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Infantile Myofibromatosis and Idiopathic Basal Ganglia Calcification via the PDGFRB Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

NGS Sequencing

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
4399 PDGFRB$690.00 81479 Add to Order
Pricing Comment

Our most cost-effective testing approach is NextGen sequencing with Sanger sequencing supplemented as needed to ensure sufficient coverage and to confirm NextGen calls that are pathogenic, likely pathogenic or of uncertain significance. If, however, full gene Sanger sequencing only is desired (for purposes of insurance billing or STAT turnaround time for example), please see link below for Test Code, pricing, and turnaround time information.

For Sanger Sequencing click here.
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

Pathogenic variants in the PDGFRB gene are the major cause of familial IM; they were found in 12 out of 13 IM-affected families (Cheng et al. 2013; Martignetti et al. 2013). This test will detect PDGFRB pathogenic variants in ~ 4% of patients with IBGC (Nicolas et al. 2013b).

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Clinical Features

Infantile myofibromatosis (IM), previously known as congenital generalized fibromatosis, is characterized by the development of tumors in various tissues and organs. IM affects mostly infants and young children. Although tumors are usually detected at birth or during the first two years of life, uterine and adult onsets have been also reported (Chung and Enzinger 1981). Two main types of IM, solitary and multicentric, are distinguished. Each type is further divided in two groups based on the presence or absence of visceral involvement (Wiswell et al. 1988). The solitary type is characterized by the development of a single nodule mainly in the bones, striated muscle, skin, or subcutaneous tissues. In rare cases, solitary tumors have been reported in the viscera. The multicentric type is characterized by the development of multiple nodules in various organs. Visceral involvement is common in this type. The lungs, heart, gastrointestinal tract, pancreas, liver, and bones are most commonly affected. Involvement of the central nervous system appears to be rare (Wada et al. 1998). IM with visceral involvement has a poor prognosis, although spontaneous regression has been reported in some cases (Teng et al. 1963). About half the patients with IM have the solitary type and the other half have the multicentric type. The solitary type affects older individuals in about 20% of patients. Both solitary and multicentric IM have a good prognosis in the absence of visceral involvement when the tumors regress spontaneously during the first years of life. However, new tumors may develop later. IM is clinically heterogeneous. Symptoms are highly variable and depend on the number and location of tumors. The disease may be limited to the skin in some patients, while several visceral organs are involved in other patients. Affected related members may present either with the solitary type with no visceral involvement or the multicentric visceral type (Cheung et al. 2013). The tumors consist of soft tissues abnormalities, and are usually benign. However, complications may occur when the tumors affect the normal function of vital organs such as the brain or viscera. Although rare, IM has been reported in various ethnic and geographical groups (Cheung et al. 2013). Familial Idiopathic Basal Ganglia Calcification (IBGC), also known as Fahr’s syndrome, is a neurological disorder characterized by abnormal deposits of calcium in areas of the brain that control movement. The radiological characteristics of IBGC consist of bilateral and symmetrical calcification of the basal ganglia. Additional areas of the brain may also be affected. IBGC is clinically heterogeneous. Symptoms usually begin during the fourth and fifth decade of life. Childhood and adolescent onset have been also reported. Movement disorders in the form of dystonia, tremor and chorea are the initial and most common clinical manifestations of IBGC. As the disease progress neurological and neuropsychiatric abnormalities are detected and include seizures, spasticity, headache, dysarthria, psychosis, mood disturbances, cognitive decline, and dementia (Manyam 2005; Nicolas et al. 2013b). Abnormal deposit of calcium in the brain is a common finding usually associated with aging. However, familial IBGC is rare, with less than 1/1,000,000 people affected worldwide (Ellie et al. 1989).

Genetics

In most of the IM-affected families reported, the disease is inherited in an autosomal dominant manner. In rare families, a recessive mode of transmission is speculated. It has been argued that family history may be difficult to obtain due to the spontaneous regression of tumors (Narchi 2001). Autosomal Dominant IM is genetically heterogeneous. Two genes, PDGFRB and NOTCH3 have been recently implicated in the disease. Two germline missense mutations in the PDGFRB gene, c.1681C>T (p.Arg561Cys) and c.1978C>A (p.Pro660Thr) have been reported. The c.1681C>T variant was reported in families from different ethnic and geographical populations (Cheng et al. 2013; Martignetti et al. 2013). Familial IBGC is a genetically heterogeneous autosomal dominant disorder. Simplex cases with no apparent family history have been also reported. To date, three genes have been associated with the disease: SLC20A2, PDGFB, and PDGFRB. Three pathogenic missense variants in PDGFRB have been recently reported both in familial and apparently simplex cases (Nicolas 2013a; 2013b). PDGFRB encodes the platelet-derived growth factor receptor beta, a tyrosine kinase receptor that has been involved in several cellular processes including proliferation, differentiation, survival, and migration. It has also been suggested that the PDGFRB/ PDGFB pathway is involved in the calcification of vascular smooth muscle cells (Diliberto et al. 1991).

Testing Strategy

For this NextGen test, the full coding regions plus ~20 bp of non-coding DNA flanking each exon are sequenced for the gene listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

Indications for Test

Patients with clinical and radiological findings suggestive of infantile myofibromatosis or Idiopathic Basal Ganglia Calcification are candidates.

Gene

Official Gene Symbol OMIM ID
PDGFRB 173410
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) via the NOTCH3 Gene
Idiopathic Basal Ganglia Calcification Sequencing Panel
Infantile Myofibromatosis Sequencing Panel

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Cheung YH, Gayden T, Campeau PM, LeDuc CA, Russo D, Nguyen V-H, Guo J, Qi M, Guan Y, Albrecht S, Moroz B, Eldin KW, et al. 2013. A recurrent PDGFRB mutation causes familial infantile myofibromatosis. Am. J. Hum. Genet. 92: 996–1000. PubMed ID: 23731537
  • Chung EB, Enzinger FM. 1981. Infantile myofibromatosis. Cancer 48: 1807–1818. PubMed ID: 7284977
  • Diliberto PA, Gordon G, Herman B. 1991. Regional and mechanistic differences in platelet-derived growth factor-isoform-induced alterations in cytosolic free calcium in porcine vascular smooth muscle cells. J. Biol. Chem. 266: 12612–12617. PubMed ID: 1905727
  • Ellie E, Julien J, Ferrer X. 1989. Familial idiopathic striopallidodentate calcifications. Neurology 39: 381–385. PubMed ID: 2927646
  • Manyam BV. 2005. What is and what is not “Fahr”s disease’. Parkinsonism Relat. Disord. 11: 73–80. PubMed ID: 15734663
  • Martignetti JA, Tian L, Li D, Ramirez MCM, Camacho-Vanegas O, Camacho SC, Guo Y, Zand DJ, Bernstein AM, Masur SK, Kim CE, Otieno FG, et al. 2013. Mutations in PDGFRB Cause Autosomal-Dominant Infantile Myofibromatosis. The American Journal of Human Genetics 92: 1001–1007. PubMed ID: 23731542
  • Narchi H. 2001. Four half-siblings with infantile myofibromatosis: a case for autosomal-recessive inheritance. Clin. Genet. 59: 134–135. PubMed ID: 11260217
  • Nicolas G, Pottier C, Charbonnier C, Guyant-Maréchal L, Ber I Le, Pariente J, Labauge P, Ayrignac X, Defebvre L, Maltête D, Martinaud O, Lefaucheur R, et al. 2013b. Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. Brain 136: 3395–3407. PubMed ID: 24065723
  • Nicolas G, Pottier C, Maltête D, Coutant S, Rovelet-Lecrux A, Legallic S, Rousseau S, Vaschalde Y, Guyant-Maréchal L, Augustin J, Martinaud O, Defebvre L, et al. 2013a. Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology 80: 181–187. PubMed ID: 23255827
  • Teng P, Warden MJ, Cohn WL. 1963. Congenital generalized fibromatosis (renal and skeletal) with complete spontaneous regression. J. Pediatr. 62: 748–753. PubMed ID: 13980570
  • Wada H, Akiyama H, Seki H, Ichihara T, Ueno K, Miyawaki T, Koizumi S. 1998. Spinal canal involvement in infantile myofibromatosis: case report and review of the literature. J. Pediatr. Hematol. Oncol. 20: 353–356. PubMed ID: 9703012
  • Wiswell TE, Davis J, Cunningham BE, Solenberger R, Thomas PJ. 1988. Infantile myofibromatosis: the most common fibrous tumor of infancy. J. Pediatr. Surg. 23: 315–318. PubMed ID: 3385581
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TEST METHODS

NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~20 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are covered by Sanger sequencing.  All pathogenic, likely pathogenic, or variants of uncertain significance are confirmed by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign, Common Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (http://www.hgvs.org).  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~20 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

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Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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