 gene must not be overlooked in female patients.

Abnormal expansion of nucleotide repeats was first identified 34 years ago as a unique mutational mechanism. It is now linked to numerous neurogenetic disorders, several of which discovered only recently. The identification of these expansions has led to various classifications based on clinical presentation, repeat nature and genomic location (coding or non-coding regions). Precise diagnosis of these conditions relies on molecular testing, currently performed on a gene-by-gene basis. Their analysis remains challenging, especially for long expansions. We evaluated CRISPR-Cas9-mediated target enrichment coupled to Oxford Nanopore Technologies (ONT) long read sequencing, to accelerate and improve the time-consuming molecular diagnosis of repeat expansion disorders. We simultaneously targeted nine loci involved in 10 repeat expansion disorders in a single capture panel, including FMR1, HTT, DMPK, CNBP/ZNF9, ATXN2, JPH3, FXN, C9ORF72 and RFC1, covering a broad range of repeat types, sizes and diagnostic needs. Results were compared with standard routine testing methods. ONT sequencing using Flongle flow cells yielded results consistent with standard techniques for most loci, particularly for non-complex repeats. However, limitations were observed for structurally complex regions such as RFC1, and inter-run variability required the aggregation of multiple Flongle runs per sample to achieve robust genotyping. These findings highlight both the potential and current limitations of CRISPR-Cas9-enriched ONT sequencing for multiplex diagnosis of repeat expansion disorders in a clinical setting. The approach deserves further development, particularly optimisation of protocols, inclusion of larger sample sizes, and comparison with alternative technologies.

Albinism is characterized by generalized hypopigmentation and ocular features resulting from impaired melanin biosynthesis. Most known pathogenic variants are rare (MAF < 0.001) and found in coding regions. The role of non-coding variants, especially those with higher allele frequencies, is generally not investigated. Our next generation sequencing panel that includes the entire sequence of five major albinism genes (TYR, OCA2, SLC45A2, GPR143 and HPS1) identified compound OCA2 heterozygosity in a patient with a rare (MAF:0,0003) coding variant, NM_000275.3:c.1025 A > G;p.(Tyr342Cys) and a more common intronic variant, NM_000275.3:c.574-19 A > G (MAF:0,0087, with 80 homozygotes in the control population GnomADv4.1.0). In silico prediction tools indicated that this intronic variant could alter splicing. RT-PCR analysis on RNA extracted from the patient's blood revealed the skipping of exons 6 and 7, which resulted in the in-frame deletion of 78 amino acids. Protein modelling suggested that this deletion disrupts the GOLD-like domain and leads to the loss of conserved N-glycosylation sites, likely impairing protein folding and intracellular trafficking. These findings provided strong evidence for a deleterious effect on OCA2 function. Therefore, the variant was classified as likely pathogenic, allowing to establish the diagnosis in the patient. The relatively high allele frequency of this variant suggests that it behaves as a hypomorphic allele leading to disease in a compound heterozygous state. This underscores that intronic variants outside the canonical splice sites must be taken in consideration and functionally tested, and that common variants should not be systematically discarded in the diagnosis of albinism, and, similarly, of other rare diseases.

Oculocutaneous albinism type 1 (OCA1) caused by pathogenic variants of the TYR gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in skin, hair, and eyes. We had the opportunity to examine five East Cameroon Baka rainforest hunter-gatherers (historically called "Pygmies") with albinism and belonging to three different families. Screening of known albinism genes revealed a homozygous missense variant in the TYR gene, NM_000372.5: c.1109T>C; p.Met370Thr. In addition, one patient was also hemizygous for a variant in GPR143, the gene involved in ocular albinism (OA1). Another patient was also heterozygous for the common African and Afro-American 2.7-kb deletion in the OCA2 gene indicating admixture of one parent with neighboring Nzimé Bantu-speaking farmers. This is the first report of the occurrence of OCA1 in African rainforest hunter-gatherers.

BACKGROUND:Albinism, a group of rare genetic conditions characterized by visual impairment and variable hypopigmentation, is extensively studied in biomedical research. However, the psychosocial aspects, particularly in France, remain under-investigated, contributing to the invisibility of this sensory disability. OBJECTIVES:The ALBIPSY project aimed to explore the lived experience of persons with albinism (PWAs) and their significant others (SOs), and to examine the role of dyadic adjustment in maintaining their quality of life. METHODS AND SETTINGS:This study employed a sequential mixed-methods design, beginning with an exploratory qualitative phase involving nine dyads (PWAs and one of their parents), followed by a correlational quantitative study covering the entire sample (N = 38 dyads). RESULTS:Qualitative results highlighted several critical themes, including the perception of albinism (as a disease or not), perceived difficulties, resources and facilitators, and the crucial role of the dyadic relationship in adaptation. Intriguingly, enhanced adaptive capacities sometimes co-existed with a significant, high subjective burden associated with albinism. Counter-intuitively, quantitative data suggested that higher levels of dyadic coping were associated with increased anxiety in PWA. This finding warrants further reflection on the influence of ableist norms, transmitted parental values, and the perception of albinism as an illness. CONCLUSION:This paper reviews the main findings and underscores the necessity of a multidisciplinary approach sensitive to the relational dynamics and specific needs of PWA and their partners.

The molecular diagnosis of albinism is hampered by a significant number of genetic variants of unknown significance (VUS) including a majority of missense and in-frame insertion deletion variants. This contributes to the high rate of unresolved genetic diagnosis for this disease. We designed a straightforward test of missense VUS in albinism genes based on functional rescue. As a proof of concept, the assay was set up for testing variants in the TYR gene associated with oculocutaneous albinism type 1. The TYR gene was knocked-out in the human melanogenic MNT1 cell line and the resulting unpigmented clones used as host cells for rescue experiments. Selected VUS and control sequences were run through the assay. Expression of tyrosinase was quantified by Western blot, melanin synthesis was evaluated by direct observation as well as absorbance monitoring. One VUS, p.Ser270Phe (S270F) can be classified as likely pathogenic as it fails to restore pigmentation, whereas rescue was achieved with D305E and A391T. The two most frequent missense VUS of TYR, S192Y and R402Q, were also tested independently or in combination confirming the pathogenic effect of their association in cis. All in all, this new assay is a proof of concept and can be considered for testing variants in other albinism genes such as TYRP1 and SLC45A2.

Although it has been described for a long time, albinism remains poorly understood in many aspects. The clinical presentation is very different between subtypes of the disease and even within a single subtype. The monogenic nature of the disease is increasingly questioned. What are the functions of the proteins encoded by the genes involved in the disease and what are the pathophysiological consequences of their alteration? What is the link between defective melanogenesis and dysfunction of the neural retina? This review relates to the most recent advances in the field of albinism. As it is not possible to cover all aspects of the disease in an exhaustive way, we focus here on a selection of aspects that seem most relevant to understanding the disease and for patients’ caretaking. These are: epidemiology, genetics, clinical characterization, cell biology and pathophysiology, psycho-sociology, therapeutic education, and therapeutic approaches.

IntroductionThere is few data that investigate the genetic underpinnings of idiopathic foveal hypoplasia and assess its potential overlap with albinism-related gene variants in a cohort devoid of familial albinism history.MethodsThis cross-sectional study included 19 participants diagnosed with idiopathic foveal hypoplasia, confirmed via optical coherence tomography (OCT). We detailed ophthalmic evaluations and genotyping using a panel of 33 genes related to foveal hypoplasia.ResultsOf the 19 participants, 2 (10%) exhibited heterozygous pathogenic variants in genes typically associated with albinism (TYR and OCA2). Eyes from participants with variants had statistically significant lower central macula thickness than those without.DiscussionThe study reveals some albinism-associated variants among participants with idiopathic foveal hypoplasia, suggesting a possible genetic basis for this condition in a subset of cases

The major spliceosome contains five small nuclear RNAs (snRNAs; U1, U2, U4, U5 and U6) essential for splicing. Variants in RNU4-2, encoding U4, cause a neurodevelopmental disorder called ReNU syndrome. We investigated de novo variants in 50 snRNA-encoding genes in a French cohort of 23,649 individuals with rare disorders and gathered additional cases through international collaborations. Altogether, we identified 145 previously unreported probands with (likely) pathogenic variants in RNU4-2 and 21 individuals with de novo and/or recurrent variants in RNU5B-1 and RNU5A-1, encoding U5. Pathogenic variants typically arose de novo on the maternal allele and cluster in regions critical for splicing. RNU4-2 variants mainly localize to two structures, the stem III and T-loop/quasi-pseudoknot, which position the U6 ACAGAGA box for 5' splice site recognition and associate with different phenotypic severity. RNU4-2 variants result in specific defects in alternative 5' splice site usage and methylation patterns (episignatures) that correlate with variant location and clinical severity. This study establishes RNU5B-1 as a neurodevelopmental disorder gene, suggests RNU5A-1 as a strong candidate and highlights the role of de novo variants in snRNAs.

Albinism classically encompasses several forms: oculocutaneous (OCA), ocular (OA1 and Foveal hypoplasia optic nerve decussation defect anterior segment dysgenesis syndrome [FHONDA]), and syndromic (Hermansky-Pudlak syndrome [HPS], Chediak-Higashi syndrome [CHS]), with all being autosomal recessive except X-linked recessive OA1. Twenty-one genes are identified to date, with OCA1 being most common in Europeans or patients of European descent and OCA2 in Sub-Saharan Africans. Their sequencing provides a diagnostic rate of ∼70%, though unresolved cases may arise from variants in poorly explored non-coding regions, undetected genes, or differential diagnoses. The cellular and molecular mechanisms underlying non-syndromic forms of albinism affect the ability of pigment cells to synthesize melanin pigments in melanosomes, mainly through defects in melanogenic enzymes, or in ion channels or transporters affecting melanosome pH regulation. In contrast, syndromic forms of albinism (e.g., HPS subtypes) are membrane trafficking disorders caused by mutations in multi-subunit protein complexes (e.g., BLOC1, BLOC2, BLOC3, or AP-3) targeting the formations and functions of certain lysosome-related organelles (LROs), of which the melanosome is a prototypical member. Integrating clinical, genetic and fundamental research is essential for a comprehensive understanding of albinism, from patient manifestations to identifying molecular targets and elucidating their cell and tissue-specific functions, ultimately paving the way for improved diagnostics and therapeutic strategies.

Pigmentation is orchestrated by hundreds of genes involved in cellular functions going from early developmental fate of pigment cells to melanin synthesis. The Two Pore Channel 2 (TPC2) a Ca2+ and Na+ channel acidifies melanosomal pH and thus inhibits pigmentation. A young patient was recently reported with generalized hypopigmentation but uneventful ocular examination, caused by the de novo heterozygous TPCN2 variant c.628C>T;p.Arg210Cys that constitutively activates TPC2. Here we report a young patient with the same de novo variant presenting with generalized hypopigmentation, and ophthalmologic features including low grade retinal hypopigmentation and foveal hypoplasia, photophobia, mild hypermetropia, and astigmatism, which are features of albinism. Skin fragility and episodes of fever with diarrhea and fatigue were also observed. This extends the phenotype of patients with TPCN2 variants, warranting further investigations in patients with alterations of this gene, and raises the question whether TPCN2 might be considered as an albinism gene.

Pathogenic variants in the OCA2 gene result in oculocutaneous albinism. In humans and several other mammalian species, OCA2 is transcribed into two coding mRNAs, a major transcript that encodes the full-length protein and a minor transcript that skips in-frame exon 10 and has no identified function. By contrast, rodents and non-mammalian vertebrates only express the major transcript. Several rare variants of human OCA2 have been reported to be pathogenic due to increased exon 10 skipping. To understand the vulnerability of human OCA2 to exon 10 skipping and its impact on pigmentation, we first functionally tested a series of rare missense variants spread across exon 10. We found that each variant significantly influences the skipping ratio either positively or negatively. By combining human and murine sequences in functional assays, we found that the skipping ratio depends on particular exonic and intronic combinations. Next, we focused on the most frequent exonic single nucleotide variant of human OCA2, rs1800404-T (c.1065G > A/p.Ala355=), located in exon 10. We show that this variant significantly promotes exon 10 skipping on its own and exhibits an additive effect in cis to previously identified splicing variants likely contributing to their pathogenicity. Association studies reveal that rs1800404-T is tightly associated with lighter skin and hair pigmentation in a representative European population, as has been observed in other populations around the world. Our structural models of the skipped transcript-derived protein support causality by predicting that it could exert a dominant-negative effect, which is consistent with a dose-dependent hypopigmentation response in both pathological and physiological contexts. Overall, the modulation of OCA2 exon 10 skipping by both benign and pathogenic variants provides a basis for improving the genetic diagnosis of albinism, and paves the way for research into the molecular and evolutionary mechanisms behind human pigmentation diversity.

Serotonin and other tryptophan-derived metabolites are altered in patients with albinism, with a distinct shift towards the serotonin pathway and impaired serotonin degradation. These metabolic disturbances suggest a potential link between tryptophan metabolism and pigmentation defects. Tryptophan profiling may offer novel diagnostic or therapeutic avenues for albinism.

Background FLNA loss of function manifests across a broad spectrum of phenotypes, ranging from severe prenatal onset to asymptomatic cases. Bilateral periventricular nodular heterotopia (BPNH) consistently occurs in affected individuals. This retrospective study involving French patients with BPNH evaluates the prevalence of FLNA gene dosage anomalies and investigates genotype-phenotype correlations in a large cohort of French patients with BPNH.Methods A retrospective observational study was conducted on 391 individuals diagnosed with BPNH confirmed by brain MRI. Sequencing analysis using Sanger or next-generation sequencing was complemented by targeted array-comparative genomic hybridisation to identify copy number variants (CNVs).Results FLNA variants were identified in 40% of females and 12% of males. Among these, 87% were single nucleotide variants (SNVs), while CNVs accounted for 13%, all of which were deletions. Half of the CNVs involved a recurrent deletion spanning exons 31-48, often accompanied by a duplication of the neighbouring EMD gene. This del-dup was associated with a milder phenotype, whereas smaller de novo deletions correlated with severe outcomes. Mosaicism was also detected in three cases.Conclusion FLNA CNV analysis, particularly for recurrent deletions and mosaicism, is essential in the genetic evaluation of BPNH. Integrating CNV detection with SNV analysis improves diagnostic accuracy and enhances understanding of genotype-phenotype correlations.

Background Limited standardized empirical research exists in France on the psychosocial implications of albinism, prompting an investigation into how affected persons adapt to their disabilities. Recent advancements in health psychology have led researchers to adopt a systemic approach, considering disabilities and involving close relatives in the adaptation process. The aim of this study was to explore the mediating role of dyadic coping within family dyads, where one is a person with albinism (PWA) and the other is a close relative. Methods The study included 38 family dyads with each member responding individually to an online standardized protocol. Participants were recruited through convenience sampling, facilitated by a patient association (Genespoir) and professionals from medical referral centers involved in the project. Dyads with a PWA born, raised, or residing in Africa during the study were excluded. Three statistical models based on Actor-Partner Interdependence Mediation Model (APIMeM) were Bayesian-tested using weakly informative priors. Results Models 2 and 3 emerged as the most effective at explaining the data. Model 2 showed the mediating role of common dyadic coping between the quality of the relationship and anxiety level and suggested that PWAs tend to feel more anxious when they report high levels of shared adaptation with their close relative. Model 3 highlighted the role of albinism-related emotional impact in mediating the relationship between stigma consciousness and overall quality of life, but this was observed only among PWAs. Greater consciousness of stigma among PWAs was associated with increased emotional impact, resulting in a more impaired quality of life. Conclusions Social implications of albinism seem to be crucial in dyadic adjustment to albinism. Personal perceptions and the associated stigma (i.e., ableism) linked to albinism may influence the ambivalent manner in which individuals adapt to their condition. Future studies should further investigate these intricate mechanisms, as outlined by our proposed conceptual model.

Pathogenic variants in the Dopachrome tautomerase (DCT) gene (NM_001129889.2) have recently been associated with a novel oculocutaneous albinism (OCA) subgroup, type 8 (OCA8). Here, we report the establishment of an induced pluripotent stem cell (iPSC) line, INMi007-A, derived from the skin fibroblasts of an individual compound heterozygous for two pathogenic variants in DCT, using the non-integrative Sendai virus reprogramming method. This iPSC line harbors a single-nucleotide variant in exon 1 of DCT (c.118T > A; p.(Cys40Ser)) and a 14-bp deletion in exon 9 (c.1406_1419del; p.(Phe469*)). This cell line represents an important tool for studying the pathophysiology of OCA8.

Oculocutaneous albinism type 1 is caused by variants in the TYR ( tyrosinase ) gene. We describe a family with two affected sibs who inherited the pathogenic missense TYR variant c.1146C > A;p.(Asn382Lys) from their mother and a deletion encompassing 65 kilobase pairs of the upstream region of the gene between hg38 coordinates chr11:89110944 and chr11:89175770, from their father. The deletion likely arose by non-homologous recombination since the regions including the two deletion breakpoints share no sequence homology. The deletion contains a single enhancer element that is homologous to a 5 ' Tyr core regulatory element in the mouse. A luciferase reporter assay showed that this element had a positive regulatory activity. This represents to our knowledge the first deletion solely restricted to non-coding upstream sequences of the TYR gene. It is assumed that the deletion down-regulates expression of the TYR gene and is therefore pathogenic, allowing to establish the diagnosis of OCA 1 in the patients. This study underscores the need to extend the search for pathogenic variants to regulatory regions either by whole genome sequencing or by targeted next generation sequencing of a panel including entire genes (exons, introns, flanking sequences) in order to improve the diagnostic rate in patients with albinism.

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.