Clinical characteristics.

WFS1 spectrum disorder (WFS1-SD) comprises classic WFS1 spectrum disorder and nonclassic WFS1 spectrum disorder.

• Classic WFS1-SD, a progressive neurodegenerative disorder, is characterized by onset of diabetes mellitus and optic atrophy before age 16 years. Additional complications may include one or more of the following: variable hearing impairment / deafness, diabetes insipidus, neurologic abnormalities, neurogenic bladder, and psychiatric abnormalities.
• Nonclassic WFS1-SD is less common than classic WFS1-SD. Phenotypes that appear to be milder than classic WFS1-SD include: optic atrophy and hearing impairment; neonatal diabetes, profound congenital deafness, and cataracts; isolated diabetes mellitus; isolated congenital cataracts; and isolated congenital, slowly progressive, and low-frequency (<2000 Hz) sensorineural hearing loss.

Diagnosis/testing

• Classic WFS1-SD. The diagnosis is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in WFS1 identified by molecular genetic testing.
• Nonclassic WFS1-SD. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant identified by molecular genetic testing.

Management.

There is no cure for WFS1-SD.

Treatment of manifestations: Supportive care (based on the manifestations of classic or nonclassic WFS1-SD) is often provided by multidisciplinary specialists in diabetic care, endocrinology, ophthalmology and low vision, audiology, speech-language therapy, neurology, pulmonology, psychiatry / psychology / mental health, urology, gastroenterology, social work, and medical genetics.

Surveillance: For both classic and nonclassic WFS1-SD, regular monitoring of existing manifestations, the response of an individual to supportive care, and the emergence of new manifestations is recommended.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment for the earliest manifestations of WFS1-SD: diabetes mellitus, optic atrophy, and sensorineural hearing loss.

Pregnancy management: Pregnant women with insulin-dependent diabetes mellitus, a characteristic of both classic and nonclassic WFS1-SD, have a two- to eightfold higher risk of having a child with a birth defect or a pattern of birth defects (diabetic embryopathy) than women who do not have diabetes. Optimizing glucose control before and during pregnancy can reduce – but not eliminate – the risk for diabetic embryopathy. Because women with classic WFS1-SD may develop diabetes insipidus during pregnancy, monitoring for diabetes insipidus during pregnancy is warranted. Consultation with a maternal fetal medicine specialist during pregnancy should be considered for all women with WFS1-SD.

Genetic counseling

• Classic WFS1-SD is caused by biallelic WFS1 pathogenic variants and is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a WFS1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Nonclassic WFS1-SD is caused by a heterozygous pathogenic variant and can either be inherited in an autosomal dominant manner from an affected parent or result from a de novo WFS1 pathogenic variant. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%. If the WFS1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism.
• Both classic and nonclassic WFS1-SD. Once the WFS1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for classic and nonclassic WFS1-SD are possible.

Suggestive Findings – Classic WFS1 Spectrum Disorder

Classic WFS1-SD should be suspected in individuals with any of the following clinical findings and family history.

Major clinical findings [Barrett et al 1995, Urano 2016]:

• Diabetes mellitus (onset age usually <16 years)
• Optic atrophy (onset age usually <16 years)

Additional clinical findings may include one or more of the following:

• High-tone sensorineural hearing impairment
• Cerebellar ataxia
• Psychiatric illness
• Neurogenic bladder (overactive or underactive)
• Other endocrine findings:
  • Central diabetes insipidus
  • Delayed puberty, particularly in males, associated with hypogonadism
  • Non-autoimmune hypothyroidism
• Structural congenital heart defects

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Suggestive Findings – Nonclassic WFS1 Spectrum Disorder

Nonclassic WFS1-SD should be suspected in individuals with any or the following clinical findings and family history.

Clinical findings (one or more) [Urano 2016]:

• Diabetes mellitus (onset age usually >16 years)
• Optic atrophy (onset age usually >16 years)
• Low-tone sensorineural hearing impairment including profound hearing loss in infancy
• Neonatal diabetes, congenital deafness, and/or cataracts

Family history may suggest autosomal dominant inheritance (e.g., affected males and females in more than one generation) or the proband may have a de novo pathogenic variant and be the only affected family member. Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis of WFS1 Spectrum Disorder

The diagnosis of classic WFS1 spectrum disorder is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in WFS1 identified by molecular genetic testing (see Table 1).

The diagnosis of nonclassic WFS1 spectrum disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

• A deafness, retinal dystrophy, or monogenic diabetes multigene panel that includes WFS1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description – Classic WFS1 Spectrum Disorder

Classic WFS1 spectrum disorder (WFS1-SD) is characterized by childhood-onset diabetes mellitus and progressive optic atrophy, with variable hearing impairment / deafness, diabetes insipidus, neurologic abnormalities, and psychiatric abnormalities (see Table 2).

A comprehensive review of classic WFS1-SD, genotype-phenotype correlations, pathophysiology, and therapeutic strategies is available [Mishra et al 2021].

Classic WFS1-SD is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 16 years, and frequently associated with sensorineural hearing loss, progressive neurologic abnormalities, and other endocrine abnormalities. Several organ systems may be affected; however, because only a minority of published cases have had extensive clinical workup, the natural history of these multiorgan findings in classic WFS1-SD is largely unknown.

The natural history of classic WFS1-SD was described in 45 individuals in 29 families in the United Kingdom [Barrett et al 1995]. Hearing impairment was present in 64% by age 20 years. Sixty percent of all individuals studied (mean age: 16 years, range: 5-32 years) had one or more of the following: cerebellar ataxia, peripheral neuropathy, intellectual disability, dementia, psychiatric illness, and urinary tract atony. In the families of British, Pakistani, and mixed Arab/African origin, WFS1 pathogenic variants were subsequently identified in 17 of 19 probands [Hardy et al 1999].

Diabetes mellitus (DM). Median age of onset of DM was before age ten years (age range: <1-17 years). Almost all individuals with DM were insulin dependent. DM may present with ketoacidosis; however, the overall course is milder than that seen in isolated DM, with lower prevalence of microvascular complications.

Optic atrophy (OA) occurs eventually in all known individuals with classic WFS1-SD. OA is progressive; the median age of onset is before ten years. Note: Visual acuity of 6/60, signifying that the tested person sees at six meters that which an average person sees at 60 meters, is the definition of "registered vision impaired" in the United Kingdom and "legally blind" in the United States. Most individuals with classic WFS1-SD gradually progress to severe vision impairment (visual acuity of 3/60) over years.

Very rarely, WFS1 pathogenic variants may be associated with isolated optic atrophy with autosomal recessive inheritance [Grenier et al 2016].

Sensorineural hearing impairment, present in about 66% of individuals with classic WFS1-SD, ranges from congenital deafness to a milder, sometimes progressive sensorineural hearing impairment. Median age of onset in one report was 12.5 years [Barrett et al 1995]. A multicenter study confirmed the preferential involvement of high frequencies and the slowly progressive rate of hearing loss, but did not confirm any sex differences in degree of hearing loss [Plantinga et al 2008].

A longitudinal study of 40 individuals showed that high-frequency hearing loss worsened and speech intelligibility index worsened over time, but the change over one year was subclinical, suggesting gradual progression over years [Karzon et al 2018].

Neurologic abnormalities were present in 62% of the individuals (mean age: 30 years, range: 5-44 years) studied by Barrett et al [1995] before molecular confirmation of the diagnosis was possible. However, very limited data are available regarding the frequency of the types of neurologic abnormalities.

Current experience indicates the presence of symptomatic neurologic findings by the fourth decade, with presymptomatic onset typically between the first and second decades.

Neurologic findings were progressive and resulted from general brain atrophy with brain stem and cranial nerve involvement [Barrett et al 1995, Chaussenot et al 2015]. Abnormal cerebral MRIs found in eight of 45 affected individuals typically showed generalized brain atrophy most prominently of the cerebellum, medulla, and pons; and reduced signal intensity of the optic nerves and the posterior of the hypothalamus [Barrett et al 1995].

• Truncal or gait ataxia was found in 15 of 45 individuals [Barrett et al 1995].
• Episodes of central apnea, a serious manifestation, occurred in five of 45 individuals [Barrett et al 1995].
• A significantly increased risk of psychiatric illness including suicidal behavior has been reported [Eiberg et al 2006, Astuti et al 2017], as has dementia, occasionally seen as part of the wider neurodegeneration.
• Intellectual disability is not a common feature.

Brain MRI findings in 30 individuals with classic WFS1-SD followed for a median of five years [Samara et al 2020] include:

• Absent or diminished posterior pituitary bright spot (first visit, 53%; last visit, 70%)
• T₁-/T₂-weighted pons signal abnormalities (first visit, 53%; last visit, 67%)
• Optic nerve atrophy (first visit, 30%; last visit, 80%)
• White matter T₂-weighted hyperintensities (first visit, 27%; last visit, 35%)
• Cerebellar atrophy (first visit, 23%; last visit, 70%)

Other endocrine findings

• Diabetes insipidus of central origin occurred in 72% of affected individuals, with a median age of onset of 15.5 years. The range in age of onset was broad, possibly because of delays in establishing the correct diagnosis.
• Hypogonadism is more prevalent in males than in females. It can be either hypogonadotropic (i.e., central) or hypergonadotropic (i.e., secondary to gonadal failure). The underlying pathology of either type is not understood. Females usually retain their ability to become pregnant; about six successful pregnancies are described in the literature. One female had absence of the uterus [L Tranebjærg, personal observation]. Fertility is reduced, more severely in males than in females [Haghighi et al 2013].
• Hypothyroidism. Frequency is not known.
• Growth restriction. Most affected individuals achieve an adult height in the normal range.

Urinary tract. Dilated renal outflow tracts (hydroureter), urinary incontinence, and recurrent infections are common signs of neurogenic bladder. Sixteen of 29 affected individuals had such signs, with a median age of onset of 22 years (age range: 10-44 years) [Barrett et al 1995]. Urodynamic examinations showed incomplete bladder emptying or complete bladder atony, progressing to megacystis and potentially acute urinary outflow obstruction [Wragg et al 2018].

Gastrointestinal dysmotility and celiac disease. Constipation, chronic diarrhea, and other bowel dysfunction is reported in up to 25% of individuals with classic WFS1-SD.

Prognosis. Ten of the 45 individuals with classic WFS1-SD reported in Barrett et al [1995] had died at the time of that report. The causes of death included hypoglycemic coma, status epilepticus, end-stage kidney disease from recurrent urinary tract infection, central respiratory failure associated with brain stem atrophy, and suicide. However, the median age of death is now recognized to be much older than that reported in Barrett et al [1995]. In a national specialist multidisciplinary team clinic for 40 affected adults, the median age in the clinic was 37 years, and the oldest individual was 65 years [B Wright, personal communication].

Clinical Description – Nonclassic WFS1 Spectrum Disorder

Nonclassic WFS1-SD is less common than classic WFS1-SD. At least 14 families with nonclassic WFS1-SD have been reported to date [Eiberg et al 2006, Hogewind et al 2010, Rendtorff et al 2011, Berry et al 2013, Bonnycastle et al 2013, De Franco et al 2017]. In a multidisciplinary clinical service in the UK, only about 15 of more than 100 individuals with WFS1 pathogenic variants presented with nonclassic WFS1-SD [T Barrett, D Williams, B Wright, personal observation].

Most affected individuals have isolated optic atrophy and congenital deafness. Some families also have diabetes mellitus that is isolated or in combination with optic atrophy and deafness. Although published data on follow up are limited, the findings appear to be non-progressive, with a milder phenotype than classic WFS1-SD. Furthermore, affected individuals do not appear to develop progressive neurodegeneration, and no brain MRI findings have been reported to date.

Additionally, five probands were reported with neonatal diabetes mellitus, congenital cataracts, and sensorineural deafness [De Franco et al 2017]; no follow-up data have been reported.

Autosomal dominant optic atrophy and hearing impairment. Autosomal dominantly inherited optic atrophy and hearing impairment was first described in a three-generation Danish family, followed for more than 30 years [Eiberg et al 2006]. Four family members had childhood-onset optic atrophy but retained color vision and useful visual acuity into their seventh decade. In addition, they had moderately severe hearing impairment, present since childhood. Audiograms showed a flat or U-shaped pattern. Although one individual had diabetes mellitus and one had impaired glucose tolerance at ages 70 and 67 years, respectively, this may have been coincidental, as type 2 diabetes is common in the elderly.

In a family of Dutch origin, three affected members from two generations had childhood-onset optic atrophy and hearing impairment [Hogewind et al 2010]. They had vision impairment, partial loss of color vision, and abnormal visual evoked potentials. Audiograms showed a relatively flat pattern of hearing loss across all frequencies in the two older individuals, and low-tone loss in the youngest. No other features of classic WFS1-SD (including diabetes mellitus, diabetes insipidus, kidney abnormalities, or psychiatric issues) were identified.

Eight families from the UK, US, and Sweden also had autosomal dominantly inherited optic atrophy and sensorineural deafness. Optic atrophy, which presented in childhood or adulthood, was very slowly progressive. Early-childhood-onset sensorineural hearing loss was profound; several family members required cochlear implants.

Autosomal dominant diabetes mellitus was reported in a four-generation family from Finland in which eight members had adult-onset diabetes mellitus (diagnosed between ages 18 and 51 years) [Bonnycastle et al 2013]. Diabetes mellitus did not present with diabetic ketoacidosis; seven of the eight individuals were insulin dependent, and six were of normal weight. Detailed clinical examination of the family members with diabetes did not reveal any other features of classic WFS1-SD, including hearing impairment in audiograms, optic atrophy or vision impairment in annual ophthalmologic examinations, or diabetes insipidus.

Autosomal dominant nuclear cataracts. In a four-generation Irish family, 11 family members were affected without other ocular or systemic features [Berry et al 2013].

Autosomal dominant low-frequency sensorineural hearing loss (DFNA6/14/38; see Genetic Hearing Loss Overview) has been reported in individuals without ocular or other systemic features. Because hearing loss in these individuals is congenital, slowly progressive, and low frequency (<2000 Hz), it is often not diagnosed until after language is acquired. (Note: It is unknown why hearing loss is high frequency in classic WFS1-SD and low frequency in DFNA6/14/38.) Unlike classic WFS1-SD, the decline in speech recognition scores in DFNA6/14/38 correlates to the level of hearing impairment.

Neonatal diabetes, profound congenital deafness, and cataracts. This phenotype was reported in five probands who represented simplex cases (i.e., a single occurrence in a family) and had de novo WFS1 pathogenic variants [De Franco et al 2017]. To date no long-term outcome data are available on these children.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified for classic WFS1-SD or nonclassic WFS1-SD.

Prevalence

Classic WFS1-SD. A study prior to the availability of molecular genetic testing estimated a prevalence of classic WFS1-SD of 1:550,000 children in the UK [Barrett et al 1995].

Recent epidemiologic studies based on molecularly confirmed classic WFS1-SD reviewed in Mishra et al [2021] estimated a prevalence of:

• 1:54,478 in the Messina district of northeast Sicily [Lombardo et al 2014];
• 1:1,351,000 in Italy [Rigoli et al 2020];
• 1:805,000 in northern India [Ganie et al 2011].

Nonclassic WFS1-SD. There are no prevalence figures for nonclassic WFS1-SD. However, in the authors' experience of leading a highly specialized multidisciplinary clinic in the UK for more than ten years, of 100 individuals seen with WFS1 pathogenic variants, 15 had nonclassic WFS1-SD [T Barrett, D Williams, B Wright, personal observation].

Other Genetic Causes of Features Seen in WFS1 Spectrum Disorder

Hearing impairment. See Genetic Hearing Loss Overview.

Monogenic diabetes syndromes. See Table 3.

Optic atrophy associated with hearing impairment. See Table 4.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with classic or nonclassic WFS1 spectrum disorder (WFS1-SD), the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

See also Wolfram Syndrome Clinical Management Guidelines, page 5, for recommended baseline investigations.

Treatment of Manifestations

There is no cure for WFS1-SD.

Management is focused on supportive care, often provided by multidisciplinary specialists in diabetic care, endocrinology, ophthalmology and low-vision clinics, audiology, speech-language therapy, neurology, pulmonology, psychiatry / psychology / mental health, urology, gastroenterology, social work, and medical genetics (see Table 6).

See also Wolfram Syndrome Clinical Management Guidelines, pages 6-12, for management recommendations.

Individualized education plan in the US (Education, Health and Care plan in the UK)

• An individualzed education plan (IEP) provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
• Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• In the US, families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Social/behavioral concerns. Consultation with a developmental or community pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.

Surveillance

See also Wolfram Syndrome Clinical Management Guidelines, pages 6-12, for surveillance recommendations.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic relatives at risk in order to identify as early as possible those who would benefit from prompt initiation of treatment for the earliest manifestations of WFS1-SD: diabetes mellitus, optic atrophy, and sensorineural hearing loss.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women with insulin-dependent diabetes mellitus, a characteristic of both classic and nonclassic WFS1-SD, have a two- to eightfold higher risk than pregnant women without diabetes of having a child with a birth defect or a pattern of birth defects (diabetic embryopathy). These defects can involve the craniofacial, cardiovascular, gastrointestinal, urogenital, musculoskeletal, and central nervous systems. Optimizing glucose control before and during pregnancy can reduce but does not eliminate the risk for diabetic embryopathy. High-resolution fetal ultrasonography and fetal echocardiogram are recommended to screen for congenital anomalies during pregnancy. Consultation with a maternal fetal medicine specialist during pregnancy should also be considered.

Because women with classic WFS1-SD may develop diabetes insipidus during pregnancy [Rugolo et al 2002], monitoring for diabetes insipidus during pregnancy is warranted.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

For a review of current and future therapeutic strategies, see Mishra et al [2021].

Classic WFS1-SD. An ongoing multicenter randomized double-blind controlled pivotal clinical trial is evaluating the use of sodium valproate to slow the progression of neurodegeneration (EudraCT Number 2017-001215-37).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Classic WFS1 spectrum disorder (WFS1-SD) is caused by biallelic pathogenic variants and inherited in an autosomal recessive manner.

Nonclassic WFS1-SD is caused by heterozygous pathogenic variants and inherited in an autosomal dominant manner.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of a child with classic WFS1-SD are presumed to be heterozygous for a WFS1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a WFS1 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• There is no conclusive evidence that the heterozygous parents of a child with WFS1-SD caused by biallelic WFS1 pathogenic variants are at any increased risk for components of WFS1-SD.

Sibs of a proband

• If both parents are known to be heterozygous for a WFS1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• The clinical course of classic WFS1-SD is highly variable (even between sibs with the same biallelic pathogenic variants) and is not predictable from the type or location of the familial pathogenic variants.
• There is no conclusive evidence that the heterozygous sibs of a proband with WFS1-SD caused by biallelic WFS1 pathogenic variants are at any increased risk for components of WFS1-SD.

Offspring of a proband. The offspring of an individual with WFS1-SD caused by biallelic pathogenic variants are obligate heterozygotes for a pathogenic variant in WFS1.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a WFS1 pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the WFS1 pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with nonclassic WFS1-SD have the disorder as the result of a de novo WFS1 pathogenic variant.
• Some individuals diagnosed with nonclassic WFS1-SD have an affected parent.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    * A parent with somatic and germline mosaicism for a WFS1 pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with nonclassic WFS1-SD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Clinical variability may be observed between affected family members with the same WFS1 pathogenic variant [Eiberg et al 2006].
• If the WFS1 pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the WFS1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs are still presumed to be at increased risk for nonclassic WFS1-SD because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with nonclassic WFS1-SD caused by a heterozygous pathogenic variant has a 50% chance of inheriting the WFS1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the WFS1 pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults with WFS1-SD and to young adults who are at risk of having WFS1 pathogenic variant(s).

Prenatal Testing and Preimplantation Genetic Testing

Once the WFS1 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for classic and nonclassic WFS1-SD are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

WFS1 spectrum disorder (WFS1-SD) is considered a prototype of endoplasmic reticulum (ER) disease [Mishra et al 2021]. WFS1 encodes wolframin, an endoglycosidase H-sensitive ER transmembrane glycoprotein. The precise function of wolframin has not been established, but deficiency is thought to lead to ER stress, impair cell cycle progression, and affect calcium homeostasis. There is no direct interaction between wolframin and the ER intermembrane small protein encoded by CISD2, pathogenic variants of which cause WFS2 (see Differential Diagnosis) [Amr et al 2007].

Wolframin is widely expressed, including in retinal ganglion cells and optic nerve glia in monkeys.

There is some in vitro evidence that WFS1 pathogenic variants are associated with systemic inflammation, opening up a new avenue for therapeutic strategies [Panfili et al 2021].

Mechanism of disease causation. Pathogenic variants in WFS1 result in loss of wolframin function.

Author Notes

Professor Timothy Barrett is based at the Institute of Cancer and Genomic Sciences, University of Birmingham, and Honorary Consultant in Pædiatric Endocrinology and Diabetes at Birmingham Women's and Children's Hospital. He has published more than 200 research papers in scientific journals as well as reviews and book chapters in the fields of pediatrics, diabetes, and genetics of childhood diabetes syndromes. His research interests include functional genetics, rare diabetes syndromes, and translational research to early-phase clinical trials in rare disease.

Acknowledgments

The Audiogenetic Research Group, headed by Lisbeth Tranebjærg, receives financial support from Widex AS and other research grants.

Timothy Barrett is supported by UK Medical Research Council grant "Development of a Novel Repurposed Drug Treatment for the Neurodegeneration and Diabetes in Wolfram Syndrome" (MR/P007732/1); NIHR Wellcome Clinical Research Facility (Birmingham); and NIHR Programme Grant "Improving Outcomes for Children and Young People with Diabetes from Socio-Economically Deprived and/or Ethnic Minority Populations" (NIHR202358). He holds an NIHR Senior Investigator award.

Revision History

• 1 December 2022 (bp) Comprehensive update posted live
• 9 April 2020 (bp) Comprehensive update posted live
• 19 December 2013 (me) Comprehensive update posted live
• 24 February 2009 (me) Review posted live
• 12 August 2008 (lt) Original submission

Literature Cited

• al-Sheyyab M, Jarrah N, Younis E, Shennak MM, Hadidi A, Awidi A, El-Shanti H, Ajlouni K. Bleeding tendency in Wolfram syndrome: a newly identified feature with phenotype genotype correlation. Eur J Pediatr. 2001;160:243–6. [PubMed: 11317648]
• Amr S, Heisey C, Zhang M, Shows KH, Ajlouni K, Pandya A, Satin LS, El-Shanti H, Shiang R. A homozygous mutation in a novel Zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am J Hum Genet. 2007;81:673–83. [PMC free article: PMC2227919] [PubMed: 17846994]
• Astuti D, Sabir A, Fulton P, Zatyka M, Williams D, Hardy C, Milan G, Favaretto F, Yu-Wai-Man P, Rohayem J, López de Heredia M, Hershey T, Tranebjaerg L, Chen JH, Chaussenot A, Nunes V, Marshall B, McAfferty S, Tillmann V, Maffei P, Paquis-Flucklinger V, Geberhiwot T, Mlynarski W, Parkinson K, Picard V, Bueno GE, Dias R, Arnold A, Richens C, Paisey R, Urano F, Semple R, Sinnott R, Barrett TG. Monogenic diabetes syndromes: Locus-specific databases for Alström, Wolfram, and thiamine-responsive megaloblastic anemia. Hum Mutat. 2017;38:764–77. [PMC free article: PMC5535005] [PubMed: 28432734]
• Barrett TG, Bundey SE, Macleod AF. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346:1458–63. [PubMed: 7490992]
• Berry V, Gregory-Evans C, Emmett W, Waseem N, Raby J, Prescott D, Moore AT, Bhattacharya SS. Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans. Eur J Hum Genet. 2013;21:1356–60. [PMC free article: PMC3831071] [PubMed: 23531866]
• Bonnycastle LL, Chines PS, Hara T, Huyghe JR, Swift AJ, Heikinheimo P, Mahadevan J, Peltonen S, Huopio H, Nuutila P, Narisu N, Goldfeder RL, Stitzel ML, Lu S, Boehnke M, Urano F, Collins FS, Laakso M. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes. 2013;62:3943–50. [PMC free article: PMC3806620] [PubMed: 23903355]
• Chaussenot A, Rouzier C, Quere M, Plutino M, Ait-El-Mkadem S, Bannwarth S, Barth M, Dollfus H, Charles P, Nicolino M, Chabrol B, Vialettes B, Paquis-Flucklinger V. Mutation update and uncommon phenotypes in a French cohort of 96 patients with WFS1-related disorders. Clin Genet. 2015;87:430–9. [PubMed: 24890733]
• De Franco E, Flanagan SE, Yagi T, Abreu D, Mahadevan J, Johnson MB, Jones G, Acosta F, Mulaudzi M, Lek N, Oh V, Petz O, Caswell R, Ellard S, Urano F, Hattersley AT. Dominant ER stress-inducing WFS1 mutations underlie a genetic syndrome of neonatal/infancy-onset diabetes, congenital sensorineural deafness, and congenital cataracts. Diabetes. 2017;66:2044–53. [PMC free article: PMC5482085] [PubMed: 28468959]
• Eiberg H, Hansen L, Kjer B, Hansen T, Pedersen O, Bille M, Rosenberg T, Tranebjærg L. Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene. J Med Genet. 2006;43:435–40. [PMC free article: PMC2649014] [PubMed: 16648378]
• Elli FM, Ghirardello S, Giavoli C, Gangi S, Dioni L, Crippa M, Finelli P, Bergamaschi S, Mosca F, Spada A, Beck-Peccoz P. A new structural rearrangement associated to Wolfram syndrome in a child with a partial phenotype. Gene. 2012;509:168–72. [PubMed: 22771918]
• Ganie MA, Laway BA, Nisar S, Wani MM, Khurana ML, Ahmad F, Ahmed S, Gupta P, Ali I, Shabir I, Shadan A, Ahmed A, Tufail S. Presentation and clinical course of Wolfram (DIDMOAD) syndrome from North India. Diabetic Med. 2011;28:1337–42. [PubMed: 21726277]
• Grenier J, Meunier I, Daien V, Baudoin C, Halloy F, Bocquet B, Blanchet C, Delettre C, Esmenjaud E, Roubertie A, Lenaers G, Hamel CP. WFS1 in optic neuropathies: mutation findings in nonsyndromic optic atrophy and assessment of clinical severity. Ophthalmology. 2016;123:1989–98. [PubMed: 27395765]
• Haghighi A, Haghighi A, Setoodeh A, Saleh-Gohari N, Astuti D, Barrett TG. Identification of homozygous WFS1 mutations (p.Asp211Asn, p.Gln486*) causing severe Wolfram syndrome and first report of male fertility. Eur J Hum Genet. 2013;21:347–51. [PMC free article: PMC3573194] [PubMed: 22781099]
• Hardy C, Khanim F, Torres R, Scott-Brown M, Seller A, Poulton J, Collier D, Kirk J, Polymeropoulos M, Latif F, Barrett T. Clinical and molecular genetic analysis of 19 Wolfram syndrome kindreds demonstrating a wide spectrum of mutations in WFS1. Am J Hum Genet. 1999;65:1279–90. [PMC free article: PMC1288280] [PubMed: 10521293]
• Hogewind BF, Pennings RJ, Hol FA, Kunst HP, Hoefsloot EH, Cruysberg JR, Cremers CW. Autosomal dominant optic neuropathy and sensorineural hearing loss associated with a novel mutation of WFS1. Mol Vis. 2010;16:26–35. [PMC free article: PMC2805421] [PubMed: 20069065]
• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
• Karzon R, Narayanan A, Chen L, Lieu JEC, Hershey T. Longitudinal hearing loss in Wolfram syndrome. Orphanet J Rare Dis. 2018;13:102. [PMC free article: PMC6020390] [PubMed: 29945639]
• Lombardo F, Salzano G, Di Bella C, Aversa T, Pugliatti F, Cara S, Valenzise M, De Luca F, Rigoli L. Phenotypical and genotypical expression of Wolfram syndrome in 12 patients from a Sicilian district where this syndrome might not be so infrequent as generally expected. J Endocrinol Invest. 2014;37:195–202. [PubMed: 24497219]
• Lusk L, Black E, Vengoechea J. Segregation of two variants suggests the presence of autosomal dominant and recessive forms of WFS1-related disease within the same family: expanding the phenotypic spectrum of Wolfram syndrome. J Med Genet. 2020;57:121–3. [PubMed: 31363008]
• Mishra R, Chen BS, Richa P, Yu-Wai-Man P. Wolfram syndrome: new pathophysiological insights and therapeutic strategies. Ther Adv Rare Dis. 2021;2. Available online. Accessed 6-28-23. [PMC free article: PMC10032446] [PubMed: 37181110]
• Mozzillo E, Delvecchio M, Carella M, Grandone E, Palumbo P, Salina A, Aloi C, Buono P, Izzo A, D'Annunzio G, Vecchio G, Orrico A, Genesio R, Simonelli F, Franzese A. A novel CISD2 intragenic deletion, optic neuropathy and platelet aggregation defect in Wolfram syndrome type 2. BMC Med Genet. 2014;15:88. [PMC free article: PMC4121299] [PubMed: 25056293]
• Panfili E, Mondanelli G, Orabona C, Belladonna M, Gargaro M, Fallarino F, Orecchini E, Prontera P, Proietti E, Frontino G, Tirelli E, Iacono A, Vacca C, Puccetti P, Grohmann U, Esposito S, Pallotta M. Novel mutations in the WFS1 gene are associated with Wolfram syndrome and systemic inflammation. Hum Mol Genet. 2021;30:265–76. [PMC free article: PMC8091036] [PubMed: 33693650]
• Plantinga RF, Pennings RJ, Huygen PL, Bruno R, Eller P, Barrett TG, Vialettes B, Paquis-Fluklinger V, Lombardo F, Cremers CW. Hearing impairment in genotyped Wolfram syndrome patients. Ann Otol Rhinol Laryngol. 2008;117:494–500. [PubMed: 18700423]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Rendtorff ND, Lodahl M, Boulahbel H, Johansen IR, Pandya A, Welch KO, Norris VW, Arnos KS, Bitner-Glindzicz M, Emery SB, Mets MB, Fagerheim T, Eriksson K, Hansen L, Bruhn H, Möller C, Lindholm S, Ensgård S, Lesperance MM, Tranebjaerg L. Identification of p.A684V missense mutation in the WFS1 gene as a frequent cause of autosomal dominant optic atrophy and hearing impairment. Am J Med Genet Part A. 2011;155A:1298–313. [PMC free article: PMC3100366] [PubMed: 21538838]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, 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. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rigoli L, Aloi C, Salina A, Di Bella C, Salzano G, Caruso R, Mazzon E, Maghnie M, Patti G, D'Annunzio G, Lombardo F. Wolfram syndrome 1 in the Italian population: genotype-phenotype correlations. Pediatr Res. 2020;87:456–62. [PubMed: 31266054]
• Rohayem J, Ehlers C, Wiedemann B, Holl R, Oexle K, Kordanouri O, Salzano G, Meissner T, Burger W, Schober E, Huebner A, Lee-Kirsch MA, et al. Diabetes and Neurodegeneration in Wolfram syndrome. A multicenter study of phenotype and genotype. Diabetes Care. 2011;34:1503–1510. [PMC free article: PMC3120194] [PubMed: 21602428]
• Rondinelli M, Novara F, Calcaterra V, Zuffardi O, Genovese S. Wolfram syndrome 2: a novel CISD2 mutation identified in Italian siblings. Acta Diabetol. 2015;52:175–8. [PubMed: 25371195]
• Rouzier C, Moore D, Delorme C, Lacas-Gervais S, Ait-El-Mkadem S, Fragaki K, Burté F, Serre V, Bannwarth S, Chaussenot A, Catala M, Yu-Wai-Man P, Paquis-Flucklinger V. A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. Hum Mol Genet. 2017;26:1599–611. [PMC free article: PMC5411739] [PubMed: 28335035]
• Rugolo S, Mirabella D, Palumbo MA, Chiantello R, Fiore G. Complete Wolfram's syndrome and successful pregnancy. Eur J Obstet Gynecol Reprod Biol. 2002;105:192–3. [PubMed: 12381487]
• Samara A, Lugar H, Hershey T, Shimony J. Longitudinal assessment of neuroradiological features in Wolfram syndrome. Am J Neuroradiol. 2020;41:2364–9. [PMC free article: PMC7963228] [PubMed: 33122205]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Urano F. Wolfram syndrome: diagnosis, management, and treatment. Curr Diab Rep. 2016;16:6. [PMC free article: PMC4705145] [PubMed: 26742931]
• Wragg R, Dias R, Barrett T, McCarthy L. Bladder dysfunction in Wolfram syndrome is highly prevalent and progresses to megacystis. J Pediatr Surg. 2018;53:321–5. [PubMed: 29277467]