Genetic variation of TLR3 gene is associated with the outcome of hepatitis b infection in mauritanian patients: case control study.

BACKGROUND: Toll-Like receptors (TLRs) play an important role in the immune response during hepatitis B virus (HBV) infection. In this study, we evaluated the association between two SNP variants (TLR3 rs3775290 and TLR4 rs4986790) and susceptibility to chronic HBV infection in Mauritania. SUBJECTS AND METHODS: A total of 188 subjects were recruited for this study: 102 chronically infected patients and 86 individuals with spontaneously resolved HBV infection who were considered controls. Targeted PCR products were sequenced using Sanger sequencing. RESULTS: We found that TLR3 rs3775290 was significantly more frequent in patients with chronic HBV than in the control population (p = 0.03). However, no association was found between the TLR4 rs3775290 polymorphism and chronic infection. CONCLUSION: Our results suggest that the TLR3 rs3775290 polymorphism may be a risk factor for susceptibility to chronic HBV infection in the Mauritanian population.

Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health.

Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007-2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice.

Novel pathogenic WHRN variant causing hearing loss in a moroccan family.

OBJECTIVES: The most prevalent sensory disease in humans is deafness. A variety of genes have been linked to hearing loss, which can either be isolated (non-syndromic) or associated with lesions in other organs (syndromic). It has been discovered that WHRN variants are responsible for non-syndromic hearing loss and Usher syndrome type II. METHODS AND RESULTS: Exome sequencing in a consanguineous Moroccan patient with severe hearing loss identified a single homozygous mutation c.619G > T; p.Ala207Ser in WHRN, encoding a cytoskeletal scaffold protein that binds membrane protein complexes to the cytoskeleton in ocular photoreceptors and ear hair cell stereocilia. Bioinformatics methods and molecular dynamic modeling were able to predict the pathogenic implications of this variation. CONCLUSION: We used whole exome sequencing to find a homozygous WHRN gene variant in a Moroccan family. Numerous bioinformatics methods predict that this modification might result in a change in the WHRN protein's structure.

Homozygous Missense Variants in FOXI1 and TMPRSS3 Genes Associated with Non-syndromic Deafness in Moroccan Families.

One of the most prevalent sensorineural disorders, autosomal recessive non-syndromic hearing loss (ARNSHL) which can affect all age groups, from the newborn (congenital) to the elderly (presbycusis). Important etiologic, phenotypic, and genotypic factors can cause deafness. So far, the high genetic variability that explains deafness makes molecular diagnosis challenging. In Morocco, the GJB2 gene is the primary cause of non-syndromic hereditary deafness, while the existence of a variant in the LRTOMT gene is the second cause of this condition. After excluding these two frequently occurring GJB2 and LRTOMT variants, whole-exome sequencing was carried out in two Moroccan consanguineous families with hearing loss. As a result, two novel variants in the TMPRSS3 (c.1078G>A, p. Ala 360Thr) and FOXI1 (c.6C>G, p. Ser 2Arg) genes have been discovered in deaf patients and the pathogenic effect has been anticipated by several bioinformatics and molecular modeling systems. For the first time, these variants are identified in the Moroccan population, showing the population heterogeneity and demonstrating the value of the WES in hearing loss diagnosis.

Single-cell transcriptomic profiling of the mouse cochlea: An atlas for targeted therapies.

Functional molecular characterization of the cochlea has mainly been driven by the deciphering of the genetic architecture of sensorineural deafness. As a result, the search for curative treatments, which are sorely lacking in the hearing field, has become a potentially achievable objective, particularly via cochlear gene and cell therapies. To this end, a complete inventory of cochlear cell types, with an in-depth characterization of their gene expression profiles right up to their final differentiation, is indispensable. We therefore generated a single-cell transcriptomic atlas of the mouse cochlea based on an analysis of more than 120,000 cells on postnatal day 8 (P8), during the prehearing period, P12, corresponding to hearing onset, and P20, when cochlear maturation is almost complete. By combining whole-cell and nuclear transcript analyses with extensive in situ RNA hybridization assays, we characterized the transcriptomic signatures covering nearly all cochlear cell types and developed cell type-specific markers. Three cell types were discovered; two of them contribute to the modiolus which houses the primary auditory neurons and blood vessels, and the third one consists in cells lining the scala vestibuli. The results also shed light on the molecular basis of the tonotopic gradient of the biophysical characteristics of the basilar membrane that critically underlies cochlear passive sound frequency analysis. Finally, overlooked expression of deafness genes in several cochlear cell types was also unveiled. This atlas paves the way for the deciphering of the gene regulatory networks controlling cochlear cell differentiation and maturation, essential for the development of effective targeted treatments.

Deafness: from genetic architecture to gene therapy.

Progress in deciphering the genetic architecture of human sensorineural hearing impairment (SNHI) or loss, and multidisciplinary studies of mouse models, have led to the elucidation of the molecular mechanisms underlying auditory system function, primarily in the cochlea, the mammalian hearing organ. These studies have provided unparalleled insights into the pathophysiological processes involved in SNHI, paving the way for the development of inner-ear gene therapy based on gene replacement, gene augmentation or gene editing. The application of these approaches in preclinical studies over the past decade has highlighted key translational opportunities and challenges for achieving effective, safe and sustained inner-ear gene therapy to prevent or cure monogenic forms of SNHI and associated balance disorders.

Identification a novel pathogenic LRTOMT mutation in Mauritanian families with nonsyndromic deafness.

PURPOSE: Although recessive mutations in GJB2 are the common genetic etiology of sensorineural hearing impairment (SNHI), variants in LRTOMT gene were also identified, mostly in Middle East and North African populations. METHODS: Using Sanger sequencing we screened the exon 7 of LRTOMT in a cohort of 128 unrelated Mauritanian children with congenital deafness. RESULTS: Only one biallelic missense mutation, predicted as pathogenic (c.179 T > C;p.Leu60Pro) was found at homozygous state in four families. This variant, not reported before, showed a deleterious effect by SIFT (score: 0.01) and a disease-causing effect by Mutation Taster (prob: 1). Exploration of the encoded protein 3D structure revealed a disruption from an organized α helix (in the normal protein structure) into a random conformation. Early fitting of a cochlear implant seemed to improve the audition ability of the mutation carrier. CONCLUSION: Further screening using a panel of deafness genes may expose other variants underlying hearing impairment in our population.

Screening of BRCA1/2 variants in Mauritanian breast cancer patients.

BACKGROUND AND STUDY AIM: Carrying a pathogenic BRCA1/2 variant increases greatly young women's risk of developing breast cancer (BC). This study aimed to provide the first genetic data on BC in Mauritania. METHODS: Using NGS based screening; we searched for BRCA1/2 variants in DNA samples from 137 patients diagnosed for hereditary BC. RESULTS: We identified 16 pathogenic or likely pathogenic (PV) variants carried by 38 patients. Two predominant BRCA1 PV variants were found: c.815_824dup and c.4986 + 6 T > C in 13 and 7 patients, respectively. Interestingly, three novels BRCA1/2 predicted pathogenic variants have also been detected. Notably, no specific distribution of BRCA1/2 variants was observed regarding triple negative breast cancer (TNBC) or patient gender status. CONCLUSIONS: In this first genetic profiling of BC in Mauritania, we identified a substantial number of BRCA1/2 pathogenic variants. This finding could be important in the future diagnosis and prevention policy of hereditary BC in Mauritania.

Retinal Phenotype of Patients with CLRN1-Associated Usher 3A Syndrome in French Light4Deaf Cohort.

Purpose: Biallelic variants in CLRN1 are responsible for Usher syndrome 3A and non-syndromic rod-cone dystrophy (RCD). Retinal findings in Usher syndrome 3A have not been well defined. We report the detailed phenotypic description of RCD associated with CLRN1 variants in a prospective cohort. Methods: Patients were clinically investigated at the National Reference Center for rare ocular diseases at the Quinze-Vingts Hospital, Paris, France. Best-corrected visual acuity (BCVA) tests, Goldmann perimetry, full-field electroretinography (ffERG), retinal photography, near-infrared reflectance, short-wavelength and near-infrared autofluorescence, and optical coherence tomography (OCT) were performed for all patients. Results: Four patients from four unrelated families were recruited. Mean follow-up was 11 years for three patients, and only baseline data were available for one subject. Median BCVA at baseline was 0.2 logMAR (range, 0.3-0). ffERG responses were undetectable in all subjects. The III4e isopter of the Goldmann visual field was constricted to 10°. The retinal phenotype was consistent in all patients: small whitish granular atrophic areas were organized in a network pattern around the macula and in the midperiphery. OCT showed intraretinal microcysts in all patients. Upon follow-up, all patients experienced a progressive BCVA loss and further visual field constriction. Four distinct pathogenic variants were identified in our patients: two missense (c.144T>G, p.(Asn48Lys) and c.368C>A, p.(Ala123Asp)) and two frameshift variants (c.176del, p.(Gly59Valfs*13) and c.230dup, p.(Ala78Serfs*52)). Conclusions: RCD in Usher 3A syndrome has some distinctive features. It is a severe photoreceptor dystrophy with whitish granular posterior pole appearance and cystic maculopathy.

Genetic heterogeneity in GJB2, COL4A3, ATP6V1B1 and EDNRB variants detected among hearing impaired families in Morocco.

BACKGROUND: Deafness is the most prevalent human sensorineural defect. It may occur as a result of an external auditory canal involvement, or a deficiency in the sound conduction mechanism, or an impairment of the cochlea, the cochlear nerve or central auditory perception. The genetic causes are the most common, as approximately 70% of hearing disorders are of hereditary origin, divided into two groups, syndromic (associated with other symptoms) and no syndromic (isolated deafness). METHODS: A whole exome sequencing was performed to identify the genetic cause of hearing loss in six Moroccan families and Sanger sequencing was used to validate mutations in these genes. THE RESULTS: The results of four out of the six families revealed four genetic variants in the genes GJB2, COL4A3, ATP6V1B1 and EDNRB responsible for non-syndromic and syndromic hearing loss. Multiple Bioinformatics programs and molecular modelling predicted the pathogenic effect of these mutations. CONCLUSIONS: We identified in Moroccan deaf patients four homozygous mutations. These results show the importance of whole exome sequencing to identify pathogenic mutations in heterogeneous disorders with multiple genes responsible.

Characteristics of Retinitis Pigmentosa Associated with ADGRV1 and Comparison with USH2A in Patients from a Multicentric Usher Syndrome Study Treatrush.

In contrast to USH2A, variants in ADGRV1 are a minor cause of Usher syndrome type 2, and the associated phenotype is less known. The purpose of the study was to characterize the retinal phenotype of 18 ADGRV1 patients (9 male, 9 female; median age 52 years) and compare it with that of 204 USH2A patients (111 male, 93 female; median age 43 years) in terms of nyctalopia onset, best corrected visual acuity (BCVA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) features. There was no statistical difference in the median age at onset (30 and 18 years; Mann-Whitney U test, p = 0.13); the mean age when 50% of the patients reached legal blindness (≥1.0 log MAR) based on visual acuity (64 years for both groups; log-rank, p = 0.3); the risk of developing advanced retinal degeneration (patch or atrophy) with age (multiple logistic regression, p = 0.8); or the frequency of cystoid macular edema (31% vs. 26%, Fisher's exact test, p = 0.4). ADGRV1 and USH2A retinopathy were indistinguishable in all major functional and structural characteristics, suggesting that the loss of function of the corresponding proteins produces similar effects in the retina. The results are important for counseling ADGRV1 patients, who represent the minor patient subgroup.

Alpha-mannosidosis in Tunisian consanguineous families: Potential involvement of variants in GHR and SLC19A3 genes in the variable expressivity of cognitive impairment.

Alpha-Mannosidosis (AM) is an ultra-rare storage disorder caused by a deficiency of lysosomal alpha-mannosidase encoded by the MAN2B1 gene. Clinical presentation of AM includes mental retardation, recurrent infections, hearing loss, dysmorphic features, and motor dysfunctions. AM has never been reported in Tunisia. We report here the clinical and genetic study of six patients from two Tunisian families with AM. The AM diagnosis was confirmed by an enzymatic activity assay. Genetic investigation was conducted by Sanger sequencing of the mutational hotspots for the first family and by ES analysis for the second one. In the first family, a frameshift duplication p.(Ser802GlnfsTer129) was identified in the MAN2B1 gene. For the second family, ES analysis led to the identification of a missense mutation p.(Arg229Trp) in the MAN2B1 gene in four affected family members. The p.(Ser802GlnfsTer129) mutation induces a premature termination codon which may trigger RNA degradation by the NMD system. The decrease in the levels of MAN2B1 synthesis could explain the severe phenotype observed in the index case. According to the literature, the p.(Arg229Trp) missense variant does not have an impact on MAN2B1 maturation and transportation, which correlates with a moderate clinical sub-type. To explain the intra-familial variability of cognitive impairment, exome analysis allowed the identification of two likely pathogenic variants in GHR and SLC19A3 genes potentially associated to cognitive decline. The present study raises awareness about underdiagnosis of AM in the region that deprives patients from accessing adequate care. Indeed, early diagnosis is critical in order to prevent disease progression and to propose enzyme replacement therapy.

Mutated CCDC51 Coding for a Mitochondrial Protein, MITOK Is a Candidate Gene Defect for Autosomal Recessive Rod-Cone Dystrophy.

The purpose of this work was to identify the gene defect underlying a relatively mild rod-cone dystrophy (RCD), lacking disease-causing variants in known genes implicated in inherited retinal disorders (IRD), and provide transcriptomic and immunolocalization data to highlight the best candidate. The DNA of the female patient originating from a consanguineous family revealed no large duplication or deletion, but several large homozygous regions. In one of these, a homozygous frameshift variant, c.244_246delins17 p.(Trp82Valfs*4); predicted to lead to a nonfunctional protein, was identified in CCDC51. CCDC51 encodes the mitochondrial coiled-coil domain containing 51 protein, also called MITOK. MITOK ablation causes mitochondrial dysfunction. Here we show for the first time that CCDC51/MITOK localizes in the retina and more specifically in the inner segments of the photoreceptors, well known to contain mitochondria. Mitochondrial proteins have previously been implicated in IRD, although usually in association with syndromic disease, unlike our present case. Together, our findings add another ultra-rare mutation implicated in non-syndromic IRD, whose pathogenic mechanism in the retina needs to be further elucidated.

Phylogenetic analysis of Harmonin homology domains.

BACKGROUND: Harmonin Homogy Domains (HHD) are recently identified orphan domains of about 70 residues folded in a compact five alpha-helix bundle that proved to be versatile in terms of function, allowing for direct binding to a partner as well as regulating the affinity and specificity of adjacent domains for their own targets. Adding their small size and rather simple fold, HHDs appear as convenient modules to regulate protein-protein interactions in various biological contexts. Surprisingly, only nine HHDs have been detected in six proteins, mainly expressed in sensory neurons. RESULTS: Here, we built a profile Hidden Markov Model to screen the entire UniProtKB for new HHD-containing proteins. Every hit was manually annotated, using a clustering approach, confirming that only a few proteins contain HHDs. We report the phylogenetic coverage of each protein and build a phylogenetic tree to trace the evolution of HHDs. We suggest that a HHD ancestor is shared with Paired Amphipathic Helices (PAH) domains, a four-helix bundle partially sharing fold and functional properties. We characterized amino-acid sequences of the various HHDs using pairwise BLASTP scoring coupled with community clustering and manually assessed sequence features among each individual family. These sequence features were analyzed using reported structures as well as homology models to highlight structural motifs underlying HHDs fold. We show that functional divergence is carried out by subtle differences in sequences that automatized approaches failed to detect. CONCLUSIONS: We provide the first HHD databases, including sequences and conservation, phylogenic trees and a list of HHD variants found in the auditory system, which are available for the community. This case study highlights surprising phylogenetic properties found in orphan domains and will assist further studies of HHDs. We unveil the implication of HHDs in their various binding interfaces using conservation across families and a new protein-protein surface predictor. Finally, we discussed the functional consequences of three identified pathogenic HHD variants involved in Hoyeraal-Hreidarsson syndrome and of three newly reported pathogenic variants identified in patients suffering from Usher Syndrome.

Contributions of Age-Related and Audibility-Related Deficits to Aided Consonant Identification in Presbycusis: A Causal-Inference Analysis.

The decline of speech intelligibility in presbycusis can be regarded as resulting from the combined contribution of two main groups of factors: (1) audibility-related factors and (2) age-related factors. In particular, there is now an abundant scientific literature on the crucial role of suprathreshold auditory abilities and cognitive functions, which have been found to decline with age even in the absence of audiometric hearing loss. However, researchers investigating the direct effect of aging in presbycusis have to deal with the methodological issue that age and peripheral hearing loss covary to a large extent. In the present study, we analyzed a dataset of consonant-identification scores measured in quiet and in noise for a large cohort (n = 459, age = 42-92) of hearing-impaired (HI) and normal-hearing (NH) listeners. HI listeners were provided with a frequency-dependent amplification adjusted to their audiometric profile. Their scores in the two conditions were predicted from their pure-tone average (PTA) and age, as well as from their Extended Speech Intelligibility Index (ESII), a measure of the impact of audibility loss on speech intelligibility. We relied on a causal-inference approach combined with Bayesian modeling to disentangle the direct causal effects of age and audibility on intelligibility from the indirect effect of age on hearing loss. The analysis revealed that the direct effect of PTA on HI intelligibility scores was 5 times higher than the effect of age. This overwhelming effect of PTA was not due to a residual audibility loss despite amplification, as confirmed by a ESII-based model. More plausibly, the marginal role of age could be a consequence of the relatively little cognitively-demanding task used in this study. Furthermore, the amount of variance in intelligibility scores was smaller for NH than HI listeners, even after accounting for age and audibility, reflecting the presence of additional suprathreshold deficits in the latter group. Although the non-sense-syllable materials and the particular amplification settings used in this study potentially restrict the generalization of the findings, we think that these promising results call for a wider use of causal-inference analysis in audiology, e.g., as a way to disentangle the influence of the various cognitive factors and suprathreshold deficits associated to presbycusis.

A homozygous MPZL2 deletion is associated with non syndromic hearing loss in a moroccan family.

Adhesion glycoproteins are implicated in the pathophysiology of hearing loss, the most frequent inherited sensory disorder, affecting 1 in 1000 new-borns. Exome sequencing of a consanguineous Moroccan patient with mild hearing loss identified for the first time in a North African family a single homozygous mutation c.72delA in MPZL2 gene, encoding the Myelin Protein Zero-Like 2, reported as causing deafness in two other populations. Variable tandem repeat genotyping of this family revealed that the c.72delA MPZL2 allele shared a common haplotype with Turkish and Dutch families. These results confirm the pathogenicity of this MPZL2 mutation in recessive mild to moderate non-syndromic deafness.

Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis.

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

Novel Mutation in AIFM1 Gene Associated with X-Linked Deafness in a Moroccan Family.

INTRODUCTION: Auditory neuropathy is a hearing disorder where outer hair cell function within the cochlea is normal, but inner hair cell and/or the auditory nerve function is disrupted. It is a heterogeneous disorder, which can have either congenital or acquired causes. METHODS: We found a disease-segregating mutation in the X-linked AIFM1 gene through whole-exome sequencing, encoding the apoptosis-inducing factor mitochondrion-associated 1. RESULTS: The impact of the c.1045A>G; p.(Ser349Gly) mutation on the AIFM1 protein was predicted using different bioinformatics tools. The pedigree analysis in the examined family was consistent with X-linked dominant inheritance. DISCUSSION/CONCLUSION: To our knowledge, this is the first study that identifies a mutation in the AIFM1 gene in Moroccan patients suffering from X-linked auditory neuropathy.

Retinal findings in pediatric patients with Usher syndrome Type 1 due to mutations in MYO7A gene.

PURPOSE: To describe retinal alterations detected by swept-source optical coherence tomography (SS-OCT) in paediatric patients with Usher syndrome type 1 (USH1) and to compare these findings to previously published reports. METHODS: Thirty-two eyes from 16 patients (11 males and 5 females) with a genetic diagnosis of USH1 because of MYO7A mutations underwent SS-OCT. Patients ranged in age from 4 to 17 years (mean, 11,13 ± 4,29). The subfoveal and macular area were analysed with SS-OCT at 1050 nm using 12 radial scans of 12.0 mm. Structural abnormalities were evaluated and correlated with best-corrected visual acuity (BCVA). RESULTS: The most common qualitative retinal abnormality was external layer damage in macular area. Specific alterations included external limiting membrane loss/disruption (27 eyes; 84.4%), disruption of the Myoid zone (27 eyes; 84.4%); Ellipsoid zone disruption (28 eyes; 87.5%), and loss of the outer segments (29 eyes; 90.6%). The damage of the retinal pigment epithelium was divided according to the loss of the different layers: phagosome zone (30 eyes; 93.8%), melanosome zone (29 eyes; 90.6%) and mitochondria zone (0 eyes; 0%). The presence of cystoid macular oedema (CMO) was significantly correlated with alterations in photoreceptors. Disruption or absence of the myoid and ellipsoid zones of the photoreceptors were the only variables independently associated with decreased BCVA. CONCLUSIONS: The findings of this study suggest that the physiopathologic basis of early-stage Usher syndrome (USH) may be changes in the outer retinal layer, particularly the photoreceptors, which in turn may cause alterations-such as CMO-in the inner retinal layers. Accordingly, monitoring the condition of photoreceptors during follow-up may be advisable for the early detection of pathologic changes.

PHENOTYPIC CHARACTERISTICS OF ROD-CONE DYSTROPHY ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT.

PURPOSE: To document the rod-cone dystrophy phenotype of patients with Usher syndrome type 1 (USH1) harboring MYO7A mutations. METHODS: Retrospective cohort study of 53 patients (42 families) with biallelic MYO7A mutations who underwent comprehensive examination, including functional visual tests and multimodal retinal imaging. Genetic analysis was performed either using a multiplex amplicon panel or through direct sequencing. Data were analyzed with IBM SPSS Statistics software v. 21.0. RESULTS: Fifty different genetic variations including 4 novel were identified. Most patients showed a typical rod-cone dystrophy phenotype, with best-corrected visual acuity and central visual field deteriorating linearly with age. At age 29, binocular visual field demonstrated an average preservation of 50 central degrees, constricting by 50% within 5 years. Structural changes based on spectral domain optical coherence tomography, short wavelength autofluorescence, and near-infrared autofluorescence measurements did not however correlate with age. Our study revealed a higher percentage of epiretinal membranes and cystoid macular edema in patients with MYO7A mutations compared with rod-cone dystrophy patients with other mutations. Subgroup analyses did not reveal substantial genotype-phenotype correlations. CONCLUSION: To the best of our knowledge, this is the largest French cohort of patients with MYO7A mutations reported to date. Functional visual characteristics of this subset of patients followed a linear decline as in other typical rod-cone dystrophy, but structural changes were variable indicating the need for a case-by-case evaluation for prognostic prediction and choice of potential therapies.