Wolfram Syndrome Panel

Wolfram syndrome (WFS) is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 15 years, typically associated with sensorineural hearing loss, progressive neurologic abnormalities (ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony), and other endocrine abnormalities. Median age at death is 30 years. WFS1 is also sometimes referred to as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Wolfram Syndrome Type 2 is characterized by juvenile-onset diabetes mellitus, optic atrophy, high-frequency sensorineural hearing impairment, urinary tract dilatation, impaired renal function, hypogonadism, and severe gastrointestinal ulcer and bleeding, but not diabetes insipidus (Amr et al. 2007; Tranebjaerg et al. 2009). WFS1-related disorders range from Wolfram syndrome (WFS1) to WFS1-related low-frequency sensory hearing loss (also known as DFNA6/14/38 low-frequency sensorineural hearing loss [LFSNHL]). WFS-like disorder is characterized by sensorineural hearing loss, diabetes mellitus, psychiatric illness, and variable optic atrophy. WFS1-related LFSNHL is characterized by congenital, nonsyndromic, slowly progressive, low-frequency (< 2000 Hz) sensorineural hearing loss (Tranebjaerg et al. 2009).

WFS1: Estimated prevalence is 1 in 500,000 people worldwide with an autosomal recessive mode of inheritance. Mutations in the WFS1 gene account for more than 90 percent of Wolfram syndrome type 1 cases. WFS1 produces a protein called wolframin that is thought to regulate the amount of calcium in cells. Mutations in the gene lead to reduced or absent function, causing disease. At least 200 variants in WFS1 have been found to cause Wolfram syndrome, including nonsense, missense, inframe deletions, duplications as well as frameshift mutations. WFS1-related Disorders: Though WFS1 is inherited in an autosomal recessive manner, carriers of WFS1 mutations do appear to have an increased risk of hearing impairment (Pennings et al. 2004), but it is as yet unknown whether they could be at higher risk for diabetes mellitus and psychiatric disorders (Swift et al. 1998). WFS-like disorder is inherited in an autosomal dominant manner. WFS2: Prevalence of CISD2-associated Wolfram syndrome type 2 is currently unknown. The exact function of the CISD2 protein is unknown, but limited studies suggest that it helps regulate mitochondrial function. Identification of a single homozygous missense mutation in affected individuals suggests an autosomal recessive mode of inheritance (El-Shanti et al. 2000). No other mutations have been identified.

WFS1-related disorders occur due to a wide variety of mutations in the WFS1 gene, including nonsense, missense, inframe deletions and duplications as well as frameshift mutations. Most mutations occur in exon 8, and no founder mutations have thus far been identified (Hardy et al. 1999). Our full gene sequencing test is expected to detect >90% of WFS1 causative mutations (Khanim et al. 2001). Only a single homozygous missense mutation at c.109G>C (Glu37Gln) in CISD2 is known to be causative for WFS2 disease (El-Shanti et al. 2000). No other causative mutations have been identified.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides full coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).