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Dawson AJ, Hovanes K, Liu J, et al. Heterozygous intragenic deletions of FREM1 are not associated with trigonocephaly. Clin Dysmorphol. 2021;30(2):83-88doi: 10.1097/MCD.0000000000000351.
Dawson, A. J., Hovanes, K., Liu, J., Marles, S., Greenberg, C., Mhanni, A., Chudley, A., Frosk, P., Sahoo, T., Schanze, D., & Zenker, M. (2021). Heterozygous intragenic deletions of FREM1 are not associated with trigonocephaly. Clinical dysmorphology, 30(2), 83-88. https://doi.org/10.1097/MCD.0000000000000351
Dawson, Angelika J, et al. "Heterozygous intragenic deletions of FREM1 are not associated with trigonocephaly." Clinical dysmorphology vol. 30,2 (2021): 83-88. doi: https://doi.org/10.1097/MCD.0000000000000351
Dawson AJ, Hovanes K, Liu J, Marles S, Greenberg C, Mhanni A, Chudley A, Frosk P, Sahoo T, Schanze D, Zenker M. Heterozygous intragenic deletions of FREM1 are not associated with trigonocephaly. Clin Dysmorphol. 2021 Apr 01;30(2):83-88. doi: 10.1097/MCD.0000000000000351. PMID: 33038106.
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Clin Dysmorphol. 2021 Apr 01;30(2):83-88. doi: 10.1097/MCD.0000000000000351.

Heterozygous intragenic deletions of FREM1 are not associated with trigonocephaly.

Clinical dysmorphology

Angelika J Dawson, Karine Hovanes, Jing Liu, Sandra Marles, Cheryl Greenberg, Aziz Mhanni, Albert Chudley, Patrick Frosk, Trilochan Sahoo, Denny Schanze, Martin Zenker

Affiliations

  1. Genomics, Shared Health Manitoba, Winnipeg.
  2. Department of Biochemistry and Medical Genetics, Program of Genetics and Metabolism, University of Manitoba, Winnipeg, Manitoba, Canada.
  3. Invitae, Irvine, California, USA.
  4. Institute of Human Genetics, University Hospital Magdeburg Leipziger Str. 44 39120 Magdeburg Germany.

PMID: 33038106 DOI: 10.1097/MCD.0000000000000351

Abstract

Recessive mutations in FRAS1-related extracellular matrix 1 (FREM1) are associated with two rare genetic disorders, Manitoba-oculo-tricho-anal (MOTA) and bifid nose with or without anorectal and renal anomalies (BNAR). Fraser syndrome is a more severe disorder that shows phenotypic overlap with both MOTA and anorectal and renal anomalies and results from mutations in FRAS1, FREM2 and GRIP1. Heterozygous missense mutations in FREM1 were reported in association with isolated trigonocephaly with dominant inheritance and incomplete penetrance. Moreover, large deletions encompassing FREM1 have been reported in association with a syndromic form of trigonocephaly and were designated as trigonocephaly type 2. Trigonocephaly results from premature closure of the metopic suture and typically manifests as a form of nonsyndromic craniosynostosis. We report on 20 patients evaluated for developmental delay and without abnormal metopic suture. Chromosomal microarray analysis revealed heterozygous FREM1 deletions in 18 patients and in 4 phenotypically normal parents. Two patients were diagnosed with MOTA and had homozygous FREM1 deletions. Therefore, although our results are consistent with the previous reports of homozygous deletions causing MOTA, we report no association between heterozygous FREM1 deletions and trigonocephaly in this cohort.

Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

References

  1. Alazami AM, Shaheen R, Alzahrani F, Snape K, Saggar A, Brinkmann B, et al. (2009). FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome. Am J Hum Genet. 85:414–418. - PubMed
  2. Beck TF, Campeau PM, Jhangiani SN, Gambin T, Li AH, Abo-Zahrah R, et al. (2015). FBN1 contributing to familial congenital diaphragmatic hernia. Am J Med Genet A. 167A:831–836. - PubMed
  3. Bouaoud J, Olivetto M, Testelin S, Dakpe S, Bettoni J, Devauchelle B (2020). Fraser syndrome: review of the literature illustrated by a historical adult case. Int J Oral Maxillofac Surgery. https://doi.org/10.106/j.ijom.2020.01.007 - PubMed
  4. Chacon-Camacho OF, Zenker M, Schanze D, Ledesma-Gil J, Zenteno JC (2017). Novel FREM1 mutations in a patient with MOTA syndrome: clinical findings, mutation update and review of FREM1-related disorders literature. Eur J Med Genet. 60:190–194. - PubMed
  5. ClinVar. https://www.ncbi.nlm.nih.gov/clinvar/?term=frem1+only. - PubMed
  6. Decipher. https://decipher.sanger.ac.uk/ - PubMed
  7. Goos JAC, Mathijssen IMJ (2017). Genetic causes of craniosynostosis: an update. Mol Syndromol. 10:6–23. - PubMed
  8. Kohl S, Hwang DY, Dworschak GC, Hilger AC, Saisawat P, Vivante A, et al. (2014). Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. 25:1917–1922. - PubMed
  9. Lattanzi W, Bukvic N, Barba M, Tamburrini G, Bernardini C, Michetti F, Di Rocco C (2012). Genetic basis of single-suture synostoses: genes, chromosomes and clinical implications. Childs Nerv Syst. 28:1301–1310. - PubMed
  10. Marles SL, Greenberg CR, Persaud TV, Shuckett EP, Chudley AE (1992). New familial syndrome of unilateral upper eyelid coloboma, aberrant anterior hairline pattern, and anal anomalies in Manitoba Indians. Am J Med Genet. 42:793–799. - PubMed
  11. Mitter D, Schanze D, Sterker I, Müller D, Till H, Zenker M (2012). MOTA syndrome: molecular genetic confirmation of the diagnosis in a newborn with previously unreported clinical features. Mol Syndromol. 3:136–139. - PubMed
  12. Mocquard C, Aillet S, Riffaud L (2019). Recent advances in trigonocephaly. Neurochirurgie. 65:246–251. - PubMed
  13. Nathanson J, Swarr DT, Singer A, Liu M, Chinn A, Jones W, et al. (2013). Novel FREM1 mutations expand the phenotypic spectrum associated with Manitoba-oculo-tricho-anal (MOTA) syndrome and bifid nose renal agenesis anorectal malformations (BNAR) syndrome. Am J Med Genet A. 161A:473–478. - PubMed
  14. Schanze I, Bunt J, Lim JWC, Schanze D, Dean RI, et al. (2018). NFIB haploinsufficiency is associated with intellectual disability and macrocepahly. Am J Hum Genet. 103:752–768. - PubMed
  15. Slavotinek AM, Baranzini SE, Schanze D, Labelle-Dumais C, Short KM, Chao R, et al. (2011). Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1. J Med Genet. 48:375–382. - PubMed
  16. Timberlake AT, Persing JA (2018). Genetics of nonsyndromic craniosynostosis. Plast Reconstr Surg. 141:1508–1516. - PubMed
  17. Vissers LE, Cox TC, Maga AM, Short KM, Wiradjaja F, Janssen IM, et al. (2011). Heterozygous mutations of FREM1 are associated with an increased risk of isolated metopic craniosynostosis in humans and mice. Plos Genet. 7:e1002278. - PubMed
  18. Wang Q, Pierce-Hoffman E, Cummings BB, Alföldi J, Francioli LC, Gauthier LD, et al. (2020). Landscape of multi-nucleotide variants in 125,748 human exomes and 15,798 genomes. Nat Commun. 11:2539. - PubMed

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