Jalili syndrome (JS) is an autosomal recessive disorder with cone-rod dystrophy and amelogenesis imperfecta caused by CNNM4 variants. This study describes salivary proteome patterns observed in a small female JS cohort to characterize the oral molecular environment. Unstimulated saliva was collected from three related female JS patients carrying CNNM4 c.1475G>A (p.Gly492Asp) and six age-matched female unaffected controls. Tandem mass tag (TMT)-based quantitative proteomics was performed. Eighty-seven uniquely quantified salivary proteins were identified. Thirty-three proteins showed higher abundance in JS saliva (log2FC > 0.6; adjusted p < 0.05), including neutrophil/innate immune proteins (MPO, CTSG, SERPINB1) and carbohydrate-metabolism enzymes (ENO1/ENO2, GAPDH, TKT, TALDO1). LDHA showed a group-specific detection pattern, being detected in all JS samples but not detected in controls under the current workflow. Functional annotation and interaction analyses highlighted themes related to innate immunity and carbohydrate metabolism. In this small female-only cohort, the salivary proteome profile observed in JS was characterized by increased abundance of proteins annotated to innate immune defense and carbohydrate-associated metabolic processes. These findings are descriptive and should be interpreted in the context of oral clinical status.

To report two cases of Jalili syndrome (JS) harboring a novel mutation in the CNNM4 gene, review previously published studies on JS, and analyze factors potentially associated with visual acuity in patients with JS. Two JS patients from a non-consanguineous Chinese family underwent comprehensive ophthalmic evaluations. Next-generation sequencing (NGS) was performed to identify pathogenic variants, and Sanger sequencing was used for validation. A literature search was conducted to retrieve studies on JS published up to January 31, 2025; only studies with detailed records of visual acuity and mutation sites were included. Correlations between visual acuity and age, as well as between visual acuity and mutation domain, were analyzed. A total of 53 patients with detailed visual acuity and mutation site records from previous studies were included in the analysis. The mean logarithm of the minimum angle of resolution (logMAR) visual acuity was 1.15 (range: 0.69-2.00). Spearman's correlation analysis showed a positive correlation between visual acuity (logMAR) and age (rs =0.502, P<0.001). No association was found between logMAR visual acuity and mutation domain (P=0.748). The 6-year-old proband and her 3-year-old brother carried a novel homozygous missense variant c.949A>C (p.Ser317Arg) in CNNM4. Both patients presented with reduced visual acuity, pendular nystagmus, photophobia, night blindness, color vision loss, macular atrophy, and amelogenesis imperfecta. Optical coherence tomography (OCT) revealed atrophy of the outer retinal layers, and electroretinography (ERG) showed extinguished cone and rod responses. Fundus autofluorescence (FAF) and fundus fluorescein angiography (FFA) of the proband demonstrated bilateral retinal pigment epithelium (RPE) defects around the optic disc, vascular arcades, and macular region. At the latest follow-up (30mo), the proband's condition remained stable: best-corrected visual acuity was 2.00 logMAR (right eye) and 1.30 (left eye), with no changes in fundus appearance. The younger brother had a best-corrected visual acuity of 1.52 logMAR in both eyes at the latest follow-up, accompanied by severe bilateral macular atrophy and obvious dentin discoloration due to progressive enamel thinning. This study reports a novel homozygous missense variant c.949A>C (p.Ser317Arg) in CNNM4 in a Chinese JS family. Visual acuity in JS patients deteriorates with increasing age.

To report a novel homozygous mutation in CNNM4 gene associated with Jalili syndrome (JS) which is a rare, recessively inherited oculo-dental syndrome which encompasses cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI). A 4-year-old male patient of consanguineous Egyptian parents, who presented with progressive visual impairment and tooth decay underwent complete ophthalmological examination, dental, and systemic examination. Additionally, color fundus photography, fundus autofluorescence (FAF), spectral domain optical coherence tomography (SD-OCT) of the macula, full field electroretinogram (ffERG) were obtained. Orthopantomogram (OPG) were also obtained. NGS-based gene panel testing was done in a commercial laboratory from a peripheral blood sample. Fundus examination demonstrated typical features of CORD in the form of loss of foveal reflexes with macular retinal pigment epithelial mottling and atrophy reminiscent of bull's eye maculopathy. Dental assessment revealed evidence of AI. NGS-based gene panel identified a novel mutation in CNMM4 gene c.1423 G>A consistent with a diagnosis JS, thereby confirming the rare diagnosis. To the best of our knowledge, this is the first report of Jalili syndrome in Egypt. We are reporting a novel mutation in CNMM4 gene. We are also expanding the clinical spectrum of dental manifestation by reporting early eruption of the first permanent molars and suggesting that hyperopia could be a rather constant feature of JS. This case emphasizes the importance of comprehensive multidisciplinary assessment beyond visual complaints in IRD patients in order to reach an accurate diagnosis.

To correlate histopathologic findings in an eye with Jalili syndrome with clinical and imaging results available before enucleation. Case report with histopathologic analysis. Histopathologic analysis of an enucleated eye from a 63-year-old woman diagnosed with Jalili syndrome. Age at diagnosis, symptoms, personal and family history, and genetic testing results and previous retinal imaging were retrieved from the patient file. The ocular specimen was dissected, retinal sections were prepared, and analysis with hematoxylin and eosin staining and fluorescent immunohistochemistry was performed. The histopathologic findings were compared with the patient's imaging results available before enucleation. The ocular specimen analyzed belonged to a 63-year-old woman with Jalili syndrome, homozygous for the likely pathogenic c.971T>C p.(Leu324Pro) variant in the CNNM4 gene (NM_020184.3). This patient had no light perception bilaterally and suffered from bilateral, painful, severe dry eye, with refractory to conservative treatment for 7 years before enucleation. At 1-month follow-up after enucleation and orbital implant placement, the socket was fully recovered, and a custom ocular prosthesis was adapted. The patient experienced total pain relief, improved quality of life, and a good cosmetic result. The histopathologic analyses revealed loss of photoreceptor cells, accumulation of autofluorescent material in the subretinal space, partial preservation of the inner retinal lamination, Müller glial cell disorganization, and increased number of microglial cells in the nuclear layers. Our findings highlight the severe nature of this inherited retinal degenerative disease with significant damage to the outer retinal layers, absence of synaptic terminals, and loss of photoreceptors, indicating an advanced disease stage. The presence of microglial cells in the remaining nuclear layers suggests a role in photoreceptor degeneration. This study represents the first comprehensive description of clinical, genetic, imaging, and histopathologic findings in Jalili syndrome. The authors have no proprietary or commercial interest in any materials discussed in this article.