• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The PTCH1 gene is associated with autosomal dominant basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (MedGen UID: 2554). Additionally, the PTCH1 gene has preliminary evidence supporting a correlation with autosomal dominant holoprosencephaly (HPE) (MedGen: 372134).

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The Sonic Hedgehog (Shh) cellular signaling cascade is one of the central regulatory networks in embryonic patterning and development. The PTCH1 gene encodes the Patched protein, which is expressed on the cell surface and represses the Shh signaling cascade. Upon binding of the extracellular Shh ligand, Patched suppression is relieved, activating the Shh signaling cascade (PMID: 25206052).

OMIM: 601309

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 to develop 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 be present in childhood as brownish, pink, or orange basal cell nevi that may lie 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. Accessed October 2016). 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).

Up to 90% of affected individuals develop benign tumors of the jaw called keratocystic odontogenic tumors. These tumors usually first appear during adolescence and may continue to develop until approximately age 30, but rarely develop later in adulthood. Keratocystic odontogenic tumors usually present as painless swellings, but if left untreated, they can lead to major tooth disruption and jaw fracture (Genetics Home Reference. Gorlin syndrome. Accessed October 2016).

Approximately 5% of individuals with NBCCS develop a type of brain tumor called medulloblastoma, which typically presents in childhood. The risk related to the PTCH1 gene specifically appears to be less than 2%, with the risk much higher for individuals with NBCCS due to another gene known as SUFU (PMID: 25403219). Medulloblastoma is a primitive neuroectodermal tumor (PNET)—generally of the desmoplastic subtype, which is 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 have been reported (PMID: 22829011).

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 usually cause no obvious symptoms; however, in some cases, they may obstruct blood flow or cause arrhythmia (PMID: 20301330). Rhabdomyomas may occur in the heart (cardiac) or elsewhere in the body (PMID: 15586876). Ovarian fibromas are seen in roughly 20% of affected females and are usually an incidental finding on ultrasound examination or at caesarean section (PMID: 20301330). They may cause torsion of the ovary but are not thought to affect fertility. They can become large and calcified, though malignant transformation is uncommon (PMID: 20301330, Genetics Home Reference. Gorlin syndrome. Accessed October 2016).

Characteristic physical findings are seen in approximately 60% of affected individuals which includes macrocephaly, frontal bossing (prominent forehead), 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 age 20 years. (PMID: 7627481, 9096761, 8326488, 12879481, 9231911, 20301330, 15545745). Epidermal cysts and palmar or plantar pits are found in the majority of affected individuals (PMID: 20301330).

Other less common congenital malformations, found in approximately 5% of cases, 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 and jaw keratocysts. 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 age five. There is currently no significant evidence to suggest global delays (PMID: 20301330). Life expectancy in NBCCS is not significantly different from the average (PMID:22362873).

Additionally, there is evidence to suggest an association between PTCH1 and autosomal dominant holoprosencephaly (HPE) (PMID: 11941477, 17001668, 11430830) and this gene is therefore available as a “preliminary-evidence” gene on the Invitae Holoprosencephaly Panel. Preliminary-evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary-evidence genes.

Gene information
PTCH1 is a tumor suppressor gene that encodes a member of the patched gene family. The encoded protein is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis (NCBI Gene. Gene ID: 5727. http://www.ncbi.nlm.nih.gov/gene/5727. Accessed October 2016). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers and tumors may be increased.

Nevoid basal cell carcinoma syndrome has autosomal dominant inheritance. This means that an individual with a pathogenic variant in PTCH1 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 who has parents who do not have it). Postzygotic mosaicism that clinically mimics a germline pathogenic variant has been reported (PMID: 27658957).

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.
    • Developmental assessment and physical examination every six months may be warranted (PMID: 23139577).
    • There is not sufficient evidence to recommend regular neuroimaging. Frequent computed tomography (CT) scans should be avoided because of risks associated with radiation sensitivity.
    • Annual head MRI scans until age eight years in affected children has been suggested, though this should be considered along with the accompanied risks of general anesthesia versus a 2% risk of tumor development. A baseline MRI in adulthood may also be considered, 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 by a provider familiar with NBCCS.
  • X-ray the jaw (orthopantogram) of an individual aged eight years or older to evaluate for jaw keratocysts and other anomalies. If present, surgical excision is often required.
  • Skin should be examined at least annually. Some physicians recommend skin examination by a professional every three to six months (PMID: 23139577), particularly in adulthood or after first BCC diagnosis (PMID:21834049).
    • Early treatment of BCCs is essential to prevent long-term cosmetic problems, particularly on the face, with focus of both complete removal of the cancer and preservation of normal tissue. This is accomplished via several treatment modalities including surgery, photodynamic therapy, retinoids, and sonic hedgehog inhibitors.
  • Nutritional assessment to include Vitamin A, B, C, and D levels on an annual basis (PMID: 21834049).
  • Prior to pregnancy, ultrasound examination of the ovaries is recommended to evaluate for ovarian fibromas.
  • Medical genetics consultation.

Radiotherapy can lead to the development of many BCCs in the radiation field. If there are alternative treatments, 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 PTCH1 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 PTCH1 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: November 2016

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
PTCH1 NM_000264.3