Skip to main content

A novel VPS13B mutation in Cohen syndrome: a case report and review of literature

Abstract

Background

Cohen syndrome, an autosomal recessive syndrome, is a rare syndrome with diverse clinical manifestations including failure to thrive, hypotonia, hypermobile joints, microcephaly, intellectual disabilities, craniofacial and limb anomalies, neutropenia and a friendly character. It is associated with mutations of the vacuolar protein sorting 13 homolog B (VPS13B) gene, which is involved in the development of the ocular, hematological and central nervous systems. This gene encodes a transmembrane protein playing a crucial role in preserving the integrity of the Golgi complex. To date, more than 150 mutations of VPS13B have been reported in over 200 Cohen syndrome patients. Missense or nonsense mutations are the most common mutations.

Case presentation

A 4-year-old girl, born to consanguineous parents, was referred to the pediatric clinical immunology outpatient clinic for investigation of recurrent neutropenia with a history of recurrent infections in the past year. On physical examination, she had the characteristic facial features of Cohen syndrome, developmental delay and speech disorder. She had a cheerful disposition, and her mother gave a history of feeding difficulties in her first months of life. She did not present any ophthalmologic or cardiac abnormalities. Her lab results revealed moderate neutropenia. Serum IgG, IgM, IgA and IgE levels were normal. She fulfilled the clinical diagnostic criteria for Cohen syndrome. WES revealed a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49). Currently, she is not experiencing any severe problem, and she undergoes irregular medical treatment once her neutrophil count decreases under the normal limit. Her verbal and motor abilities have improved as a result of speech and occupational therapies.

Conclusion

We reported a novel homozygous frameshift variant in VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49) in a 4-year-old girl with Cohen syndrome. Cohen syndrome should be considered in differential diagnosis of any child with intellectual disability and neutropenia.

Peer Review reports

Background

Cohen syndrome (CS) (OMIM No. # 216550), a rare autosomal recessive syndrome, was first reported in 1973 by Cohen and his colleagues [1, 2]. Cohen syndrome has been reported in more than 200 cases to date. Patients with this syndrome manifest characteristic facial features together with psychomotor developmental delay. This syndrome involves ocular, hematologic, musculoskeletal, nervous, gastrointestinal, cardiovascular, and endocrine systems [3,4,5,6,7].

Missense or nonsense mutations in the Vacuolar protein sorting 13 homolog B (VPS13B) gene are the cause for Cohen syndrome with more than 150 known variants reported in The Human Gene Mutation Database [8,9,10]. Members of the VPS13 protein family are all involved in membrane fusion events and vesicular transport mechanisms. While mutations in VPS13B cause CS, the family members VPS13A and VPS13C cause an autosomal recessive Huntington’s-like neurodegenerative disease chorea acanthocytosis [11] and a Parkinson’s-like syndrome, respectively [12].

VPS13B, an essential protein for maintaining the integrity and function of the Golgi apparatus [7], is a large protein with > 4000 amino acids having lipid binding capacity [13, 14]. It is likely that different protein-protein interactions intrinsic to the VPS13 domain architectures are the reason for the diverse human disease manifestations caused by the vps13 gene family.

We reported a novel homozygous frameshift variant in the VPS13B gene in a girl born to a consanguineous family with recurrent infections and neutropenia, which are rarely reported as initial manifestations of CS. In addition to our case report, we conducted a mini reviewed of the current literature on CS.

Case presentation

A four-year-old girl born to a consanguineous family was referred to the pediatric clinical immunology outpatient clinic for diagnostic workup of recurrent infections and recurrent neutropenia in the past year. The medical history, indicated a delay in motoric milestones and feeding difficulties in her first months of life. Currently, she is not able to eat solid food. She had no history of seizures. Her parents were disease free and none of her relative had experienced similar symptoms, she has no siblings. Her mother had a history of stillbirth in her first pregnancy. On clinical examination, the patient had microcephaly, hypotonia, hypermobile joints, motor developmental delay, slender fingers, and a cheerful disposition. She had speech delay and had just started to utter some words. Her facial characteristics included low hairline, short philtrum, prominent upper central incisors, wave-shaped eyelids, thick and long eyelashes and prominent root of nose (Fig. 1). Unlike many other cases of CS [15], the eye examination was normal.

Fig. 1
figure1

Low hairline, short philtrum, prominent upper central incisors, wave-shaped eyelids, thick and long eyelashes and prominent root of nose in the patient with Cohen syndrome

In review of her lab results in the period of past 6 months, absolute neutrophil count ranged from 0.5–2.32 (103/μL), neutrophil percentile ranged from 7.8–30%, and other components of complete blood count were normal. Erythrocyte sedimentation rate (ESR), serum IgG, IgM, IgA and IgE levels (assessed with ELISA test), serum T3 and T4, TSH, urea, creatinine and fasting blood sugar were normal. Serum alkaline phosphatase was lower than normal (135 U/L). Table 1 indicates the summary of the patient’s lab results.

Table 1 Summary of the patient’s lab results

Given the patient’s history, physical examination, and lab results, different subtypes of congenital neutropenia, including G6PC3 deficiency, cartilage-hair hypoplasia, ELANE-Related neutropenia and WAS-Related disorders were considered as differential diagnosis. Based on her developmental delay, friendly disposition and facial features, CS was our primary diagnosis. However, due to expenses of Whole exome sequencing in the patient’s country, the test was performed in a foreign country and confirming the final diagnosis took longer than anticipated.

Whole exome sequencing for the patient was performed at the Dr. von Hauner Children’s hospital NGS facility using Agilent V6 + UTR library preparation and an Illumina NextSeq 500 sequencing platform. The bioinformatics analysis pipeline uses Burrows-Wheeler Alingner (BWA 0.7.15). Genome Analysis Tool Kit (GATK 3.6), Variant Effect Predictor (VEP 89) and frequency filters with public and in house databases (e.g. ExAC [16], GenomAD [17] and GME [18]). We found a novel homozygous frameshift variant in the VPS13B gene: VPS13B (LRG_351t1: c.7095del; p.Ser2366AlafsTer49). Based on the classical 5-tiered system introduced by the American College of Medical Genetics and Genomics, this variant is classified as a pathogenic variant and there is very strong evidence for its pathogenicity [19, 20]. This mutation confirmed our early diagnosis.

Currently, the patient is not experiencing any severe problem. No unanticipated adverse effect has been observed. The patient undergoes irregular medical treatment with 300 μg/injection granulocyte colony stimulating factor (GCSF) once her neutrophil count decreases under the normal limit. Also, Co-Trimoxazole 80 mg/400 mg has been prescribed for infection prophylaxis. Her eye examination remained normal. Her verbal and motor abilities have improved as a result of speech and occupational therapies. She is able to say some simple words like mom and dad. She is also able to walk with her parents’ assistance. Lastly, due to the high likelihood of developing ocular abnormalities, the patient is evaluated by an ophthalmologist periodically.

Discussion and conclusion

We reported a novel homozygous frameshift variant in the VPS13B gene (LRG_351t1: c.7095del; p.Ser2366AlafsTer49), leading to loss of function, in a 4-year-old girl with CS born to a consanguineous heterozygous family of Iranian descent.

In this case, the patient’s most prominent manifestations were intellectual disability and neutropenia. Unlike most of other cases, our patient did not present any ophthalmologic abnormality. She also did not present any cardiologic abnormality, which may be seen in some cases of CS. Thus, the combination of intellectual disability and neutropenia can be a red flag for CS.

Cohen and his colleagues reported CS in two siblings and an isolated patient for the first time in 1973 [1, 2]. Even though they did not indicate neutropenia as a key component of this syndrome, later in 1984, Norio et al. revealed that neutropenia is one of the major findings in these patients [21]. The manifestations of this syndrome may be widely varied; however, the Finnish cases are reported to present similar phenotypes [22]. The heterogeneous presentation makes the diagnosis of this syndrome tricky. Nowadays, it is believed that “Mishosseini-Holmes-Walton syndrome” is, in fact, CS [5].

The mutant gene in CS, VPS13B (also known as COH1), is located on chromosome 8q22.2 [5]. VPS13 plays an important role for several cellular functions, e.g. (1) preserving the integrity and function of the Golgi apparatus, (2) protein glycosylations, and (3) endosomal-lysosomal trafficking [5, 9, 23, 24].

To date 173 VPS13B variants have been reported,157 of which 157 are associated with CS [10]. Patients’ different phenotypes are explained by different VPS13B variants. Recurrent neutropenia in CS can be caused by a mutation in the VPS13B gene, which is linked to increased apoptosis of neutrophils and decreased expression of SerpinB1, which is a vital element for survival of neutrophil [25].

Table 2 summarizes Cohen syndrome’s clinical manifestations. Table 3 illustrates the paraclinical findings in this syndrome.

Table 2 Summary of Cohen syndrome’s clinical manifestations [1, 3,4,5, 22, 25,26,27,28,29]
Table 3 Paraclinical findings [4, 5, 30, 31]

Management of CS includes regular monitoring and rehabilitation. Recombinant human granulocyte colony stimulating factor (rHG-CSF) can be used in neutropenia management. For monitoring neutropenia, serial absolute neutrophil count (ANC) is recommended. Moreover, since these patients are prone to develop insulin resistance, blood pressure, fasting blood sugar levels, lipid metabolism, and hemoglobin A1C levels should be monitored annually. Moreover, in adolescence, performing oral glucose tolerance tests every 5 years is recommended. Furthermore, speech and physical therapy can help in improving the speech and motor developmental delay, respectively.

Prognosis of CS suggests a normal life expectancy associated with severe ocular diseases and a higher risk of cardiovascular disorders [4, 6].

Kolehmainen et al. reported that the diagnosis of CS can be established when at least six out of the following eight manifestations are present: (1) facial features of Cohen syndrome as described earlier, (2) developmental retardation, (3) microcephaly, (4) cheerful disposition, (5) hypermobile joints, (6) neutropenia, (7) truncal obesity with slender limbs, (8) chorioretinal dystrophy and/or myopia [8, 26]. In addition to this clinical diagnosis criteria, due to the heterogeneous manifestations, we strongly suggest that genetic assessments should be performed whenever CS is suspected. Notably, enlargement of the corpus callosum on the brain magnetic resonance imaging (MRI) in infancy and early childhood can indicate CS [4].

To conclude, we found a novel mutation in VPS13B gene in an Iranian 4-year old girl. She presented neutropenia in addition to motor and speech delay, which can be characteristic features of CS caused by VPS13B mutation. This case showed that CS should be considered in differential diagnosis of patients with intellectual disability and neutropenia.

Availability of data and materials

The variant generated during the current study is available in the ClinVar repository, with an accession number of VCV000916582.1 (https://www.ncbi.nlm.nih.gov/clinvar/variation/916582/). The raw sequence datasets generated during the current study are not publicly available because it is possible that individual privacy could be compromised.

Abbreviations

VPS13B:

Vacuolar protein sorting 13 homolog B

MRI:

Magnetic resonance imaging

GCSF:

Granulocyte colony stimulating factor

rHG-CSF:

Recombinant human granulocyte colony stimulating factor: rHG-CSF

ANC:

Absolute neutrophil count

References

  1. 1.

    Cohen MM Jr, Hall BD, Smith DW, Graham CB, Lampert KJ. A new syndrome with hypotonia, obesity, mental deficiency, and facial, oral, ocular, and limb anomalies. J Pediatr. 1973;83(2):280–4.

    PubMed  Google Scholar 

  2. 2.

    Carey JC, Hall BD. Confirmation of the Cohen syndrome. J Pediatr. 1978;93(2):239–44.

    CAS  PubMed  Google Scholar 

  3. 3.

    Chandler KE, Kidd A, Al-Gazali L, Kolehmainen J, Lehesjoki AE, Black GC, Clayton-Smith J. Diagnostic criteria, clinical characteristics, and natural history of Cohen syndrome. J Med Genet. 2003;40(4):233–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Kivitie-Kallio S, Norio R. Cohen syndrome: essential features, natural history, and heterogeneity. Am J Med Genet. 2001;102(2):125–35.

    CAS  PubMed  Google Scholar 

  5. 5.

    Rodrigues JM, Fernandes HD, Caruthers C, Braddock SR, Knutsen AP. Cohen syndrome: review of the literature. Cureus. 2018;10(9):e3330.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Cohen Syndrome [https://www.ncbi.nlm.nih.gov/books/NBK1482/].

  7. 7.

    Seifert W, Kuhnisch J, Maritzen T, Horn D, Haucke V, Hennies HC. Cohen syndrome-associated protein, COH1, is a novel, giant Golgi matrix protein required for Golgi integrity. J Biol Chem. 2011;286(43):37665–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Kolehmainen J, Wilkinson R, Lehesjoki AE, Chandler K, Kivitie-Kallio S, Clayton-Smith J, Traskelin AL, Waris L, Saarinen A, Khan J, et al. Delineation of Cohen syndrome following a large-scale genotype-phenotype screen. Am J Hum Genet. 2004;75(1):122–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Kolehmainen J, Black GC, Saarinen A, Chandler K, Clayton-Smith J, Traskelin AL, Perveen R, Kivitie-Kallio S, Norio R, Warburg M, et al. Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport. Am J Hum Genet. 2003;72(6):1359–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    VPS13B [http://www.hgmd.cf.ac.uk/ac/gene.php?gene=VPS13B].

  11. 11.

    Peikert K, Danek A, Hermann A. Current state of knowledge in chorea-Acanthocytosis as core Neuroacanthocytosis syndrome. Eur J Med Genet. 2018;61(11):699–705.

    PubMed  Google Scholar 

  12. 12.

    Lesage S, Drouet V, Majounie E, Deramecourt V, Jacoupy M, Nicolas A, Cormier-Dequaire F, Hassoun SM, Pujol C, Ciura S, et al. Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent Mitophagy. Am J Hum Genet. 2016;98(3):500–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Rzepnikowska W, Flis K, Munoz-Braceras S, Menezes R, Escalante R, Zoladek T. Yeast and other lower eukaryotic organisms for studies of Vps13 proteins in health and disease. Traffic. 2017;18(11):711–9.

    CAS  PubMed  Google Scholar 

  14. 14.

    De M, Oleskie AN, Ayyash M, Dutta S, Mancour L, Abazeed ME, Brace EJ, Skiniotis G, Fuller RS. The Vps13p-Cdc31p complex is directly required for TGN late endosome transport and TGN homotypic fusion. J Cell Biol. 2017;216(2):425–39.

    PubMed  PubMed Central  Google Scholar 

  15. 15.

    Chandler KE, Biswas S, Lloyd IC, Parry N, Clayton-Smith J, Black GC. The ophthalmic findings in Cohen syndrome. Br J Ophthalmol. 2002;86(12):1395–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Karczewski KJ, Francioli LC, Tiao, G. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43. https://doi.org/10.1038/s41586-020-2308-7.

  18. 18.

    Scott EM, Halees A, Itan Y, Spencer EG, He Y, Azab MA, Gabriel SB, Belkadi A, Boisson B, Abel L, et al. Characterization of greater middle eastern genetic variation for enhanced disease gene discovery. Nat Genet. 2016;48(9):1071–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, 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(5):405–24.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capella G, den Dunnen JT, et al. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet. 2014;46(2):107–15.

    CAS  PubMed  Google Scholar 

  21. 21.

    Norio R, Raitta C, Lindahl E. Further delineation of the Cohen syndrome; report on chorioretinal dystrophy, leukopenia and consanguinity. Clin Genet. 1984;25(1):1–14.

    CAS  PubMed  Google Scholar 

  22. 22.

    Jones KLJM, del Campo MG. Cohen Syndrome. In: Smith’s recognizable patterns of human malformation. 7th ed. Philadelphia: Elsevier Saunders; 2013. p. 280–1.

    Google Scholar 

  23. 23.

    Duplomb L, Duvet S, Picot D, Jego G, El Chehadeh-Djebbar S, Marle N, Gigot N, Aral B, Carmignac V, Thevenon J, et al. Cohen syndrome is associated with major glycosylation defects. Hum Mol Genet. 2014;23(9):2391–9.

    CAS  PubMed  Google Scholar 

  24. 24.

    Seifert W, Kuhnisch J, Maritzen T, Lommatzsch S, Hennies HC, Bachmann S, Horn D, Haucke V. Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. J Biol Chem. 2015;290(6):3349–58.

    CAS  PubMed  Google Scholar 

  25. 25.

    Duplomb L, Riviere J, Jego G, Da Costa R, Hammann A, Racine J, Schmitt A, Droin N, Capron C, Gougerot-Pocidalo MA, et al. Serpin B1 defect and increased apoptosis of neutrophils in Cohen syndrome neutropenia. J Mol Med (Berl). 2019;97(5):633–45.

    CAS  Google Scholar 

  26. 26.

    El Chehadeh-Djebbar S, Blair E, Holder-Espinasse M, Moncla A, Frances AM, Rio M, Debray FG, Rump P, Masurel-Paulet A, Gigot N, et al. Changing facial phenotype in Cohen syndrome: towards clues for an earlier diagnosis. Eur J Hum Genet. 2013;21(7):736–42.

    PubMed  Google Scholar 

  27. 27.

    Chandler KE, Moffett M, Clayton-Smith J, Baker GA. Neuropsychological assessment of a group of UK patients with Cohen syndrome. Neuropediatrics. 2003;34(1):7–13.

    CAS  PubMed  Google Scholar 

  28. 28.

    Karpf J, Turk J, Howlin P. Cognitive, language, and adaptive behavior profiles in individuals with a diagnosis of Cohen syndrome. Clin Genet. 2004;65(4):327–32.

    CAS  PubMed  Google Scholar 

  29. 29.

    Kivitie-Kallio S, Autti T, Salonen O, Norio R. MRI of the brain in the Cohen syndrome: a relatively large corpus callosum in patients with mental retardation and microcephaly. Neuropediatrics. 1998;29(6):298–301.

    CAS  PubMed  Google Scholar 

  30. 30.

    Kivitie-Kallio S, Summanen P, Raitta C, Norio R. Ophthalmologic findings in Cohen syndrome. A long-term follow-up. Ophthalmology. 2000;107(9):1737–45.

    CAS  PubMed  Google Scholar 

  31. 31.

    Kivitie-Kallio S, Eronen M, Lipsanen-Nyman M, Marttinen E, Norio R. Cohen syndrome: evaluation of its cardiac, endocrine and radiological features. Clin Genet. 1999;56(1):41–50.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not Applicable.

Funding

This study was not funded.

Author information

Affiliations

Authors

Contributions

NR: critically revised the manuscript for important intellectual content, approved the final version to be published and supervised the study; SM: Drafted the manuscript; ER: critically revised the manuscript for important intellectual content, participated in the patient’s follow up and data gathering; SS: critically revised the manuscript for important intellectual content, participated in the patient’s follow up and data gathering; MR: critically revised the manuscript for important intellectual content and approved the final version to be published. He is a member of Dr. Klein’s lab and an important member in reporting the genetics; CK: critically revised the manuscript for important intellectual content. He and his lab were responsible for the genetic analysis. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Nima Rezaei.

Ethics declarations

Ethics approval and consent to participate

The study design was approved by the ethics committee of Tehran University of Medical Sciences and Ludwig Maximilian University of Munich. The Ethics committee approval number from Tehran University of Medical Sciences is IR.TUMS.VCR.REC.1395.1055 for the research project number 32345. The Ethics committee approval number from Ludwig Maximilian University of Munich is 66–14. Written informed consent was obtained from the patients’ parents.

Consent for publication

patients’ parents gave a written consent for publication.

Competing interests

The authors declare that they have 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

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Momtazmanesh, S., Rayzan, E., Shahkarami, S. et al. A novel VPS13B mutation in Cohen syndrome: a case report and review of literature. BMC Med Genet 21, 140 (2020). https://doi.org/10.1186/s12881-020-01075-1

Download citation

Keywords

  • Cohen syndrome
  • Neutropenia
  • Frameshift mutation
  • Vesicular transport proteins
  • VPS13B protein