Variable Expressivity of Wolfram Syndrome in a Family with Multiple Affected Subjects


Purpose: To study the genetic basis and clinical manifestations of Wolfram syndrome in a multi-affected family.

Methods: Complete clinical examinations including urological, ophthalmic, neurological, and endocrinologic assessment were performed for three affected family members. Genomic DNA was extracted from peripheral blood leukocytes with salting out method and all WFS1 exons and their flanking regions were sequenced. Candidate variation was screened for segregation in the pedigree by Sanger sequencing.

Results: A known pathogenic missense mutation in WFS1 gene (c.1885C>T which leads to p.Arg629Trp in the encoded protein) was identified in all affected individuals. Both clinical and genetic investigations confirmed Wolfram syndrome diagnosis with variable phenotypic features.

Conclusion: Identical mutations in the Wolfram syndrome causative gene can lead to variable manifestations of the syndrome even in the same family. Although the medical findings and clinical examination are imperative for the diagnosis of Wolfram syndrome, genetic testing is useful to confirm the diagnosis, especially in cases with possible reduced penetrance of the characteristic signs.


Variable Clinical Manifestations, WFS1 Gene, Wolfram Syndrome

1. Pallotta MT, Tascini G, Crispoldi R, Orabona C, Mondanelli G, Grohmann U, et al. Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives. J Transl Med 2019;17:238.

2. Wolfram D, Wagener HP, editor. Diabetes mellitus and simple optic atrophy among siblings. Mayo Clin Proc 1938;13:715–718.

3. Naderian G, Ashtari F, Nouri-Mahdavi K, Sajjadi V. A case of wolfram syndrome. J Ophthalmic Vis Res 2010;5:53.

4. Rigoli L, Lombardo F, Di Bella C. Wolfram syndrome and WFS1 gene. Clin Genet 2011;79:103–117.

5. Amr S, Heisey C, Zhang M, Xia XJ, Shows KH, Ajlouni K, et al. A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am J Hum Genet 2007;81:673–683.

6. Eller P, Föger B, Gander R, Sauper T, Lechleitner M, Finkenstedt G, et al. Wolfram syndrome: a clinical and molecular genetic analysis. J Med Genet 2001;38:e37.

7. Urano F. Wolfram syndrome: diagnosis, management, and treatment. Curr Diab Rep 2016;16:6.

8. Ari Ş, Keklíkçí U, Çaça İ, Ünlü K, Kayabaşi H. Wolfram syndrome: case report and review of the literature. Compr Ther 2007;33:18–20.

9. Bodoor K, Batiha O, Abu-Awad A, Al-Sarihin K, Ziad H, Jarun Y, et al. Identification of a novel WFS1 homozygous nonsense mutation in Jordanian children with Wolfram syndrome. Meta Gene 2016;9:219–224.

10. Cano A, Rouzier C, Monnot S, Chabrol B, Conrath J, Lecomte P, et al. Identification of novel mutations in WFS1 and genotype–phenotype correlation in Wolfram syndrome. Am J Med Genet A 2007;143:1605–1612.

11. Aloi C, Salina A, Pasquali L, Lugani F, Perri K, Russo C, et al. Wolfram syndrome: new mutations, different phenotype. PLoS One 2012;7:e29150.

12. Marshall BA, Permutt MA, Paciorkowski AR, Hoekel J, Karzon R, Wasson J, et al. Phenotypic characteristics of early Wolfram syndrome. Orphanet J Rare Dis 2013;8:64.

13. Sobhani M, Tabatabaiefar MA, Rajab A, Kajbafzadeh AM, Noori-Daloii MR. Significant expressivity of Wolfram syndrome: phenotypic assessment of two known and one novel mutation in the WFS1 gene in three Iranian families. Mol Biol Rep 2014;41:7499–7505.

14. Kinsley BT, Swift M, Dumont RH, Swift RG. Morbidity and mortality in the Wolfram syndrome. Diabetes Care 1995;18:1566–1570.

15. Inoue H, Tanizawa Y, Wasson J, Behn P, Kalidas K, Bernal- Mizrachi E, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet 1998;20:143.

16. Rohayem J, Ehlers C, Wiedemann B, Holl R, Oexle K, Kordonouri O, et al. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype. Diabetes Care 2011;34:1503–1510.

17. Megighian D, Savastano M. Wolfram syndrome. Int J Pediatr Otorhinolaryngol 2004;68:243–247.

18. Genis D, Davalos A, Molins A, Ferrer I. Wolfram syndrome: a neuropathological study. Acta Neuropathologica 1997;93:426–429.

19. Tekgul S, Oge O, Simsek E, Yordam N, Kendi S. Urological manifestations of the Wolfram syndrome: observations in 14 patients. J Urol 1999;161:616–617.

20. Aboseif S, Gasparini M, Schmidt R, Tanagho E. Wolfram’s (DIDMOAD) syndrome and its urological manifestation. Br J Urol 1993;72:106–111.