• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit




Associated disorders

The SUFU gene is associated with autosomal dominant basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (MedGen UID: 2554) and autosomal recessive Joubert syndrome (MedGen UID: 1626697).

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The SUFU gene is a tumor suppressor that encodes a negative regulator protein of the hedgehog signaling pathway. This pathway is involved in early human development and plays a role in pattern formation and cellular proliferation.

SUFU heterozygote
MedGen UID: 2554

Clinical condition
Nevoid basal cell carcinoma syndrome (NBCCS), also called Gorlin syndrome, is an inherited, multisystemic disorder that is associated with an increased risk of certain cancerous and noncancerous tumors. The clinical features among affected individuals are highly variable.

The most common type of cancer that develops in NBCCS is basal cell carcinoma (BCC), which is also the most common form of skin cancer in the general population. In this condition, BCCs typically develop during adolescence or early adulthood, but may also present in childhood as brownish, pink, or orange basal cell nevi that may be quiescent without evidence of aggressive behavior (PMID: 20301330). These most often occur on the face, chest, and back. Active BCCs can grow from existing basal cell nevi that may be numerous, or typical BCCs may appear from virtually blemish-free skin. BCCs may also crust, bleed, and ulcerate, or they may present as a localized infection (PMID: 20301330). The number of BCCs that develop during a lifetime varies among affected individuals: Approximately 10% of cases never develop any BCCs while others may develop thousands. Affected individuals with fair skin may be more likely to develop BCCs than others (Genetics Home Reference. Gorlin syndrome. https://ghr.nlm.nih.gov/condition/gorlin-syndrome. Accessed July 2017). Some also appear to be particularly radiosensitive, with new BCCs appearing in the field of radiation following radiotherapy (PMID: 20301330).

Other skin manifestations include meibomian cysts in the eyelids, sebaceous cysts, and dermoid cysts. Skin tags, particularly around the neck, often have the histologic appearance of BCCs but do not act aggressively (PMID: 20301330). Of note, jaw keratocysts are common in PTCH1-related NBCCS, but have not been described in individuals with SUFU-related NBCCS (PMID: 25403219).

The risk of developing medulloblastoma in individuals with SUFU-related NBCCS is up to 33% (PMID: 25403219, 22508808, 24651015). Medulloblastoma is a primitive neuroectodermal tumor (PNET)—generally of the desmoplastic subtype—most often diagnosed in the first two years of life and tends to have a favorable prognosis (PMID: 20301330). The risk for other malignant tumors does not appear to be increased, although lymphoma (PMID: 21623100) and meningioma (PMID: 22829011, 22958902) have been reported.

Individuals with NBCCS also have an increased risk of developing other benign tumors. Fibromas can occur in the heart or ovaries in females. Cardiac fibromas develop in approximately 2% of those with NBCCS, typically in infancy, and are usually benign; however, in some cases, they may obstruct blood flow or cause arrhythmia (PMID: 20301330). Rhabdomyomas may occur in the heart or elsewhere in the body (PMID: 15586876). Ovarian fibromas have been reported in 20-50% of affected females (PMID: 20301330, 25403219). They may cause torsion of the ovary but are not thought to affect fertility. They can also become large and calcified, though malignant transformation is uncommon (PMID: 20301330; Genetics Home Reference. Gorlin syndrome. https://ghr.nlm.nih.gov/condition/gorlin-syndrome. Accessed July 2017).

Characteristic physical findings include macrocephaly, frontal bossing, coarse facial features, and facial milia (PMID: 20301330). In addition, most individuals have skeletal anomalies (e.g., bifid ribs, wedge-shaped vertebrae) that may not be evident at birth. Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by 20 years of age (PMID: 7627481, 9096761, 8326488, 12879481, 9231911, 20301330, 15545745). Epidermal cysts and palmar or plantar pits have also been reported (PMID: 20301330).

Other less common congenital malformations include cleft lip/palate, polydactyly, and severe eye anomalies. Eye findings include strabismus, cataract, orbital cyst, microphthalmia, and pigmentary changes of the retinal epithelium (PMID: 12925203, 16024850).
The major morbidity associated with NBCCS is the cosmetic effects, mostly from the treatment of multiple skin tumors. Poor cosmetic outcome can be associated with various social and employment difficulties (PMID: 20301330). Some affected individuals also experience delay in motor milestones, but most catch up by 5 years of age. There is currently no significant evidence to suggest global delays (PMID: 20301330). Life expectancy in NBCCS is not significantly different from average (PMID: 22362873).

Gene information
SUFU is a negative regulator of the hedgehog signaling pathway. This pathway is a signaling cascade that plays a role in pattern formation and cellular proliferation during early human development. A pathogenic variant that prevents normal gene function can increase the risk of developing certain types of cancers and tumors (NCBI Gene. Gene ID: 51684. https://www.ncbi.nlm.nih.gov/gene/51684. Accessed July 2017).

Nevoid basal cell carcinoma syndrome has autosomal dominant inheritance. This means that an individual with a pathogenic variant in SUFU has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. Approximately 70%–80% of cases are inherited from a parent and the remainder occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it; PMID: 20301330).

Due to the multi-system involvement and variable expressivity of NBCCS, a multidisciplinary approach to management and periodic follow-up are advocated (PMID: 23139577). To establish the extent of disease and needs of an individual diagnosed with NBCCS, the following evaluations are recommended (PMID: 20301330, 23139577, 21834049):

  • Baseline measurement of the head circumference, preferably with plotting on a chart that accounts for height; evidence of rapid increase in centiles should prompt further investigation to exclude hydrocephalus
  • Physical examination for birth defects of clinical significance
  • Echocardiography in the first year of life to evaluate for cardiac fibromas
  • X-ray to evaluate for rib and vertebral anomalies and falx calcification
  • Awareness of risks of medulloblastoma in the first years of life:
    • Consideration of developmental assessment and physical examination every six months (PMID: 23139577)
    • Insufficient evidence to recommend regular neuroimaging;
      • frequent CT scans should be avoided due to risks associated with radiation sensitivity
    • Consideration of annual brain MRI scans until 8 years of age (PMID: 21834049)
      • Elevated risk of medulloblastoma in SUFU-NBCCS could justify brain MRI with contrast for infants every 3 months until 2 years of age and then every 6 months to the age of 3 years (PMID: 25403219)
      • Consideration of baseline MRI in adulthood, if not previously performed (PMID: 21834049)
  • Ophthalmologic evaluation for evidence of strabismus, cataract, orbital cyst, microphthalmia, and pigmentary changes of the retinal epithelium
  • Dental or orthodontic evaluation
    • However, jaw keratocysts have not been reported in individuals with pathogenic SUFUvariants, and the role of this screening is unknown
  • At least annual dermatology examination
    • Some recommend professional evaluation every 3-6 months (PMID: 23139577), particularly in adulthood or after first BCC diagnosis (PMID: 21834049)
    • Early treatment of BCCs to prevent long-term cosmetic problems, particularly on the face
      • focus should be on both complete removal of the cancer and preservation of normal tissue via various treatment modalities including surgery, photodynamic therapy, retinoids, and sonic hedgehog inhibitors
  • Annual nutritional assessment including levels of vitamins A, B, C, and D (PMID: 21834049)
  • Ultrasound examination of the ovaries to evaluate for ovarian fibromas prior to pregnancy
  • Medical genetics consultation

Radiotherapy can lead to the development of meningioma and many BCCs in the radiation field. If there are alternative treatment options, other therapies should be considered, particularly in childhood. Diagnostic X-rays should be used sparingly. Individuals with NBCCS should also be advised to avoid direct sun exposure as much as possible (PMID: 20301330, 23139577).
An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic variant in SUFU is present is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding SUFU are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow condition-specific screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Review date: July 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
SUFU NM_016169.3