Analysis of ocular clinical features of <i>KIF11</i> mutation induced microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability syndrome_Chinese Journal of Ocular Fundus Diseases

Authors：

Shi Liying ¹ , Lu Yuebing ¹ , Sun Shuang ¹ , Xu Lihui ¹ , Liu Ting ¹ , Bai Dayong ² ,  Sun Xiantao ¹

1. Department of Ophthalmology, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450018, China;
2. Department of Ophthalmology, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing 100045, China;

Corresponding author：

Sun Xiantao, Email: sunxt38019896@163.com

Keywords：

Chorioretinopathy; KIF11 gene; Microcephaly; Nystagmus

DOI：

10.3760/cma.j.cn511434-20240122-00043

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Objective To observe and analyze the clinical characteristics of children with autosomal dominant hereditary microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability syndrome (MCLMR). Methods A retrospective clinical study. In September 2023, the first patient and three family members (parents, brother) of MCLMR who were diagnosed through ophthalmic examination and genetic testing at Department of Ophthalmology of Henan Children's Hospital were included in the study. Clinical data were collected, inquired about medical history and family history in detail, and performed best corrected visual acuity (BCVA), optical coherence tomography (OCT), fluorescein angiography (FFA), flash visual evoked potential (F-VEP), full field electroretinogram (ERG), cranial magnetic resonance imaging (MRI), and systemic examination. 3 ml of peripheral venous blood were collected from the proband, her parents and younger brother, and extracted whole genome DNA. Second generation sequencing technology was used for gene sequencing. For suspected pathogenic sites, Sanger sequencing was used for validation, and bioinformatics analysis was performed to determine the pathogenicity of the genetic variant sites. The relevant literature of PubMed of the National Library of Medicine and Wan Fang Med Online by computer were searched. The genetic characteristics and conducted literature review were summarized. Results The proband (Ⅱ-1) was an 8-year-old and 5-month-old female. Her head was relatively small, the lower jaw was small, the ears protrude, the nose was wide, the eyelid was tilted upwards, philtrum was long. Mild intellectual disability, no history of lymphedema. The BCVA values for the right and left eyes were 0.08 and 0.1, respectively. Bilateral nystagmus. Atrophic lesioned in the macular area and below choroid retina of both eyes. FFA examination showed mottled fluorescent staining in the macular area and the below retina, with no obvious fluorescein leakage in the late stage. OCT examination revealed shallow macular fovea morphology, absence of ellipsoidal bands, unclear layers, thinning of the entire retina, and significant atrophy of the choroid and retina beneath the macula. F-VEP examination, no waveform was detected in both eyes. Full field ERG examination showed severe reduction in amplitude of a wave and b wave in both eyes. Head magnetic resonance imaging showed widening of the subarachnoid space in the left temporal region, with no significant abnormal signals observed in the brain parenchyma. Her father (Ⅰ-1) had mild nystagmus and strabismus. The phenotypes of the eyes of the mother (Ⅰ-2) and brother (Ⅱ-2) were not significantly abnormal. The genetic testing results showed that the proband (Ⅱ-1) had a heterozygous missense mutation c.895A>G (p.Ile299Val) in exon 8 of the KIF11 gene, which was a known mutation. Her parents (Ⅰ-1, Ⅰ-2) and younger brother (Ⅱ-2) were both wild-type. The bioinformatics analysis results indicated that this mutation is a potentially pathogenic variant. A total of 109 cases were retrieved from 20 relevant literatures. Among them, 55 were male, 54 were females. There were 61 cases with family history and 48 cases without family history, respectively. Among the 109 cases, 98 cases (89.9%, 98/109) had microcephaly, 2 cases had premature closure of cranial sutures, and 11 patients underwent cranial MRI, which showed 11 cases of small head with simplified development of the cerebral gyrus. 50 cases (45.9%, 50/109) of lymphedema. 83 cases (76.1%, 83/109) of intellectual developmental disorders. 92 cases (84.4%, 92/109) had ocular abnormalities, 69 cases (63.3%, 69/109) had chorioretinopathy, 20 cases (18.3%, 20/109) had retinal folds, 10 cases (9.2%, 10/109) had nystagmus, and 17 cases (15.6%, 17/109) had retinal detachment. Conclusions The main clinical manifestations of MCLMR are microcephaly, chorioretinopathy, with or without lymphedema, and intellectual disability. The main manifestations of eye diseases are low vision, nystagmus, and chorioretinopathy. The heterozygous missense mutation c.895A>G (p.Ile299Val) in exon 8 of KIF11 gene is the pathogenic variant of this family.

Citation： Shi Liying, Lu Yuebing, Sun Shuang, Xu Lihui, Liu Ting, Bai Dayong, Sun Xiantao. Analysis of ocular clinical features of KIF11 mutation induced microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability syndrome. Chinese Journal of Ocular Fundus Diseases, 2024, 40(11): 825-832. doi: 10.3760/cma.j.cn511434-20240122-00043 Copy

1.	Mears K, Bakall B, Harney LA, et al. Autosomal dominant microcephaly associated with congenital lymphedema and chorioretinopathy due to a novel mutation in KIF11[J]. JAMA Ophthalmol, 2015, 133(6): 720-721. DOI: 10.1001/jamaophthalmol.2015.199.
2.	Ostergaard P, Simpson MA, Mendola A, et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy[J]. Am J Hum Genet, 2012, 90(2): 356-362. DOI: 10.1016/j.ajhg.2011.12.018.
3.	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.
4.	Mirzaa GM, Enyedi L, Parsons G, et al. Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature[J]. Am J Med Genet A, 2014, 164(11): 2879-2886. DOI: 10.1002/ajmg.a.36707.
5.	Mirzaa GM, Collins S, Dobyns WB. Corrigendum to "Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature. Am J Med Genet Part A 2014 164A: 2879-86"[J]. Am J Med Genet A, 2016, 170(2): 547. DOI: 10.1002/ajmg.a.37449.
6.	Shurygina MF, Simonett JM, Parker MA, et al. Genotype phenotype correlation and variability in microcephaly associated with chorioretinopathy or familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2020, 61(13): 2. DOI: 10.1167/iovs.61.13.2.
7.	Li JK, Fei P, Li Y, et al. Identification of novel KIF11 mutations in patients with familial exudative vitreoretinopathy and a phenotypic analysis[J/OL]. Sci Rep, 2016, 6: 26564[2016-05-23]. https://pubmed.ncbi.nlm.nih.gov/27212378/. DOI: 10.1038/srep26564.
8.	Malvezzi JV, H Magalhaes I, S Costa S, et al. KIF11 microdeletion is associated with microcephaly, chorioretinopathy and intellectual disability[J/OL]. Hum Genome Var, 2018, 5: 18010[2018-03-29]. https://pubmed.ncbi.nlm.nih.gov/31428438/. DOI: 10.1038/hgv.2018.10.
9.	Jones GE, Ostergaard P, Moore AT, et al. Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations[J]. Eur J Hum Genet, 2014, 22(7): 881-887. DOI: 10.1038/ejhg.2013.263.
10.	Rososinski A, Tran T, Galvin J, et al. New findings from multimodal fundus imaging over 3 years of a patient with microcephaly, chorioretinopathy, and KIF11 mutation[J]. Retin Cases Brief Rep, 2019, 13(1): 79-83. DOI: 10.1097/icb.0000000000000538.
11.	Schlögel MJ, Mendola A, Fastré E, et al. No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome[J]. Orphanet J Rare Dis, 2015, 10: 52. DOI: 10.1186/s13023-015-0271-4.
12.	Hazan F, Ostergaard P, Ozturk T, et al. A novel KIF11 mutation in a Turkish patient with microcephaly, lymphedema, and chorioretinal dysplasia from a consanguineous family[J]. Am J Med Genet A, 2012, 158(7): 1686-1689. DOI: 10.1002/ajmg.a.35371.
13.	Güneş N, Taşdemir E, Jeffery H, et al. A novel mutation of KIF11 in a child with 22q11.2 deletion syndrome associated with MCLMR[J]. Mol Syndromol, 2019, 9(5): 266-270. DOI: 10.1159/000491568.
14.	Alahmadi G, Alshamrani AA, Albakri A. Novel variant of KIF11 associated with MCLMR syndrome[J]. Ophthalmic Genet, 2023, 44(2): 205-207. DOI: 10.1080/13816810.2022.2113540.
15.	Guo Z, Huo X, Wu D, et al. A novel variant of the KIF11 gene, c.2922G>T, is associated with microcephaly by affecting RNA splicing[J]. Dev Neurosci, 2022, 44(2): 113-120. DOI: 10.1159/000518923.
16.	Balikova I, Robson AG, Holder GE, et al. Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11[J]. Acta Ophthalmol, 2016, 94(1): 92-98. DOI: 10.1111/aos.12759.
17.	Chang H, Zhang X, Xu K, et al. Phenotype-based genetic analysis reveals missing heritability of KIF11-related retinopathy: clinical and genetic findings[J]. Genes, 2023, 14(1): 212. DOI: 10.3390/genes14010212.
18.	Robitaille JM, Gillett RM, LeBlanc MA, et al. Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations[J]. JAMA Ophthalmol, 2014, 132(12): 1393-1399. DOI: 10.1001/jamaophthalmol.2014.2814.
19.	Kondo H, Matsushita I, Nagata T, et al. Retinal features of family members with familial exudative vitreoretinopathy caused by mutations in KIF11 gene[J]. Transl Vis Sci Technol, 2021, 10(7): 18. DOI: 10.1167/tvst.10.7.18.
20.	Riedl J, Voβmerbäumer U, Stoffelns B, et al. Total retinal detachment caused by a KIF11 mutation[J/OL]. Eur J Ophthalmol, 2017, 27(5): e147-e148[2017-08-30]. https://pubmed.ncbi.nlm.nih.gov/28574136/. DOI: 10.5301/ejo.5000987.
21.	成芳, 梁建宏. KIF11基因新突变致MCLMR综合征1例[J]. 中华眼底病杂志, 2023, 39(7): 583-584. DOI: 10.3760/cma.j.cn511434-20220425-00246.Cheng F, Liang JH. MCLMR syndrome caused by new mutation of KIF11 gene: a case report[J]. Chin J Ocul Fundus Dis, 2023, 39(7): 583-584. DOI: 10.3760/cma.j.cn511434-20220425-00246.
22.	Meissner L, Niese L, Schuring I, et al. Human kinesin-5 KIF11 drives the helical motion of anti-parallel and parallel microtubules around each other[J]. EMBO J, 2024, 43(7): 1244-1256. DOI: 10.1038/s44318-024-00048-x.
23.	Birtel J, Gliem M, Mangold E, et al. Novel insights into the phenotypical spectrum of KIF11-associated retinopathy, including a new form of retinal ciliopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(10): 3950-3959. DOI: 10.1167/iovs.17-21679.
24.	Alzial C, Dufier JL, Brasnu C, et al. "True" microcephaly with dominant-inheritance chorioretinal dysplasia[J]. Ann Genet, 1980, 23(2): 91-94.
25.	Feingold M, Bartoshesky L. Microcephaly, lymphedema, and chorioretinal dysplasia: a distinct syndrome?[J]. Am J Med Genet, 1992, 43(6): 1030-1031. DOI: 10.1002/ajmg.1320430623.
26.	Gupta A, Vasudevan P, Biswas S, et al. Microcephaly with chorioretinal dysplasia: two case reports and a review of the literature[J]. Ophthalmic Genet, 2009, 30(4): 157-160. DOI: 10.3109/13816810903147980.
27.	Lee BJ, Kim JH, Yu YS. Lissencephaly and mild cerebellar vermis hypoplasia in a case of microcephaly and chorioretinal dysplasia[J]. Ophthalmic Genet, 2010, 31(2): 89-93. DOI: 10.3109/13816811003620509.
28.	Hu H, Xiao X, Li S, et al. KIF11 mutations are a common cause of autosomal dominant familial exudative vitreoretinopathy[J]. Br J Ophthalmol, 2016, 100(2): 278-283. DOI: 10.1136/bjophthalmol-2015-306878.
29.	Hull S, Arno G, Ostergaard P, et al. Clinical and molecular characterization of familial exudative vitreoretinopathy associated with microcephaly[J]. Am J Ophthalmol, 2019, 207: 87-98. DOI: 10.1016/j.ajo.2019.05.001.
30.	Wang Y, Zhang Z, Huang L, et al. Update on the phenotypic and genotypic spectrum of KIF11-related retinopathy[J]. Genes, 2022, 13(4): 713. DOI: 10.3390/genes13040713.

1. Mears K, Bakall B, Harney LA, et al. Autosomal dominant microcephaly associated with congenital lymphedema and chorioretinopathy due to a novel mutation in KIF11[J]. JAMA Ophthalmol, 2015, 133(6): 720-721. DOI: 10.1001/jamaophthalmol.2015.199.
2. Ostergaard P, Simpson MA, Mendola A, et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy[J]. Am J Hum Genet, 2012, 90(2): 356-362. DOI: 10.1016/j.ajhg.2011.12.018.
3. 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.
4. Mirzaa GM, Enyedi L, Parsons G, et al. Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature[J]. Am J Med Genet A, 2014, 164(11): 2879-2886. DOI: 10.1002/ajmg.a.36707.
5. Mirzaa GM, Collins S, Dobyns WB. Corrigendum to "Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature. Am J Med Genet Part A 2014 164A: 2879-86"[J]. Am J Med Genet A, 2016, 170(2): 547. DOI: 10.1002/ajmg.a.37449.
6. Shurygina MF, Simonett JM, Parker MA, et al. Genotype phenotype correlation and variability in microcephaly associated with chorioretinopathy or familial exudative vitreoretinopathy[J]. Invest Ophthalmol Vis Sci, 2020, 61(13): 2. DOI: 10.1167/iovs.61.13.2.
7. Li JK, Fei P, Li Y, et al. Identification of novel KIF11 mutations in patients with familial exudative vitreoretinopathy and a phenotypic analysis[J/OL]. Sci Rep, 2016, 6: 26564[2016-05-23]. https://pubmed.ncbi.nlm.nih.gov/27212378/. DOI: 10.1038/srep26564.
8. Malvezzi JV, H Magalhaes I, S Costa S, et al. KIF11 microdeletion is associated with microcephaly, chorioretinopathy and intellectual disability[J/OL]. Hum Genome Var, 2018, 5: 18010[2018-03-29]. https://pubmed.ncbi.nlm.nih.gov/31428438/. DOI: 10.1038/hgv.2018.10.
9. Jones GE, Ostergaard P, Moore AT, et al. Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations[J]. Eur J Hum Genet, 2014, 22(7): 881-887. DOI: 10.1038/ejhg.2013.263.
10. Rososinski A, Tran T, Galvin J, et al. New findings from multimodal fundus imaging over 3 years of a patient with microcephaly, chorioretinopathy, and KIF11 mutation[J]. Retin Cases Brief Rep, 2019, 13(1): 79-83. DOI: 10.1097/icb.0000000000000538.
11. Schlögel MJ, Mendola A, Fastré E, et al. No evidence of locus heterogeneity in familial microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome[J]. Orphanet J Rare Dis, 2015, 10: 52. DOI: 10.1186/s13023-015-0271-4.
12. Hazan F, Ostergaard P, Ozturk T, et al. A novel KIF11 mutation in a Turkish patient with microcephaly, lymphedema, and chorioretinal dysplasia from a consanguineous family[J]. Am J Med Genet A, 2012, 158(7): 1686-1689. DOI: 10.1002/ajmg.a.35371.
13. Güneş N, Taşdemir E, Jeffery H, et al. A novel mutation of KIF11 in a child with 22q11.2 deletion syndrome associated with MCLMR[J]. Mol Syndromol, 2019, 9(5): 266-270. DOI: 10.1159/000491568.
14. Alahmadi G, Alshamrani AA, Albakri A. Novel variant of KIF11 associated with MCLMR syndrome[J]. Ophthalmic Genet, 2023, 44(2): 205-207. DOI: 10.1080/13816810.2022.2113540.
15. Guo Z, Huo X, Wu D, et al. A novel variant of the KIF11 gene, c.2922G>T, is associated with microcephaly by affecting RNA splicing[J]. Dev Neurosci, 2022, 44(2): 113-120. DOI: 10.1159/000518923.
16. Balikova I, Robson AG, Holder GE, et al. Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11[J]. Acta Ophthalmol, 2016, 94(1): 92-98. DOI: 10.1111/aos.12759.
17. Chang H, Zhang X, Xu K, et al. Phenotype-based genetic analysis reveals missing heritability of KIF11-related retinopathy: clinical and genetic findings[J]. Genes, 2023, 14(1): 212. DOI: 10.3390/genes14010212.
18. Robitaille JM, Gillett RM, LeBlanc MA, et al. Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations[J]. JAMA Ophthalmol, 2014, 132(12): 1393-1399. DOI: 10.1001/jamaophthalmol.2014.2814.
19. Kondo H, Matsushita I, Nagata T, et al. Retinal features of family members with familial exudative vitreoretinopathy caused by mutations in KIF11 gene[J]. Transl Vis Sci Technol, 2021, 10(7): 18. DOI: 10.1167/tvst.10.7.18.
20. Riedl J, Voβmerbäumer U, Stoffelns B, et al. Total retinal detachment caused by a KIF11 mutation[J/OL]. Eur J Ophthalmol, 2017, 27(5): e147-e148[2017-08-30]. https://pubmed.ncbi.nlm.nih.gov/28574136/. DOI: 10.5301/ejo.5000987.
21. 成芳, 梁建宏. KIF11基因新突变致MCLMR综合征1例[J]. 中华眼底病杂志, 2023, 39(7): 583-584. DOI: 10.3760/cma.j.cn511434-20220425-00246.Cheng F, Liang JH. MCLMR syndrome caused by new mutation of KIF11 gene: a case report[J]. Chin J Ocul Fundus Dis, 2023, 39(7): 583-584. DOI: 10.3760/cma.j.cn511434-20220425-00246.
22. Meissner L, Niese L, Schuring I, et al. Human kinesin-5 KIF11 drives the helical motion of anti-parallel and parallel microtubules around each other[J]. EMBO J, 2024, 43(7): 1244-1256. DOI: 10.1038/s44318-024-00048-x.
23. Birtel J, Gliem M, Mangold E, et al. Novel insights into the phenotypical spectrum of KIF11-associated retinopathy, including a new form of retinal ciliopathy[J]. Invest Ophthalmol Vis Sci, 2017, 58(10): 3950-3959. DOI: 10.1167/iovs.17-21679.
24. Alzial C, Dufier JL, Brasnu C, et al. "True" microcephaly with dominant-inheritance chorioretinal dysplasia[J]. Ann Genet, 1980, 23(2): 91-94.
25. Feingold M, Bartoshesky L. Microcephaly, lymphedema, and chorioretinal dysplasia: a distinct syndrome?[J]. Am J Med Genet, 1992, 43(6): 1030-1031. DOI: 10.1002/ajmg.1320430623.
26. Gupta A, Vasudevan P, Biswas S, et al. Microcephaly with chorioretinal dysplasia: two case reports and a review of the literature[J]. Ophthalmic Genet, 2009, 30(4): 157-160. DOI: 10.3109/13816810903147980.
27. Lee BJ, Kim JH, Yu YS. Lissencephaly and mild cerebellar vermis hypoplasia in a case of microcephaly and chorioretinal dysplasia[J]. Ophthalmic Genet, 2010, 31(2): 89-93. DOI: 10.3109/13816811003620509.
28. Hu H, Xiao X, Li S, et al. KIF11 mutations are a common cause of autosomal dominant familial exudative vitreoretinopathy[J]. Br J Ophthalmol, 2016, 100(2): 278-283. DOI: 10.1136/bjophthalmol-2015-306878.
29. Hull S, Arno G, Ostergaard P, et al. Clinical and molecular characterization of familial exudative vitreoretinopathy associated with microcephaly[J]. Am J Ophthalmol, 2019, 207: 87-98. DOI: 10.1016/j.ajo.2019.05.001.
30. Wang Y, Zhang Z, Huang L, et al. Update on the phenotypic and genotypic spectrum of KIF11-related retinopathy[J]. Genes, 2022, 13(4): 713. DOI: 10.3390/genes13040713.

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