Clinical manifestations and genetic analysis of Jalili syndrome_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhou Menghan , Zhou Lingling , Ma Yazhen ,  Shen Yin

Eye Center, Renmin Hospital of Wuhan University, Wuhan 430060, China;

Corresponding?author：

Shen Yin, Email: yinshen@whu.edu.cn

Keywords：

Jalili syndrome; Cone-rod dystrophy; Amelogenesis imperfecta; Gene mutation

DOI：

10.3760/cma.j.cn511434-20251216-00583

Video：

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Objective To investigate the clinical phenotypes and genetic characteristics of Jalili syndrome. Methods A retrospective clinical study. Four patients diagnosed with Jalili syndrome by genetic testing at Eye Center of Renmin Hospital of Wuhan University from July 2023 to July 2025 were included. The patients were from 4 unrelated families. Detailed medical and family histories were obtained. All patients underwent comprehensive ophthalmic examinations, including best-corrected visual acuity, color fundus photography, ultra-widefield fundus autofluorescence imaging, and optical coherence tomography, as well as oral photography. Peripheral venous blood samples were collected from the patients and their family members for genomic DNA extraction. Whole-exome sequencing and bioinformatic analyses were performed. All identified variants were classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). Results Among the four patients, there was one male and three females, aged 5, 31 (male), 35, and 40 years. All patients presented with childhood-onset photophobia, nystagmus, and decreased visual acuity, accompanied by dental abnormalities predominantly characterized by amelogenesis imperfecta. The 5-year-old patient exhibited a bull’s-eye maculopathy and mild enamel defects. The 31- and 35-year-old patients showed progressive outer retinal structural damage and visual function decline, along with enamel hypoplasia, discoloration, or dental caries. The 40-year-old patient, from a consanguineous family, developed severe visual impairment in early childhood, accompanied by residual roots, retained primary teeth, and retinal vascular occlusion. Genetic analysis identified six CNNM4 variants highly correlated with the phenotype. Patient 1 carried a nonsense variant c.1555C>T (p.Arg519Ter) (M1) and a missense variant c.1423G>A (p.Val475Met) (M6); patient 2 carried a frameshift variant c.981dup (p.Leu328SerfsTer25) (M2) and a missense variant c.1219C>G (p.Arg407Gly) (M4); patient 3 carried two missense variants c.755T>G (p.Leu252Arg) (M3) and c.452G>T (p.Cys151Phe) (M5); patient 4 carried a homozygous frameshift variant c.981dup (p.Leu328SerfsTer25) (M2). Variants M2, M3, M4, and M5 were novel. According to ACMG guidelines, M1 and M2 were classified as pathogenic, M5 and M6 as likely pathogenic, and M3 and M4 as variants of uncertain significance. Conclusions Jalili syndrome is an early-onset, progressive CNNM4-related oculo-dental syndrome. M2, M3, M4, and M5 are new mutations reported for the first time in this study. The variants M2, M4, and M5 (missense) and M3 (frameshift) are newly identified variants.

Citation： Zhou Menghan, Zhou Lingling, Ma Yazhen, Shen Yin. Clinical manifestations and genetic analysis of Jalili syndrome. Chinese Journal of Ocular Fundus Diseases, 2026, 42(5): 434-440. doi: 10.3760/cma.j.cn511434-20251216-00583 Copy

1.	Daneshmandpour Y, Darvish H, Pashazadeh F, et al. Features, genetics and their correlation in Jalili syndrome: a systematic review[J]. J Med Genet, 2019, 56(6): 358-369. DOI: 10.1136/jmedgenet-2018-105716.
2.	Jalili IK, Smith NJ. A progressive cone-rod dystrophy and amelogenesis imperfecta: a new syndrome[J]. J Med Genet, 1988, 25(11): 738-740. DOI: 10.1136/jmg.25.11.738.
3.	Jalili IK. Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs[J]. Eye, 2010, 24(11): 1659-1668. DOI: 10.1038/eye.2010.103.
4.	Parry DA, Mighell AJ, El-Sayed W, et al. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta[J]. Am J Hum Genet, 2009, 84(2): 266-273. DOI: 10.1016/j.ajhg.2009.01.009.
5.	Rattanapornsompong K, Rinkrathok M, Sriwattanapong K, et al. Functional and pathogenic insights into CNNM4 variants in Jalili syndrome[J/OL]. Sci Rep, 2024, 14(1): 29091[2024-11-23]. https://pubmed.ncbi.nlm.nih.gov/39580587/. DOI: 10.1038/s41598-024-80720-8.
6.	Giménez-Mascarell P, Oyenarte I, González-Recio I, et al. Structural insights into the intracellular region of the human magnesium transport mediator CNNM4[J/OL]. Int J Mol Sci, 2019, 20(24): 6279[2019-12-12]. https://pubmed.ncbi.nlm.nih.gov/31842432/. DOI: 10.3390/ijms20246279.
7.	Yamazaki D, Funato Y, Miura J, et al. Basolateral Mg2+ extrusion via CNNM4 mediates transcellular Mg2+ transport across epithelia: a mouse model[J/OL]. PLoS Genet, 2013, 9(12): e1003983[2013-12-05]. https://pubmed.ncbi.nlm.nih.gov/24339795/. DOI: 10.1371/journal.pgen.1003983.
8.	Lu J, Liang SY, Li Z, et al. Novel mutation in CNNM4 gene in a Chinese family with Jalili syndrome and literature review[J]. Int J Ophthalmol, 2025, 18(12): 2354-2365. DOI: 10.18240/ijo.2025.12.18.
9.	Li S, Xi Q, Zhang X, et al. Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1[J]. Mol Genet Genomics, 2018, 293(3): 699-710. DOI: 10.1007/s00438-018-1417-6.
10.	Aldred MJ, Savarirayan R, Crawford PJ. Amelogenesis imperfecta: a classification and catalogue for the 21st century[J]. Oral Dis, 2003, 9(1): 19-23. DOI: 10.1034/j.1601-0825.2003.00843.x.
11.	Li H, Huang Y, Li J, et al. Novel homozygous nonsynonymous variant of CNNM4 gene in a Chinese family with Jalili syndrome[J/OL]. Mol Genet Genomic Med, 2022, 10(3): e1860[2022-02-12]. https://pubmed.ncbi.nlm.nih.gov/35150469/. DOI: 10.1002/mgg3.1860.
12.	Wang H, Wang X, Zou X, et al. Comprehensive molecular diagnosis of a large Chinese Leber congenital amaurosis cohort[J]. Invest Ophthalmol Vis Sci, 2015, 56(6): 3642-3655. DOI: 10.1167/iovs.14-15972.
13.	Tawfik CA, Aly HS, Kabeel M, et al. A novel mutation in CNNM4 is associated with a case of Jalili syndrome in Egypt[J]. Doc Ophthalmol, 2025, 150(3): 189-196. DOI: 10.1007/s10633-025-10018-1.
14.	Veleri S, Lazar CH, Chang B, et al. Biology and therapy of inherited retinal degenerative disease: insights from mouse models[J]. Dis Model Mech, 2015, 8(2): 109-129. DOI: 10.1242/dmm.017913.
15.	do Valle íF, Giampieri E, Simonetti G, et al. Optimized pipeline of MuTect and GATK tools to improve the detection of somatic single nucleotide polymorphisms in whole-exome sequencing data[J/OL]. BMC Bioinformatics, 2016, 17(Suppl 12): 341[2016-11-08]. https://pubmed.ncbi.nlm.nih.gov/28185561/. DOI: 10.1186/s12859-016-1190-7.
16.	Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data[J/OL]. Nucleic Acids Res, 2010, 38(16): e164[2010-07-03]. https://pubmed.ncbi.nlm.nih.gov/20601685/. DOI: 10.1093/nar/gkq603.
17.	Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
18.	Shahsavan A, Lee EL, Illes K, et al. Dimerization of the CNNM extracellular domain[J/OL]. Protein Sci, 2024, 33(2): e4860[2024-02-01]. https://pubmed.ncbi.nlm.nih.gov/38149326/. DOI: 10.1002/pro.4860.
19.	Bittles AH, Neel JV. The costs of human inbreeding and their implications for variations at the DNA level[J]. Nat Genet, 1994, 8(2): 117-121. DOI: 10.1038/ng1094-117.
20.	Rahimi-Aliabadi S, Daftarian N, Ahmadieh H, et al. A novel mutation and variable phenotypic expression in a large consanguineous pedigree with Jalili syndrome[J]. Eye (Lond), 2016, 30(11): 1424-1432. DOI: 10.1038/eye.2016.137.
21.	Doucette L, Green J, Black C, et al. Molecular genetics of achromatopsia in Newfoundland reveal genetic heterogeneity, founder effects and the first cases of Jalili syndrome in North America[J]. Ophthalmic Genet, 2013, 34(3): 119-129. DOI: 10.3109/13816810.2013.763993.
22.	Khan AO. The genetic basis of clinically suspected achromatopsia in the united arab emirates[J]. Retina, 2024, 44(11): 2019-2025. DOI: 10.1097/iae.0000000000004218.
23.	Lee JH, Park SH, Yim JS, et al. The first Korean child of Jalili syndrome with a novel missense mutation in cation transport mediator 4 (CNNM4): a case report[J]. Korean J Ophthalmol, 2023, 37(2): 195-197. DOI: 10.3341/kjo.2022.0144.
24.	Hirji N, Bradley PD, Li S, et al. Jalili syndrome: cross-sectional and longitudinal features of seven patients with cone-rod dystrophy and amelogenesis imperfecta[J]. Am J Ophthalmol, 2018, 188: 123-130. DOI: 10.1016/j.ajo.2018.01.029.
25.	Rattanapornsompong K, Gavila P, Tungsanga S, et al. Novel CNNM4 variant and clinical features of Jalili syndrome[J]. Clin Genet, 2023, 103(2): 256-257. DOI: 10.1111/cge.14258.
26.	Lopez Torres LT, Schorderet D, Valmaggia C, et al. A novel mutation in CNNM4 (G492C) associated with Jalili Syndrome[J/OL]. Acta Ophthalmol, 2015, 93(S255): ABS15-0606[2015-10-01]. https://onlinelibrary.wiley.com/doi/10.1111/j.1755-3768.2015.0606.
27.	Purwar P, Sareen S, Bhartiya K, et al. Jalili syndrome presenting with situs inversus totalis and keratoconus: the first case in the Indian subcontinent[J/OL]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2015, 120(5): e210-e218[2015-04-24]. https://pubmed.ncbi.nlm.nih.gov/40232358/. DOI: 10.1016/j.oooo.2015.04.002.
28.	Wawrocka A, Walczak-Sztulpa J, Badura-Stronka M, et al. Co-occurrence of Jalili syndrome and muscular overgrowth[J]. Am J Med Genet A, 2017, 173(8): 2280-2283. DOI: 10.1002/ajmg.a.38318.
29.	Prasov L, Ullah E, Turriff AE, et al. Expanding the genotypic spectrum of Jalili syndrome: novel CNNM4 variants and uniparental isodisomy in a North American patient cohort[J]. Am J Med Genet A, 2020, 182(3): 493-497. DOI: 10.1002/ajmg.a.61484.
30.	Fujinami K, Waheed N, Laich Y, et al. Stargardt macular dystrophy and therapeutic approaches[J]. Br J Ophthalmol, 2024, 108(4): 495-505. DOI: 10.1136/bjo-2022-323071.
31.	Thusberg J, Olatubosun A, Vihinen M. Performance of mutation pathogenicity prediction methods on missense variants[J]. Hum Mutat, 2011, 32(4): 358-368. DOI: 10.1002/humu.21445.
32.	Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders[J]. N Engl J Med, 2013, 369(16): 1502-1511. DOI: 10.1056/NEJMoa1306555.
33.	Henneman L, Borry P, Chokoshvili D, et al. Responsible implementation of expanded carrier screening[J/OL]. Eur J Hum Genet, 2016, 24(6): e1-e12[2016-03-16]. https://pubmed.ncbi.nlm.nih.gov/26980105/. DOI: 10.1038/ejhg.2015.271.
34.	Polok B, Escher P, Ambresin A, et al. Mutations in CNNM4 cause recessive cone-rod dystrophy with amelogenesis imperfecta[J]. Am J Hum Genet, 2009, 84(2): 259-265. DOI: 10.1016/j.ajhg.2009.01.006.

1. Daneshmandpour Y, Darvish H, Pashazadeh F, et al. Features, genetics and their correlation in Jalili syndrome: a systematic review[J]. J Med Genet, 2019, 56(6): 358-369. DOI: 10.1136/jmedgenet-2018-105716.
2. Jalili IK, Smith NJ. A progressive cone-rod dystrophy and amelogenesis imperfecta: a new syndrome[J]. J Med Genet, 1988, 25(11): 738-740. DOI: 10.1136/jmg.25.11.738.
3. Jalili IK. Cone-rod dystrophy and amelogenesis imperfecta (Jalili syndrome): phenotypes and environs[J]. Eye, 2010, 24(11): 1659-1668. DOI: 10.1038/eye.2010.103.
4. Parry DA, Mighell AJ, El-Sayed W, et al. Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta[J]. Am J Hum Genet, 2009, 84(2): 266-273. DOI: 10.1016/j.ajhg.2009.01.009.
5. Rattanapornsompong K, Rinkrathok M, Sriwattanapong K, et al. Functional and pathogenic insights into CNNM4 variants in Jalili syndrome[J/OL]. Sci Rep, 2024, 14(1): 29091[2024-11-23]. https://pubmed.ncbi.nlm.nih.gov/39580587/. DOI: 10.1038/s41598-024-80720-8.
6. Giménez-Mascarell P, Oyenarte I, González-Recio I, et al. Structural insights into the intracellular region of the human magnesium transport mediator CNNM4[J/OL]. Int J Mol Sci, 2019, 20(24): 6279[2019-12-12]. https://pubmed.ncbi.nlm.nih.gov/31842432/. DOI: 10.3390/ijms20246279.
7. Yamazaki D, Funato Y, Miura J, et al. Basolateral Mg2+ extrusion via CNNM4 mediates transcellular Mg2+ transport across epithelia: a mouse model[J/OL]. PLoS Genet, 2013, 9(12): e1003983[2013-12-05]. https://pubmed.ncbi.nlm.nih.gov/24339795/. DOI: 10.1371/journal.pgen.1003983.
8. Lu J, Liang SY, Li Z, et al. Novel mutation in CNNM4 gene in a Chinese family with Jalili syndrome and literature review[J]. Int J Ophthalmol, 2025, 18(12): 2354-2365. DOI: 10.18240/ijo.2025.12.18.
9. Li S, Xi Q, Zhang X, et al. Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1[J]. Mol Genet Genomics, 2018, 293(3): 699-710. DOI: 10.1007/s00438-018-1417-6.
10. Aldred MJ, Savarirayan R, Crawford PJ. Amelogenesis imperfecta: a classification and catalogue for the 21st century[J]. Oral Dis, 2003, 9(1): 19-23. DOI: 10.1034/j.1601-0825.2003.00843.x.
11. Li H, Huang Y, Li J, et al. Novel homozygous nonsynonymous variant of CNNM4 gene in a Chinese family with Jalili syndrome[J/OL]. Mol Genet Genomic Med, 2022, 10(3): e1860[2022-02-12]. https://pubmed.ncbi.nlm.nih.gov/35150469/. DOI: 10.1002/mgg3.1860.
12. Wang H, Wang X, Zou X, et al. Comprehensive molecular diagnosis of a large Chinese Leber congenital amaurosis cohort[J]. Invest Ophthalmol Vis Sci, 2015, 56(6): 3642-3655. DOI: 10.1167/iovs.14-15972.
13. Tawfik CA, Aly HS, Kabeel M, et al. A novel mutation in CNNM4 is associated with a case of Jalili syndrome in Egypt[J]. Doc Ophthalmol, 2025, 150(3): 189-196. DOI: 10.1007/s10633-025-10018-1.
14. Veleri S, Lazar CH, Chang B, et al. Biology and therapy of inherited retinal degenerative disease: insights from mouse models[J]. Dis Model Mech, 2015, 8(2): 109-129. DOI: 10.1242/dmm.017913.
15. do Valle íF, Giampieri E, Simonetti G, et al. Optimized pipeline of MuTect and GATK tools to improve the detection of somatic single nucleotide polymorphisms in whole-exome sequencing data[J/OL]. BMC Bioinformatics, 2016, 17(Suppl 12): 341[2016-11-08]. https://pubmed.ncbi.nlm.nih.gov/28185561/. DOI: 10.1186/s12859-016-1190-7.
16. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data[J/OL]. Nucleic Acids Res, 2010, 38(16): e164[2010-07-03]. https://pubmed.ncbi.nlm.nih.gov/20601685/. DOI: 10.1093/nar/gkq603.
17. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424. DOI: 10.1038/gim.2015.30.
18. Shahsavan A, Lee EL, Illes K, et al. Dimerization of the CNNM extracellular domain[J/OL]. Protein Sci, 2024, 33(2): e4860[2024-02-01]. https://pubmed.ncbi.nlm.nih.gov/38149326/. DOI: 10.1002/pro.4860.
19. Bittles AH, Neel JV. The costs of human inbreeding and their implications for variations at the DNA level[J]. Nat Genet, 1994, 8(2): 117-121. DOI: 10.1038/ng1094-117.
20. Rahimi-Aliabadi S, Daftarian N, Ahmadieh H, et al. A novel mutation and variable phenotypic expression in a large consanguineous pedigree with Jalili syndrome[J]. Eye (Lond), 2016, 30(11): 1424-1432. DOI: 10.1038/eye.2016.137.
21. Doucette L, Green J, Black C, et al. Molecular genetics of achromatopsia in Newfoundland reveal genetic heterogeneity, founder effects and the first cases of Jalili syndrome in North America[J]. Ophthalmic Genet, 2013, 34(3): 119-129. DOI: 10.3109/13816810.2013.763993.
22. Khan AO. The genetic basis of clinically suspected achromatopsia in the united arab emirates[J]. Retina, 2024, 44(11): 2019-2025. DOI: 10.1097/iae.0000000000004218.
23. Lee JH, Park SH, Yim JS, et al. The first Korean child of Jalili syndrome with a novel missense mutation in cation transport mediator 4 (CNNM4): a case report[J]. Korean J Ophthalmol, 2023, 37(2): 195-197. DOI: 10.3341/kjo.2022.0144.
24. Hirji N, Bradley PD, Li S, et al. Jalili syndrome: cross-sectional and longitudinal features of seven patients with cone-rod dystrophy and amelogenesis imperfecta[J]. Am J Ophthalmol, 2018, 188: 123-130. DOI: 10.1016/j.ajo.2018.01.029.
25. Rattanapornsompong K, Gavila P, Tungsanga S, et al. Novel CNNM4 variant and clinical features of Jalili syndrome[J]. Clin Genet, 2023, 103(2): 256-257. DOI: 10.1111/cge.14258.
26. Lopez Torres LT, Schorderet D, Valmaggia C, et al. A novel mutation in CNNM4 (G492C) associated with Jalili Syndrome[J/OL]. Acta Ophthalmol, 2015, 93(S255): ABS15-0606[2015-10-01]. https://onlinelibrary.wiley.com/doi/10.1111/j.1755-3768.2015.0606.
27. Purwar P, Sareen S, Bhartiya K, et al. Jalili syndrome presenting with situs inversus totalis and keratoconus: the first case in the Indian subcontinent[J/OL]. Oral Surg Oral Med Oral Pathol Oral Radiol, 2015, 120(5): e210-e218[2015-04-24]. https://pubmed.ncbi.nlm.nih.gov/40232358/. DOI: 10.1016/j.oooo.2015.04.002.
28. Wawrocka A, Walczak-Sztulpa J, Badura-Stronka M, et al. Co-occurrence of Jalili syndrome and muscular overgrowth[J]. Am J Med Genet A, 2017, 173(8): 2280-2283. DOI: 10.1002/ajmg.a.38318.
29. Prasov L, Ullah E, Turriff AE, et al. Expanding the genotypic spectrum of Jalili syndrome: novel CNNM4 variants and uniparental isodisomy in a North American patient cohort[J]. Am J Med Genet A, 2020, 182(3): 493-497. DOI: 10.1002/ajmg.a.61484.
30. Fujinami K, Waheed N, Laich Y, et al. Stargardt macular dystrophy and therapeutic approaches[J]. Br J Ophthalmol, 2024, 108(4): 495-505. DOI: 10.1136/bjo-2022-323071.
31. Thusberg J, Olatubosun A, Vihinen M. Performance of mutation pathogenicity prediction methods on missense variants[J]. Hum Mutat, 2011, 32(4): 358-368. DOI: 10.1002/humu.21445.
32. Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders[J]. N Engl J Med, 2013, 369(16): 1502-1511. DOI: 10.1056/NEJMoa1306555.
33. Henneman L, Borry P, Chokoshvili D, et al. Responsible implementation of expanded carrier screening[J/OL]. Eur J Hum Genet, 2016, 24(6): e1-e12[2016-03-16]. https://pubmed.ncbi.nlm.nih.gov/26980105/. DOI: 10.1038/ejhg.2015.271.
34. Polok B, Escher P, Ambresin A, et al. Mutations in CNNM4 cause recessive cone-rod dystrophy with amelogenesis imperfecta[J]. Am J Hum Genet, 2009, 84(2): 259-265. DOI: 10.1016/j.ajhg.2009.01.006.

Chinese Journal of Ocular Fundus Diseases

Clinical manifestations and genetic analysis of Jalili syndrome

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