TY  - JOUR
SN  - 1460-2083
UR  - https://doi.org/10.1093/hmg/ddz212
JF  - Human Molecular Genetics
A1  - Riachi, M
A1  - Yilmaz, S
A1  - Kurnaz, E
A1  - Aycan, Z
A1  - Çetinkaya, S
A1  - Tranebjærg, L
A1  - Rendtorff, ND
A1  - Bitner-Glindzicz, M
A1  - Bockenhauer, D
A1  - Hussain, K
SP  - 3815
VL  - 28
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
IS  - 22
ID  - discovery10084040
N2  - Wolfram Syndrome (WS) is a heterogeneous multisystem neurodegenerative disorder with two allelic variations in addition to a separate subtype known as WS type 2. The wide phenotypic spectrum of WS includes diabetes mellitus and optic atrophy which is often accompanied by diabetes insipidus, deafness, urological and neurological complications in combination or in isolation. To date, the understanding of the genotype phenotype relationship in this complex syndrome remains poorly understood. In this study we identified and explored the functionality of rare and novel variants in the two causative WS genes WFS1 and CISD2 by assessing the effects of the mutations on the encoded proteins Wolframin and ERIS, in a cohort of 12 patients with autosomal recessive WS, dominant WS and WS type 2. The identified pathogenic variants included missense changes, frameshift deletions and insertions in WFS1 and an exonic deletion in CISD2 which all altered the respective encoded protein in a manner that did not correlate to the phenome previously described. These observations suggest the lack of genotype phenotype correlation in this complex syndrome and the need to explore other molecular genetic mechanisms. Additionally, our findings highlight the importance of functionally assessing variants for their pathogenicity to tackle the problem of increasing variants of unknown significance (VUS) in the public genetic databases.
KW  - phenotype
KW  -  diabetes mellitus
KW  -  genetics
KW  -  molecular
KW  -  mutation
KW  -  diabetes insipidus
KW  -  heterogeneity
KW  -  genetic databases
KW  -  frameshift mutation function
KW  -  genes
KW  -  genotype
KW  -  neurodegenerative disorders
KW  -  optic atrophy
KW  -  wolfram syndrome
KW  -  autosomal recessive inheritance
KW  -  hearing impairment
KW  -  pathogenicity
KW  -  neurologic complications
KW  -  genotype-phenotype associations
TI  - Functional Assessment of Variants Associated with Wolfram Syndrome
EP  - 3824
AV  - public
Y1  - 2019/11/15/
ER  -