Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR; OMIM 152950) is a rare autosomal dominantly inherited syndrome. Mutations in the kinesin family member 11 (KIF11) gene have been associated with this condition. Here, we report a de novo novel heterozygous missense mutation in exon 12 of the KIF11 gene [c.1402T>G; p.(Leu468Val)] in a boy with 22q11.2 microdeletion syndrome. His major features were microcephaly, ventricular septal defect, congenital lymphedema of the feet, and distinct facial appearance including upslanting palpebral fissures, a broad nose with rounded tip, anteverted nares, long philtrum with a thin upper lip, pointed chin, and prominent ears. His right eye was enucleated due to subretinal hemorrhage and retinal detachment at age 3 months. Lacunae of chorioretinal atrophy and the pale optic disc were present in the left eye. He also had a de novo 1.6-Mb microdeletion in the Di George/VCFS region of chromosome 22q11.2 in SNP array, which was confirmed by FISH analysis. In this study, for the first time, we describe the co-occurrence of a KIF11 mutation and 22q11.2 deletion syndrome in a patient with MCLMR

Güneş, N

Jeffery, H

Ostergaard, P

Taşdemir, E

Tüysüz, B

Yetik, H

Molecular Syndromology

St George's Online Research Archive

 1 A novel mutation of KIF11 in a child with 22q11.2 deletion syndrome associated with 1 MCLMR 2  3 Nilay Güneşa, Emre Taşdemira, Heather Jefferyc, Hüseyin Yetikb, Pia Ostergaardc, Beyhan 4 Tüysüza 5  6 aDepartment of Pediatric Genetics, and bDepartment of Ophthalmology, Cerrahpaşa Medical 7 Faculty, Istanbul University, Istanbul, Turkey; cMolecular and Clinical Sciences Research 8 Institute, St George's University of London, London SW17 0RE, UK 9  10  11  12 Running title: 22q11.2 deletion syndrome and KIF11 mutation 13  14 Corresponding author: 15 Beyhan Tüysüz 16 Department of Pediatric Genetics, Cerrahpaşa Medical Faculty, Istanbul University, 34098, 17 Cerrahpaşa, Istanbul/Turkey 18 Tel.: +902124143192, Fax: +902126328633 19 E-Mail: beyhan@istanbul.edu.tr 20 21  2 Abstract 1 Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation 2 (MCLMR, OMIM 152950) is a rare autosomal dominantly inherited syndrome. Mutations in 3 the kinesin family member 11 (KIF11) gene have been associated with this condition. We 4 report here a de novo novel heterozygous missense mutation in exon 12 of the KIF11 gene 5 c.1402T>G, p.(Leu468Val) in a boy with 22q11.2 microdeletion syndrome. His major 6 features were microcephaly, ventricular septal defect (VSD), congenital lymphedema of the 7 feet, and distinct facial appearance including upslanting palpebral fissures, a broad nose with 8 rounded tip, anteverted nares, long philtrum with thin upper lip, pointed chin, and prominent 9 ears. His right eye was enucleated due to subretinal hemorrhage and retinal detachment at age 10 3 months. Lacunae of chorioretinal atrophy and the pale optic disc were present in the left 11 eye. He also had a de novo 1.6 Mb microdeletion in the Di George/VCFS region of 12 chromosome 22q11.2 in SNP-array, which was confirmed by fluorescence in situ 13 hybridization analysis. Here, we report, for the first time the co-occurrence of a KIF11 14 mutation and 22q11.2 deletion syndrome in a patient with MCLMR. 15  16 Keywords: MCLMR, microcephaly, lymphedema, chorioretinal dysplasia, KIF11, 22q11.2 17 deletion. 18 19  3 Introduction 1 There was an ongoing debate about the phenotypic overlap between microcephaly, 2 primary lymphedema and chorioretinal dysplasia syndrome (MLCRD; OMIM 152950) and 3 chorioretinal dysplasia, microcephaly and mental retardation syndrome (CDMMR; OMIM 4 156590) Angle et al., 1994; Feingold and Bartoshesky, 1992; Fryns et al., 1995. With the 5 identification of causative variants in the kinesin family member 11 (KIF11) gene in both 6 MLCRD and CDMMR cases, it was demonstrated that these conditions are allelic with highly 7 variable expression Ostergaard et al., 2012. The association of microcephaly with or without 8 chorioretinopathy, lymphedema, or mental retardation is now collectively called MCLMR and 9 merged into one entity (OMIM 152950). 10  The 22q11.2 deletion syndrome (OMIM 188400) is a frequent microdeletion 11 syndrome with an estimated incidence ranging between 1:2000 to 1:7000 live births 12 Shprintzen, 2008. The clinical features consist of conotruncal heart malformations, palatal 13 abnormalities, learning difficulties, thymus and parathyroid hypoplasia, and characteristic 14 facial features including short palpebral fissures, hypoplastic ala nasi, bulbous nasal tip, small 15 mouth and chin and overfolded helices Binenbaum et al., 2008; Forbes et al., 2007.  16 Here, we report a case with MCLMR and 22q11.2 deletion syndrome presenting with 17 overlapping clinical findings. 18  19 Subjects and Methods 20 A 1-year-old boy was referred due to the atypical facies. His healthy parents were non-21 consanguineous. His birth weight, length, and head circumference (OFC) were 3230 gr (-0.5 22 SD), 50 cm (-0.06 SD), and 30.1 cm (-2.5 SD), respectively. Postnatal echocardiography 23 revealed a perimembranous VSD. Because of bilateral edema of the dorsum of the feet, 24 lymphoscintigraphy was performed. There was no evidence of uptake of tracer in the inguinal 25  4 lymph nodes or lymphatic tracts confirming the primary lymphedema. The result is typical of 1 the functional aplasia typically observed in MCLMR Ostergaard et al., 2012. Due to the 2 prediagnosis of retinoblastoma, his right eye was enucleated and fitted with a prosthetic eye at 3 age 3 months. Pathological examination of the right eye revealed diffuse retinal detachment 4 and subretinal hemorrhage. 5 On his examination at 1-year-old, he had microcephaly (OFC: 38 cm, -6.7 SD), 6 prominent ears, upslanting palpebral fissures, a broad nose with rounded tip, anteverted nares, 7 long philtrum with thin upper lip, high arched palate, micro-retrognathia, and congenital 8 lymphedema of the feet (Fig. 1A, B). He achieved head control, sitting, and walking at 2, 8, 9 and 12 months, respectively. Complete blood count, calcium metabolism, thyroid functions, 10 immunoglobulins and T lymphocyte subsets were in normal range. Echocardiography 11 revealed spontaneous closure of the VSD. No venous insufficiency in lower extremities was 12 seen via venous Doppler. Cranial MRI revealed microcephaly without any structural 13 abnormalities. Fundoscopic examination of the left eye revealed the pale optic disc and 14 lacunar chorioretinal atrophy. Electroretinography showed generalized rod-cone dysfunction. 15 Hearing test was normal. Developmental quotient of Denver II Developmental Test at age 6, 16 was 60. He had hyperactive behavior and attention problems but could speak in long 17 sentences fluently by age 6. He has been followed up regularly and was 8 years old at the last 18 examination. During the follow-up period, his growth parameters (height and weight) were 19 normal. At 8 years of age, his weight and length were 20 kg (-1.89 SD) and 122 cm (-1.04 20 SD), respectively. However, his OFC was 45 cm (-5.3 SD) (Fig. 1C, D). The findings of the 21 left fundus remained the same. He had low visual acuity and could count fingers at 2 meters. 22 His OCT imaging revealed severe retinal thinning. The bilateral lymphedema remained more 23 pronounced on the right foot (Fig. 1E). 24  5 For detection of copy number aberrations, Human CytoSNP-12 bead chip array 1 (Illumina) which contains approximately 300.000 SNPs per sample was used with a targeted 2 and overall resolution of 62 KB and 72 KB, respectively. Fluorescence in situ hybridization 3 analysis (FISH) was carried out using the standard probe (Di George/VCFS TUPLE 1) for 4 22q11.2 deletion. MCLMR was suspected based on the retinal detachment history, 5 microcephaly, pale optic disc, chorioretinal atrophy and congenital lymphedema. Direct 6 sequencing of all 22 exons and flanking introns of KIF11 was performed using methods 7 described previously Ostergaard et al., 2012. Pathogenicity and potential functional effects 8 of detected variants in KIF11 were assessed using Mutation Taster and SIFT prediction tools 9 Schwarz et al., 2010; Kumar et al., 2009. 10  11 Results 12 The karyotype analysis was normal (46,XY). SNP-array analysis detected a de novo 13 1.6 Mb microdeletion in the Di George/VCFS region of the 22q11.2 locus (Fig. 2A), which 14 was confirmed by FISH (Fig. 2B). The SNP-array analysis showed no additional pathological 15 CNVs. A de novo heterozygous missense mutation in exon 12 of the KIF11 gene 16 (NM_004523: c.1402T>G; p.Leu468Val) was detected (Fig. 2C-E). The variant is predicted 17 pathogenic according to Mutation Taster (probability>0.9999) and SIFT (SIFT score: 0.03) 18 and has not been observed in 1000 Genome Project (http://www.internationalgenome.org/) or 19 Genome Aggregation (http://gnomad.broadinstitute.org/) databases. The variant was 20 submitted to the LOVD database (variant number #72895, 21 https://databases.lovd.nl/shared/genes/KIF11). 22  23  24  25  6 Discussion 1 KIF11 encodes a homotetrameric protein, EG5, that drives microtubule sliding and 2 contributes to the assembly of the mitotic spindle Jones et al., 2014. EG5 also has non-3 mitotic functions such as involvement in endothelial cell lineage proliferation, secretory 4 protein transportation and protein translation Bartoli et al., 2011; Exertier et al., 2013; 5 Wakana et al., 2013.  EG5 possibly also has a role in the cilia Birtel et al., 2017. 6 Jones et al. 2014 assessed 37 individuals with KIF11 mutations and found 7 microcephaly, ocular abnormality, lymphedema, epilepsy, and cardiac anomaly as major 8 clinical features.  The OFCs of the patients were ranging from -9.5 to -1.1 SDs. Similarly, 9 Robitaille et al. 2014 reported a KIF11 mutation-positive patient with microcephaly (OFC: -10 4 SD), bilateral chorioretinal atrophy and retinal detachment. Her mother, with the same 11 mutation, had borderline microcephaly (OFC: -2 SD). However, her eye examination 12 remained normal, indicating variable expression of the condition. 13 In the study of Jones et al. 2014, major ocular abnormalities were chorioretinopathy, 14 hypermetropia, myopia, bilateral retinal folds and microphtalmia. Lacunar chorioretinopathy 15 was found in approximately 60% of the patients. Balikova et al. 2016 showed generalized 16 rod-cone and severe macular dysfunction in seven, optic disc pallor in three patients with 17 KIF11 mutations. Their long-term observation of three of the KIF11 mutation positive 18 patients with chorioretinal atrophy over 2, 6 and 9 years revealed no progression of fundus 19 examinations. Consistently in our patient, focal areas of lacunar chorioretinal atrophy and 20 optic atrophy were observed. Electroretinography showed generalized rod-cone dysfunction. 21 He had unilateral retinal detachment and a history of enucleation because of the prediagnosis 22 of retinoblastoma. During his follow-up, the findings of the left fundus remained the same. 23 Therefore, we highlight that, eye findings of the condition may resemble retinoblastoma. 24  7 The lymphedema seen in KIF11 mutations is described as congenital, bilateral and 1 confined to the dorsa of the feet. However, adult onset and intermittent lymphedema were 2 also reported Jones et al., 2014. Interestingly, a very recent study has reported primary 3 lymphedema of lower limbs in four patients with 22q11.2 deletion syndrome Unolt et al., 4 2018. Unlike the patients with MCLMR, the lymphedema in these patients was not confined 5 to the feet and extended to the calves in one and to the thighs in three patients. The patient 6 presented here had a bilateral and pedal congenital lymphedema typical of that seen in other 7 MCLMR cases. Thus, we have considered that congenital lymphedema in our patient is 8 related to the KIF11 mutation rather than the 22q11.2 deletion syndrome. 9 The characteristic facial phenotype of KIF11 mutations was described as upslanting 10 palpebral fissures, broad nose with rounded tip, long philtrum with thin upper lip and 11 prominent ears Jones et al., 2014. Since bulbous nasal tip, small mouth and chin are 12 common features of the 22q11.2 deletion syndrome Binenbaum et al., 2008, we have 13 postulated that the facial features of our patient are in association with both conditions. 14 In the MCLMR review, 8% of the patients had cardiac anomalies including patent 15 foramen ovale, thickened pulmonary valve, hypertrophic cardiomyopathy and atrial septal 16 defect Jones et al., 2014. We have considered that VSD in our patient is related to the 17 22q11.2 deletion rather than the KIF11 mutation. The common findings of 22q11.2 deletion 18 syndrome, including thymus and parathyroid hypoplasia, hearing loss were not present in the 19 patient. 20 Recent observational WES studies have found that approximately 5% of patients were 21 carriers of two gene defects. Diagnosing the cases with dual molecular findings can be 22 difficult especially if the phenotypes overlap Yang et al., 2014; Posey et al., 2017. As the 23 22q11.2 deletion did not explain the whole clinical picture of our proband, MCLMR was 24 suspected based on the microcephaly, eye problems and congenital lymphedema and a novel 25  8 de novo variant in KIF11 was identified. We propose that these two genetic syndromes are the 1 cause of the mixed phenotype of the patient. 2 In conclusion, we have identified in a patient the association of 22q11.2 deletion 3 syndrome and KIF11 mutation for the first time and discussed the overlapping clinical 4 findings such as distinct facial appearance, VSD as well as microcephaly, congenital 5 lymphedema and chorioretinopathy.  6  7 Statement of Ethics 8 Signed informed consent and the permission for the publication of photos of the 9 patient were obtained from the parents. The data presented in this study was retrieved from 10 the routine clinical care facilities of Cerrahpasa School of Medicine, Istanbul, Turkey. 11  12 Conflicts of Interest 13 The authors declare no conflicts of interest. 14  15 Acknowledgements 16 This work was supported by the Turkish Pediatric Association grant date/number: 17 14.08.14/08. 18  9 References  Angle B, Holgado S, Burton BK, Miller MT, Shapiro MJ, et al: Microcephaly, lymphedema, and chorioretinal dysplasia: report of two additional cases. Am J Med Genet 53:99-101 (1994). Balikova I, Robson AG, Holder GE, Ostergaard P, Mansour S, et al: Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11. Acta Ophthalmol 94:92-98 (2016). Bartoli KM, Jakovljevic J, Woolford JL, Jr., Saunders WS: Kinesin molecular motor Eg5 functions during polypeptide synthesis. Mol Biol Cell 22:3420-3430 (2011). Binenbaum G, McDonald-McGinn DM, Zackai EH, Walker BM, Coleman K, et al: Sclerocornea associated with the chromosome 22q11.2 deletion syndrome. Am J Med Genet A 146A:904-909 (2008). Birtel J, Gliem M, Mangold E, Tebbe L, Spier I, et al: Novel insights into the phenotypical spectrum of KIF11-associated retinopathy, including a new form of retinal ciliopathy. Invest Ophthalmol Vis Sci 58:3950-3959 (2017). Exertier P, Javerzat S, Wang B, Franco M, Herbert J, et al: Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5. Oncotarget 4:2302-2316 (2013). Feingold M, Bartoshesky L: Microcephaly, lymphedema, and chorioretinal dysplasia: a distinct syndrome? Am J Med Genet 43:1030-1031 (1992). Forbes BJ, Binenbaum G, Edmond JC, DeLarato N, McDonald-McGinn DM, et al: Ocular findings in the chromosome 22q11.2 deletion syndrome. J AAPOS 11:179-182 (2007). Fryns JP, Smeets E, Van den Berghe H: On the nosology of the "primary true microcephaly, chorioretinal dysplasia, lymphoedema" association. Clin Genet 48:131-133 (1995). Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, et al: Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): review of phenotype associated with KIF11 mutations. Eur J Hum Genet 22:881-887 (2014). Kumar P, Henikoff S, Ng PC: Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 4:1073-1081 (2009). Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, et al: Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet 90:356-362 (2012). Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, et al: Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med 376:21-31 (2017). Robitaille JM, Gillett RM, LeBlanc MA, Gaston D, Nightingale M, et al: Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymphedema, and chorioretinal dysplasia caused by KIF11 mutations. JAMA Ophthalmol 132:1393-1399 (2014).  10 Schwarz JM, Rödelsperger C, Schuelke M, Seelow D: MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7:575-576 (2010). Shprintzen RJ: Velo-cardio-facial syndrome: 30 Years of study. Dev Disabil Res Rev 14:3-10 (2008). Unolt M, Barry J, Digilio MC, Marino B, Bassett A, et al: Primary lymphedema and other lymphatic anomalies are associated with 22q11.2 deletion syndrome. Eur J Med Genet (2018). https:doi.org/10.1016/j.ejmg.2018.02.006. Wakana Y, Villeneuve J, van Galen J, Cruz-Garcia D, Tagaya M, et al: Kinesin-5/Eg5 is important for transport of CARTS from the trans-Golgi network to the cell surface. J Cell Biol 202:241-250 (2013). Yang Y, Muzny DM, Xia F, Niu Z, Person R, et al: Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312:1870-1879 (2014).  11 Figure Titles and Legends  Fig. 1. The clinical appearance of the patient at different ages: At 19 months of age (A, B), 5 years and 6 months of age (C), 6 years and 6 months of age (D, E). Note prominent ears, upslanting palpebral fissures, broad nose, anteverted nares, long philtrum, thin upper lip, micro-retrognathia, a pointed chin and slender and long fingers (A, C, D). Lymphedema of the feet has remained bilaterally, dominantly on the right side (B, E).  Fig. 2. A SNP-array identified a 1.6 MB deletion of the 22q11.2 region. B The standard probe (Di George/VCFS TUPLE 1) for 22q11.2 deletion syndrome showing a single 22 homolog signal (red band indicated by white arrow) confirms the deletion. Green band (indicated by red arrows) demonstrates the 22qter control probe. C A heterozygous variant was identified in exon 22 of KIF11 by Sanger sequencing in the patient (upper panel), but not in either of the parents (mother, middle panel; father, lower panel). Schematic representation of the genomic organisation of KIF11 with the c.1402T>G mutation and the representation of the EG5 protein with the p.Leu468Val variant (D, E).  12            Figure 1 a c b d e  13         Figure 2 e d 

A novel mutation of KIF11 in a child with 22q11.2 deletion syndrome associated with MCLMR

Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR; OMIM 152950) is a rare autosomal dominantly inherited syndrome. Mutations in the kinesin family member 11 (KIF11) gene have been associated with this condition. Here, we report a de novo novel heterozygous missense mutation in exon 12 of the KIF11 gene [c.1402T>G; p.(Leu468Val)] in a boy with 22q11.2 microdeletion syndrome. His major features were microcephaly, ventricular septal defect, congenital lymphedema of the feet, and distinct facial appearance including upslanting palpebral fissures, a broad nose with rounded tip, anteverted nares, long philtrum with a thin upper lip, pointed chin, and prominent ears. His right eye was enucleated due to subretinal hemorrhage and retinal detachment at age 3 months. Lacunae of chorioretinal atrophy and the pale optic disc were present in the left eye. He also had a de novo 1.6-Mb microdeletion in the Di George/VCFS region of chromosome 22q11.2 in SNP array, which was confirmed by FISH analysis. In this study, for the first time, we describe the co-occurrence of a KIF11 mutation and 22q11.2 deletion syndrome in a patient with MCLMR. (C) 2018 S. Karger AG, Base

Jeffery, Heather

Yetik, Huseyin

Gunes, Nilay

Ostergaard, Pia

Tuysuz, Beyhan

Tasdemir, Emre

İstanbul Üniversitesi Açık Erişim Sistemi

A Novel Mutation of KIF11 in a Child with 22q11.2 Deletion Syndrome Associated with MCLMR

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A novel mutation of KIF11 in a child with 22q11.2 deletion syndrome associated with MCLMR

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