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Biallelic and monoallelic variants in EFEMP1 can cause a severe and distinct subtype of heritable connective tissue disorder

European Journal of Human Genetics volume 32, pages 1567–1573 (2024)Cite this article

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Abstract

Variants in EFEMP1, encoding Fibulin-3, were previously reported as a rare cause of heritable connective tissue disorder (HCTD) with recurrent hernias and joint hypermobility. We report three new cases with biallelic or monoallelic EFEMP1 variants and severe hernia phenotypes. Two male siblings of 10 and 13 years old presented with marfanoid habitus, recurrent inguinal and umbilical hernias, generalized joint hypermobility, and scoliosis. Parents and halfsiblings reported joint hypermobility and umbilical hernias. The eldest boy died at age 16 from incarcerated gastrointestinal herniation complicated by gastric and bowel necrosis with perforation. Autopsy revealed widespread intestinal diverticula. Immunohistochemistry of skin and fascia tissue did not reveal any abnormalities, including normal staining of elastic fibers. Both siblings harbored compound heterozygous likely pathogenic EFEMP1 variants (c.1320 + 2T > A, p.? and c.698G > A, p.Gly233Asp). An unrelated 58-year-old male had marfanoid features, high myopia, recurrent diaphragmatic and inguinal hernias, and chronic gastrointestinal dilatation with severe malabsorption. Both his dizygotic twin-brother and mother had recurrent hernias and high myopia. This man died at 59 years of age, and autopsy showed extensive diaphragmatic herniation, bowel diverticula, and pulmonary emphysema. A heterozygous EFEMP1 splice-variant (c.81 + 1G > A, p.?) was identified, causing exon skipping leading to a start-loss. Targeted genome reanalysis nor RNA-sequencing revealed a second variant at the other allele. The reported individuals expand the clinical and pathological phenotypes of EFEMP1-related disease, a distinct entity within the spectrum of HCTD. The severe and recurrent hernias, gastrointestinal dilatation, and diverticulosis result in an increased risk for life-threatening complications, demanding early recognition and close monitoring.

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Fig. 1: Distinctive craniofacial dysmorphology in all three individuals with marfanoid appearance, and pedigrees of the studied families.
Fig. 2: EFEMP1: c.81 + 1G > A causes skipping of first translated exon.

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Data availability

All data relevant to this study can be found within the manuscript. Additional data are available from the corresponding author on reasonable request.

References

  1. Nezwek TA, Varacallo M. Physiology, connective tissue. Treasure Island (FL): StatPearls Publishing; 2002. https://www.ncbi.nlm.nih.gov/books/NBK542226/.

  2. Bateman JF, Boot-Handford RP, Lamandé SR. Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations. Nat Rev Genet. 2009;10:173–83.

    Article  CAS  PubMed  Google Scholar 

  3. Pope MK, Ratajska A, Johnsen H, Rypdal KB, Sejersted Y, Paus B. Diagnostics of hereditary connective tissue disorders by genetic next-generation sequencing. Genet Test Mol Biomark. 2019;23:783–90.

    Article  Google Scholar 

  4. Steinle J, Hossain WA, Veatch OJ, Strom SP, Butler MG. Next-generation sequencing and analysis of consecutive patients referred for connective tissue disorders. Am J Med Genet A. 2022;188:3016–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Milewicz DM, Braverman AC, De Backer J, Morris SA, Boileau C, Maumenee IH, et al. Marfan syndrome. Nat Rev Dis Prim. 2021;7:64.

    Article  PubMed  Google Scholar 

  6. Malfait F, Castori M, Francomano CA, Giunta C, Kosho T, Byers PH. The Ehlers-Danlos syndromes. Nat Rev Dis Prim. 2020;6:64.

    Article  PubMed  Google Scholar 

  7. Argraves WS, Dickerson K, Burgess WH, Ruoslahti E. Fibulin, a novel protein that interacts with the fibronectin receptor beta subunit cytoplasmic domain. Cell. 1989;58:623–9.

    Article  CAS  PubMed  Google Scholar 

  8. de Vega S, Iwamoto T, Yamada Y. Fibulins: multiple roles in matrix structures and tissue functions. Cell Mol Life Sci. 2009;66:1890–902.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Debeer P, Schoenmakers EF, Twal WO, Argraves WS, De Smet L, Fryns JP, et al. The fibulin-1 gene (FBLN1) is disrupted in at (12; 22) associated with a complex type of synpolydactyly. J Med Genet. 2002;39:98–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bohlega S, Al-Ajlan H, Al-Saif A. Mutation of fibulin-1 causes a novel syndrome involving the central nervous system and connective tissues. Eur J Hum Genet. 2014;22:640–3.

    Article  CAS  PubMed  Google Scholar 

  11. Loeys B, Van Maldergem L, Mortier G, Coucke P, Gerniers S, Naeyaert JM, et al. Homozygosity for a missense mutation in fibulin-5 (FBLN5) results in a severe form of cutis laxa. Hum Mol Genet. 2002;11:2113–8.

    Article  CAS  PubMed  Google Scholar 

  12. Hucthagowder V, Sausgruber N, Kim KH, Angle B, Marmorstein LY, Urban Z. Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. Am J Hum Genet. 2006;78:1075–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stone EM, Braun TA, Russell SR, Kuehn MH, Lotery AJ, Moore PA, et al. Missense variations in the fibulin 5 gene and age-related macular degeneration. N Engl J Med. 2004;351:346–53.

    Article  CAS  PubMed  Google Scholar 

  14. Kobayashi N, Kostka G, Garbe JH, Keene DR, Bächinger HP, Hanisch FG, et al. A comparative analysis of the fibulin protein family. biochemical characterization, binding interactions, and tissue localization. J Biol Chem. 2007;282:11805–16.

    Article  CAS  PubMed  Google Scholar 

  15. Stone EM, Lotery AJ, Munier FL, Héon E, Piguet B, Guymer RH, et al. A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy. Nat Genet. 1999;22:199–202.

    Article  CAS  PubMed  Google Scholar 

  16. Fu L, Garland D, Yang Z, Shukla D, Rajendran A, Pearson E, et al. The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice. Hum Mol Genet. 2007;16:2411–22.

    Article  CAS  PubMed  Google Scholar 

  17. Mégarbané A, Hanna N, Chouery E, Jalkh N, Mehawej C, Boileau C. Marfanoid habitus, inguinal hernia, advanced bone age, and distinctive facial features: a new collagenopathy? Am J Med Genet A. 2012;158A:1185–9.

    Article  PubMed  Google Scholar 

  18. Bizzari S, El-Bazzal L, Nair P, Younan A, Stora S, Mehawej C, et al. Recessive marfanoid syndrome with herniation associated with a homozygous mutation in Fibulin-3. Eur J Med Genet. 2020;63:103869.

    Article  PubMed  Google Scholar 

  19. Driver SGW, Jackson MR, Richter K, Tomlinson P, Brockway B, Halliday BJ, et al. Biallelic variants in EFEMP1 in a man with a pronounced connective tissue phenotype. Eur J Hum Genet. 2020;28:445–52.

    Article  CAS  PubMed  Google Scholar 

  20. Verlee M, Beyens A, Gezdirici A, Gulec EY, Pottie L, De Feyter S, et al. Loss-of-function variants in EFEMP1 cause a recognizable connective tissue disorder characterized by cutis laxa and multiple herniations. Genes. 2021;12:510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Forghani I, Lang SH, Rodier MJ, Bivona SA, Undiagnosed Diseases N, Morales AA, et al. EFEMP1 haploinsufficiency causes a Marfan-like hereditary connective tissue disorder. Am J Med Genet A. 2024;194:e63556.

    Article  CAS  PubMed  Google Scholar 

  22. Li H, Durbin R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics. 2009;25:1754–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Biesecker LG, Byrne AB, Harrison SM, Pesaran T, Schäffer AA, Shirts BH, et al. ClinGen guidance for use of the PP1/BS4 co-segregation and PP4 phenotype specificity criteria for sequence variant pathogenicity classification. Am J Hum Genet. 2024;111:24–38.

    Article  CAS  PubMed  Google Scholar 

  26. Dekker J, Schot R, Bongaerts M, de Valk WG, van Veghel-Plandsoen MM, Monfils K, et al. Web-accessible application for identifying pathogenic transcripts with RNA-seq: increased sensitivity in diagnosis of neurodevelopmental disorders. Am J Hum Genet. 2023;110:251–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Franssen S, Beek MA, Lagarde SM. [A cachectic man with a severe vitamin deficiency]. Ned Tijdschr Voor Geneeskd. 2021;165:D5491.

  28. Livingstone I, Uversky VN, Furniss D, Wiberg A. The Pathophysiological Significance of Fibulin-3. Biomolecules, 2020;10:1294.

  29. Woodard DR, Daniel S, Nakahara E, Abbas A, DiCesare SM, Collier GE, et al. A loss-of-function cysteine mutant in fibulin-3 (EFEMP1) forms aberrant extracellular disulfide-linked homodimers and alters extracellular matrix composition. Hum Mutat. 2022;43:1945–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. McLaughlin PJ, Bakall B, Choi J, Liu Z, Sasaki T, Davis EC, et al. Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice. Hum Mol Genet. 2007;16:3059–70.

    Article  CAS  PubMed  Google Scholar 

  31. Gómez AE, Alvarado K, Yase RA, Hsu Y-H, Hulleman JD, Kwon RY. Dominant nonsense mutations in efemp1 alter vertebral and craniofacial characteristics in adult zebrafish. bioRxiv, 2024: p. 2024.02.16.580611.

  32. Giltay R, Timpl R, Kostka G. Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4. Matrix Biol. 1999;18:469–80.

    Article  CAS  PubMed  Google Scholar 

  33. Ellinghaus E, Ellinghaus D, Krusche P, Greiner A, Schreiber C, Nikolaus S, et al. Genome-wide association analysis for chronic venous disease identifies EFEMP1 and KCNH8 as susceptibility loci. Sci Rep. 2017;7:45652.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ahmed WU, Kleeman S, Ng M, Wang W, Auton A, Research T, et al. Genome-wide association analysis and replication in 810,625 individuals with varicose veins. Nat Commun. 2022;13:3065.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Callewaert B, Su CT, Van Damme T, Vlummens P, Malfait F, Vanakker O, et al. Comprehensive clinical and molecular analysis of 12 families with type 1 recessive cutis laxa. Hum Mutat. 2013;34:111–21.

    Article  CAS  PubMed  Google Scholar 

  36. Ahmed WU, Patel M, Ng M, McVeigh J, Zondervan K, Wiberg A, et al. Shared genetic architecture of hernias: A genome-wide association study with multivariable meta-analysis of multiple hernia phenotypes. PLoS ONE. 2022;17:e0272261.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Ehlermann J, Weber S, Pfisterer P, Schorle H. Cloning, expression and characterization of the murine Efemp1, a gene mutated in Doyne-Honeycomb retinal dystrophy. Gene Expr Patterns. 2003;3:441–7.

    Article  CAS  PubMed  Google Scholar 

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Funding

No funding was received.

Author information

Authors and Affiliations

  1. Department of Clinical Genetics, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    M. O. Mol, T. J. van Ham, H. T. Bruggenwirth, L. van Unen, V. J. M. Verhoeven & S. Demirdas

  2. Department of Pediatrics, Franciscus Gasthuis and Vlietland, Rotterdam and Schiedam, The Netherlands

    N. Bannink

  3. Department of Pediatric Gastroenterology, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    J. C. Escher

  4. Department of Pathology, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    J. M. Kros & R. M. Verdijk

  5. Department of Orthopedics and Sportsmedicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    J. J. M. Renkens

  6. Department of Pediatric Surgery, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    J. Vlot

  7. Department of Ophthalmology, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands

    V. J. M. Verhoeven

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Contributions

VV and SD: clinical data collection, conceptualization, supervision. MM: clinical data analyses, data presentation, original draft preparation. TH, HB, and LU: genetic data collection and analyses, data visualization. JK and RV: pathological data collection and analyses. NB, JE, JR, and JV: clinical data collection. All authors read, reviewed, and edited the final manuscript.

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Correspondence to M. O. Mol.

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All subjects or legal guardians provided written informed consent for publication of this manuscript. Specific informed consent was obtained for the publication of clinical pictures. Standard postmortem investigation was performed upon consent by the relatives of the deceased. The study was conducted in accordance with the 1984 Declaration of Helsinki and its subsequent revisions.

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Mol, M.O., van Ham, T.J., Bannink, N. et al. Biallelic and monoallelic variants in EFEMP1 can cause a severe and distinct subtype of heritable connective tissue disorder. Eur J Hum Genet 32, 1567–1573 (2024). https://doi.org/10.1038/s41431-024-01692-x

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