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 Table of Contents  
Year : 2022  |  Volume : 10  |  Issue : 1  |  Page : 112-115

Identification of a novel KIF11 variant p.(Leu804Thrfs Ter13) in a case with isolated microcephaly

Department of Medical Genetics, Trakya University Faculty of Medicine, Edirne, Turkey

Date of Submission04-Mar-2022
Date of Decision06-Apr-2022
Date of Acceptance16-May-2022
Date of Web Publication23-Jun-2022

Correspondence Address:
Sinem Yalcintepe
Department of Medical Genetics, Trakya University Faculty of Medicine, Edirne 22030
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jhnps.jhnps_14_22

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Microcephaly is a rare neurological condition, and it is characterized by a smaller head than other children of the same age and sex. Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MLCRD) is a syndrome with a varying spectrum that occurs as a result of variants of KIF11 gene. A 3-year-old girl was presented to our clinic with microcephaly; she had no motor or growth retardation except microcephaly. After obtaining a normal karyotype and microarray result, Trusight One-Expanded Panel analysis showed NM_004523.4 (KIF11): c. 2409dupA (p. Leu804Thrfs Ter13) heterozygous pathogenic novel variant. Patients who have KIF11 mutation often also have different clinical features; in our case, the motor development is consistent with its peers and has a history of prenatal and postnatal microcephaly. Microcephaly can be caused by a variety of genetic mutations. In our case, firstly we identify the association of a novel de novo KIF11 gene duplication variant related to isolated microcephaly.

Keywords: Isolated microcephaly, KIF11, microcephaly, next generation sequencing, novel variant

How to cite this article:
Yalcintepe S, Guler HS, Zhuri D, Eker D, Gurkan H. Identification of a novel KIF11 variant p.(Leu804Thrfs Ter13) in a case with isolated microcephaly. J Head Neck Physicians Surg 2022;10:112-5

How to cite this URL:
Yalcintepe S, Guler HS, Zhuri D, Eker D, Gurkan H. Identification of a novel KIF11 variant p.(Leu804Thrfs Ter13) in a case with isolated microcephaly. J Head Neck Physicians Surg [serial online] 2022 [cited 2023 Jun 4];10:112-5. Available from: https://www.jhnps.org/text.asp?2022/10/1/112/347982

  Introduction Top

Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (OMIM #152950) is caused by mutations in the KIF11 gene (MIM #148760) located at chromosome region 10q23. KIF11 encodes EG5, a homotetramer kinesin motor protein. The function of this protein regulates chromosome positioning, centrosome separation, and establishes a bipolar spindle during cell mitosis.[1]

Microcephaly is an autosomal dominant disorder with a variable spectrum overlapping with the central nervous system and ocular development anomalies. Microcephaly might appear from mild-to-severe clinic with development delay. Although chorioretinopathy is the most common ophthalmic abnormality, the facial phenotypic features are a wide nose with a round tip, a protruding chin with a thin long filter on the upper lip, and a prominent ear structure.[2]

A new generation sequence analysis (NGS) Trusight One-Expanded Panel study was performed on a case that has not had any pathology in other routine genetic tests, and after sequencing, it was found that the clinical findings were associated with the microcephaly syndrome. A family segregation study was performed in terms of KIF11 gene using the Sanger sequencing method. Our aim is to present a case with prenatal onset and postnatal microcephaly.

  Case Report Top

A family applied to our clinic with the clinical finding of isolated microcephaly in the prenatal and postnatal period for a 3-year-old girl. The prenatal diagnosis test was suggested during the prenatal period, but it was not accepted by the family. The patient was born with a weight of 3740 g (10–25th centile) and started speaking with a single word when she was 9–10 months old. Anterior fontanelle was closed; she had seborrheic dermatitis and raised erythematous rashes on the face. The erythematous rashes from birth gradually decreased. Cranial magnetic resonance imaging was planned, but the patient's family did not accept. Caput succedaneum was detected in the postpartum period, and the hearing test was normal. She started walking when she was 1 year and 3 months old; she could be able to say one or two words when she was 2 years and 2 months old. The current weight of the patient is 12 kg (10–25th centile) and the length is 91 cm (10–25th centile). Motor development is suitable for her peers; her head circumference measurement is 41 cm (<3rd centile).

The Trusight One-Expanded Panel study (NGS) and family segregation study were performed for the KIF11 gene of the patient. Genomic DNA was isolated from the peripheral blood by using EZ1 DNA Blood Kit. “Trusight One-Exp. Series of Sequencing Panels” contains a library of 6708 genes. The study was prepared according to the Series of Sequencing Panels protocol and sequenced in the Illumina NextSeQ 550 System. In the analysis of the data, NextSeQ-550 System Software and Genomize Seq software were used, and IGV_2.3.6 program was used for the visual evaluation of the data.

As a result of the analysis, the heterozygous pathogenic novel NM_004523.4 (KIF11):c. 2409dupA (p. Leu804Thrfs Ter13) variant was detected, as shown in [Figure 1]. The variant has not been reported in dbSNP, Clinvar, and HGMD® Professional 2020.4 databases. NM_004523.4 (KIF11):c. 2409dupA (p. Leu804Thrfs Ter13) variant was classified as a pathogenic variant according to ACMG 2015 criterias (Pathogenic PVS1, PM2, PP3), GERP Score was 6.07, and Mutation Taster reported this variant as disease causing.[3],[4]
Figure 1: (a) IGV image of NM_004523.4 (KIF11):c. 2409dupA (p. Leu804Thrfs Ter13) variant in our case, (b) Sanger sequencing analysis of the KIF11 gene in our case and family members

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To confirm the phenotype–genotype relationship of inheritance of the detected variant, the regions of the KIF11 gene in the maternal and paternal DNA were sequenced in the ABI Prism 3500XL device for family segregation. After analysis, de novo inheritance was detected, as shown in [Figure 1]. Primers for the KIF11 gene have been in-house designed.

  Discussion Top

The pathogenesis of microcephaly is a heterogeneous group in which genetic causes and various factors are effective, and it affects the brain size which develops abnormality in the prenatal and/or postnatal period.[5]

Ostergaard et al. reported in their study that three cases were detected with heterozygous KIF11 mutations in whole-exome sequencing, and subsequently, Sanger sequencing identified 12 more heterozygous mutations, and their results showed that the allelic disorders in KIF11 effect MLCRD [Table 1].
Table 1: Some cases with variants occurring in the KIF11 gene reported in the literature

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In a review article of 37 individuals from 22 different families, missense, nonsense, frameshift, and splice-site mutations were determined in the KIF11 gene, and 86% of the individuals were diagnosed with microcephaly, as shown in [Table 1].[6]

Screening of the KIF11 gene in a reported case with familial exudative vitreoretinopathy and microcephaly revealed a novel heterozygous protein-truncated variant NM_004523.3. KIF11: c. 2717del, p.(L906*), as shown in [Table 1].[7]

Rump et al., in their study, performed whole-exome sequencing in 38 patients related to microcephaly. Mutations were detected in previously identified microcephaly genes such as ASPM, RAB3GAP1, RNASEH2B, KIF11, RTTN, ERCC8, CASK, DYRK1A, and BRCA2. A frameshift mutation in the KIF11 gene was identified in a patient who had microcephaly and retinopathy. The mutation was an insertion of one base pair resulting as frameshift and after eight amino acids causing a stop codon.[8]

Patients who have KIF11 mutation often also have different clinical features such as lymphedema, exudative vitreoretinopathy, and coloboma.[9] There are multiple genes which are causing microcephaly, and this condition may be presented with different clinical findings. There may be different variants in all genes involved in microcephaly that affect the clinical severity of patients. In our case, there are no different clinical features, such as lymphedema, exudative vitreoretinopathy, and coloboma. The motor development of our case is consistent with its peers and the history of prenatal and postnatal microcephaly.

  Conclusion Top

A few genes were reported related to microcephaly. Microcephaly can be caused by a variety of genetic and environmental factors. In this case, we identified the association of a novel de novo KIF11 gene duplication variant with Microcephaly. In the literature, there is not any duplication variant of KIF11 gene in the position of c. 2409dupA (p. Leu804Thrfs). This is the first report of a novel KIF11 variant and isolated microcephaly.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


This material has never been published and is not currently under evaluation in any other peer-reviewed publication.

Ethical approval

The permission was obtaine from Institutional Ethics Committee before starting the project. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Data availability statement

The data supporting the findings of this study are available with the corresponding author upon request.

  References Top

Myers KA, Baas PW. Kinesin-5 regulates the growth of the axon by acting as a brake on its microtubule array. J Cell Biol 2007;178:1081-91.  Back to cited text no. 1
Ostergaard P, Simpson MA, Mendola A, Vasudevan P, Connell FC, van Impel A, et al. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy. Am J Hum Genet 2012;90:356-62.  Back to cited text no. 2
Cooper GM, Stone EA, Asimenos G, NISC Comparative Sequencing Program; Green ED, Batzoglou S, Sidow A. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res 2005;15:901-13.  Back to cited text no. 3
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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. Genet Med 2015;17:405-24.  Back to cited text no. 4
Woods CG, Basto R. Microcephaly. Curr Biol 2014;24:R1109-11.  Back to cited text no. 5
Jones GE, Ostergaard P, Moore AT, Connell FC, Williams D, Quarrell O, et al. Microcephaly with or without chorioretinopathy, lymphoedema, or mental retardation (MCLMR): Review of phenotype associated with KIF11 mutations. Eur J Hum Genet 2014;22:881-7.  Back to cited text no. 6
Karjosukarso DW, Cremers FP, van Nouhuys CE, Collin RW. Detection and quantification of a KIF11 mosaicism in a subject presenting familial exudative vitreoretinopathy with microcephaly. Eur J Hum Genet 2018;26:1819-23.  Back to cited text no. 7
Rump P, Jazayeri O, van Dijk-Bos KK, Johansson LF, van Essen AJ, Verheij JB, et al. Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly. BMC Med Genomics 2016;9:7.  Back to cited text no. 8
Hinds AM, Rosser E, Reddy MA. A case of exudative vitreoretinopathy and chorioretinal coloboma associated with microcephaly in a female with contiguous Xp11.3-11.4 deletion. Ophthalmic Genet 2018;39:396-8.  Back to cited text no. 9


  [Figure 1]

  [Table 1]


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