Skip to main content
SpringerLink
Log in

Novel phenotype and genotype spectrum of WDR62 in two patients with associated primary autosomal recessive microcephaly

  • Original Article
  • Published:
Irish Journal of Medical Science (1971 -) Aims and scope Submit manuscript

Abstract

Background

Microcephaly is a prominent feature of patients with primary autosomal recessive microcephaly 2 (MCPH2) caused by mutations in the WD Repeat Domain 62 (WDR62; OMIM: 613,583).

Aim

The study aimed to identify the underlying genetic factor(s) causing microcephaly in two patients in a consanguineous Iranian family.

Methods

Two male patients (11 and 27 years old) were noticed due to microcephaly, neurodevelopmental delay, and occasional seizures. The younger patient (the proband) was subjected to paired-end whole-exome sequencing followed by Sanger sequencing to detect any underlying genetic factor.

Results

Upon examination, both patients showed microcephaly as a prominent manifestation; they were under-weighted as well. The patients had a moderate gross motor impairment, severe cognitive disability and speech delay, increased deep tendon reflexes, flexible joint contractures, sensorineural hearing loss, and vertical nystagmus as a new ocular finding. The proband had more severe neurodevelopmental delay symptoms. The brain magnetic resonance imaging series revealed severe structural and cortical brain abnormalities in addition to hemiatrophy. Using Whole-exome Sequencing, a novel homozygous missense variant—NM_001083961.2; c.1598A > G: p.(His533Arg)—was identified in the WDR62. Subsequently, in silico analyses determined the possible impacts of the novel variant on the structure and function of WDR62 protein.

Conclusions

Herein, we identified a novel homozygous missense variant in the WDR62 in two patients with MCPH2. Vertical nystagmus and sensorineural hearing loss were detected as novel neurological findings. The present study expands the phenotype and genotype spectrum of MCPH2.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and materials

The variant was also submitted to ClinVar under the accession code of SCV9076660 and Leiden Open Variation Database (LOVD; individual number: 00331728).

Abbreviations

WES:

Whole-exome sequencing

MCPH2:

Primary autosomal recessive microcephaly 2

WDR62:

WD Repeat Domain 62

HC:

Head circumference

ACMG/AMP:

American College of Medical Genetics and Genomics/Association for Molecular Pathology

MRI:

Magnetic resonance imaging

MOCA:

Montreal Cognitive Assessment

References

  1. Abuelo D (2007) Microcephaly syndromes. Semin Pediatr Neurol 14(3):118–127. https://doi.org/10.1016/j.spen.2007.07.003

    Article  PubMed  Google Scholar 

  2. Woods CG, Bond J, Enard W (2005) Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet 76(5):717–728

  3. Timothy WY, Mochida GH, Tischfield DJ et al (2010) Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 42(11):1015–1020

    Article  Google Scholar 

  4. Hofman MA (1984) A biometric analysis of brain size in micrencephalics. J Neurol 231(2):87–93

  5. Barkovich AJ, Kuzniecky RI, Dobyns WB (2001) Radiologic classification of malformations of cortical development. Curr Opin Neurol 14(2):145–149

  6. Razmara E, Azimi H, Tavasoli AR et al (2020) Novel neuroclinical findings of autosomal recessive primary microcephaly 15 in a consanguineous Iranian family. Eur J Med Genet 63(12):104096

  7. Naseer MI, Rasool M, Sogaty S et al (2017) A novel WDR62 mutation causes primary microcephaly in a large consanguineous Saudi family. Ann Saudi Med 37(2):148–153

  8. Bilgüvar K, Oztürk AK, Louvi A et al (2010) Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467(7312):207–210. https://doi.org/10.1038/nature09327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bhat V, Girimaji S, Mohan G et al (2011) Mutations in WDR62, encoding a centrosomal and nuclear protein. Indian primary microcephaly families with cortical malformations. Clin Genet 80(6):532–540

    CAS  Google Scholar 

  10. Roberts E, Jackson AP, Carradice AC et al (1999) The second locus for autosomal recessive primary microcephaly (MCPH2) maps to chromosome 19q13.1–13.2. Eur J Hum Genet 7(7):815–820. https://doi.org/10.1038/sj.ejhg.5200385

  11. Morales A, Kinnamon DD, Jordan E et al (2020) Variant interpretation for dilated cardiomyopathy: refinement of the American College of Medical Genetics and Genomics/ClinGen Guidelines for the DCM Precision Medicine Study. Circ Genom Precis Med 13(4):e002480

  12. Farajollahi Z, Razmara E, Heidari E et al (2020) A novel variant of ST3GAL3 causes non‐syndromic autosomal recessive intellectual disability in Iranian patients. J Genet Med 22(11):e3253

  13. Sepahvand A, Razmara E, Bitarafan F et al (2020) A homozygote variant in the tRNA splicing endonuclease subunit 54 causes pontocerebellar hypoplasia in a consanguineous Iranian family. Mol Genet Genom Med 8(10):e1413

  14. Garshasbi M, Mahmoudi M, Razmara E et al (2020) Identification of RELN variant p.(Ser2486Gly) in an Iranian family with ankylosing spondylitis; the first association of RELN and AS. Eur J Hum Genet 1–9

  15. Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol (Clifton, NJ) 132:365–386. https://doi.org/10.1385/1-59259-192-2:365

    Article  CAS  Google Scholar 

  16. Wiel L, Baakman C, Gilissen D et al (2019) MetaDome: pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. Hum Mutat 40(8):1030–1038

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Glaser F, Pupko T, Paz I et al (2003) ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information. Bioinformatics 19(1):163–164

    Article  CAS  PubMed  Google Scholar 

  18. Frankish A, Harrow J (2014) GENCODE pseudogenes. In Pseudogenes. Springer, pp 129–155

  19. Schwarz JM, Rödelsperger C, Schuelke M, Seelow D (2010) MutationTaster evaluates disease-causing potential of sequence alterations. Nat Methods 7(8):575

    Article  CAS  PubMed  Google Scholar 

  20. Choi Y, Chan AP (2015) PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics 31(16):2745–2747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Adzhubei I, Jordan DM, Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen‐2. Curr Protoc Hum Genet 76(1):7.20. 21–27.20. 41

  22. Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31(13):3812–3814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sim N-L, Kumar P, Hu J et al (2012) SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 40(W1):W452–W457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Söding J, Biegert A, Lupas AN (2005) The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Res 33(suppl_2):W244-W248

  25. DeLano WL (2002) Pymol: an open-source molecular graphics tool. CCP4 Newsletter on Protein Crystallography 40(1):82–92

  26. Capriotti E, Fariselli P, Casadio R (2005) I-Mutant2. 0: predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Res 33(suppl_2):W306-W310

  27. Rodrigues CH, Pires DE, Ascher DB (2018) DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. Nucleic Acids Res 46(W1):W350–W355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bava KA, Gromiha MM, Uedaira H et al (2004) ProTherm, version 4.0: thermodynamic database for proteins and mutants. Nucleic Acids Res 32(suppl_1):D120-D121

  29. Lim H, Chan T, Yoong T (1994) Denver developmental screening test (DDST). Singapore Med J 35:156–160

    CAS  PubMed  Google Scholar 

  30. Nasreddine ZS, Phillips NA, Bédirian V et al (2005) The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53(4):695–699

    Article  PubMed  Google Scholar 

  31. Sherry ST, Ward M-H, Kholodov M et al (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29(1):308–311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li H, Handsaker B, Wysoker A et al (2009) 1000 Genome project data processing subgroup (2009) The sequence alignment/map format and samtools. Bioinformatics 25(16):2078–2079

    Article  PubMed Central  Google Scholar 

  33. Auer PL, Johnsen JM, Johnson AD et al (2012) Imputation of exome sequence variants into population-based samples and blood-cell-trait-associated loci in African Americans: NHLBI GO Exome Sequencing Project. Am J Hum Genet 91(5):794–808

    Article  CAS  PubMed  Google Scholar 

  34. Ferrer-Costa C, Gelpí JL, Zamakola L et al (2005) PMUT: a web-based tool for the annotation of pathological mutations on proteins. Bioinformatics 21(14):3176–3178

    Article  CAS  PubMed  Google Scholar 

  35. Landrum MJ, Lee JM, Riley GR et al (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res 42(Database issue):D980–985. https://doi.org/10.1093/nar/gkt1113

  36. Fokkema IF, Taschner PE, Schaafsma GC et al (2011) LOVD v. 2.0: the next generation in gene variant databases. Hum Mutat 32(5):557–563

  37. Nicholas AK, Khurshid M, Désir J et al (2010) WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 42(11):1010–1014

  38. Bogoyevitch MA, Yeap YY, Qu Z et al (2012) WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression. J Cell Sci 125(21):5096–5109

    PubMed  PubMed Central  Google Scholar 

  39. Thornton GK, Woods CG (2009) Primary microcephaly: do all roads lead to Rome? Trends Genet 25(11):501–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zaqout S, Morris-Rosendahl D, Kaindl AM (2017) Autosomal recessive primary microcephaly (MCPH): an update. Neuropediatrics 48(03):135–142

    Article  PubMed  Google Scholar 

  41. Barbelanne M, Tsang WY (2014) Molecular and cellular basis of autosomal recessive primary microcephaly. BioMed Res Int

  42. Nicholas AK, Khurshid M, Désir J et al (2010) WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 42(11):1010–1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Timothy WY, Mochida GH, Tischfield DJ et al (2010) Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet 42(11):1015–1020

  44. Farag HG, Froehler S, Oexle K et al (2013) Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation. Orphanet J Rare Dis 8(1):1–14

    Article  Google Scholar 

  45. Faheem M, Naseer MI, Rasool M et al (2015) Molecular genetics of human primary microcephaly: an overview. BMC Med Genomics 8(1):1–11

    CAS  Google Scholar 

  46. Ruaud L, Drunat S, Elmaleh-Bergès M et al ( 2021) Neurological outcome in WDR62 primary microcephaly. Dev Med Child Neurol (DMCN) n/a (n/a). https://doi.org/10.1111/dmcn.15060

  47. Naseer MI, Rasool M, Sogaty S et al (2017) A novel WDR62 mutation causes primary microcephaly in a large consanguineous Saudi family. Ann Saudi Med 37(2):148–153

    Article  PubMed  PubMed Central  Google Scholar 

  48. Slezak R, Smigiel R, Obersztyn E et al (2021) Further delineation of phenotype and genotype of primary microcephaly syndrome with cortical malformations associated with mutations in the WDR62 gene. Genes 12(4). https://doi.org/10.3390/genes12040594

  49. Banerjee S, Chen H, Huang H et al (2016) Novel mutations c. 28G > T (p. Ala10Ser) and c. 189G > T (p. Glu63Asp) in WDR62 associated with early onset acanthosis and hyperkeratosis in a patient with autosomal recessive microcephaly type 2. Oncotarget 7(48):78363

Download references

Acknowledgements

We are grateful to the family for their willing participation and cooperation with us.

Author information

Authors and Affiliations

  1. National Institute for Genetic Engineering and Biotechnology, Tehran, Iran

    Hajar Aryan

  2. Farhud Medical Genetics Laboratory, Tehran, Iran

    Hajar Aryan, Shaghayegh Zokaei & Dariush Farhud

  3. School of Advanced Medical Science, Islamic Azad University, Tehran, Iran

    Shaghayegh Zokaei

  4. School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

    Dariush Farhud

  5. Endocrinology and Metabolism Population Sciences Institute, Non-Communicable Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Mohammad Keykhaei

  6. Pediatric Neurology Division, Children’s Medical Center, Pediatrics Center of Excellence, Myelin Disorders Clinic, Tehran University of Medical Sciences, Tehran, Iran

    Mahmoud Reza Ashrafi & Ali Reza Tavasoli

  7. School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Maryam Rasulinezhad & Seyyed Mohammad Mahdi Hosseini

  8. Australian Regenerative Medicine Institute, Monash University, Melbourne, 3800, Australia

    Ehsan Razmara

Authors
  1. Hajar Aryan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaghayegh Zokaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dariush Farhud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Keykhaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mahmoud Reza Ashrafi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maryam Rasulinezhad
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seyyed Mohammad Mahdi Hosseini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ehsan Razmara
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ali Reza Tavasoli
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Hajar Aryan: conceptualization, data curation, formal analysis, methodology, validation. Shaghayegh Zokaei: formal analysis, methodology, validation, visualization, software, writing — original draft, writing — review and editing. Dariush Farhud: data curation, formal analysis. Mohammad Keykhaei: data curation, writing — review and editing. Mahmoud Reza Ashrafi: formal analysis. Maryam Rasulinezhad: formal analysis, validation. Seyyed Mohammad Mahdi Hosseini: formal analysis. Ehsan Razmara: formal analysis, validation, visualization, software, writing — original draft, writing — review and editing. Ali Reza Tavasoli: funding acquisition, resources, methodology, project administration, investigation, writing — review and editing.

Corresponding author

Correspondence to Ali Reza Tavasoli.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the ethics committee of Tarbiat Modares University, Tehran, Iran and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent for publication

Written informed consent was obtained from the patient and patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Aryan, H., Zokaei, S., Farhud, D. et al. Novel phenotype and genotype spectrum of WDR62 in two patients with associated primary autosomal recessive microcephaly. Ir J Med Sci 191, 2733–2741 (2022). https://doi.org/10.1007/s11845-021-02890-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11845-021-02890-y

Keywords

Search

Navigation