Combined Pituitary Hormone Deficiency-2 (CPHD2) via the PROP1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
1226 PROP1$490.00 81404 Add to Order
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 18 days.

Clinical Sensitivity

This test is predicted to detect pathogenic variants in PROP1 in 50% of familial Combined Pituitary Hormone Deficiency and 1%-2% of sporadic CPHD (Bottner et al. 2004; Turton et al. 2005).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 PROP1$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

To date, 5 large deletions in the PROP1 gene have been reported in patients affected with CPHD (Abrão et al. 2006; Kelberman et al. 2009; Zhang et al. 2010).

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Clinical Features

Combined pituitary hormone deficiency (CPHD) is a condition that characterized by a shortage of several hormones produced by anterior pituitary. PROP1-related CPHD2 is associated with deficiencies of growth hormone (GH), thyroid-stimulating hormone (TSH), gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), prolactin (PrL), and occasionally adrenocorticotropic hormone (ACTH) ( de Graaff et al. 2014). The clinical phenotype of PROP1-related CPHD is highly variable both within and between pedigrees with respect to the degree of pituitary hormone deficiency and the age of onset of the deficiency. Most affected individuals are ascertained because of a failure to grow and short stature starting in infancy or early childhood. People with CPHD2 may have mild hypothyroidism which could cause poor weight gain and fatigue. Other features of CPHD2 include absent or delayed puberty and incomplete secondary sexual development with infertility. Untreated males usually present hypogonadism while females often lack breast development or menses. ACTH deficiency is less common and does not occur until adulthood (Flück et al. 1998; Bottner et al. 2004].


50% of CPHD has a genetic basis and pathogenic variants in at least eight genes are found to cause genetically determined CPHD. PROP1 pathogenic variants are the most common known cause of this disorder, accounting for approximately 50% of familiar cases, although the incidence in sporadic cases is much lower (de Graaff et al. 2014). PROP1 is a pituitary-specific paired-like homeodomain transcription factor that plays a crucial role in the proper development of the pituitary gland and the specialization of its cell types (Duquesnoy et al. 1998). Pathogenic variants in PROP1 perturb ontogenesis of pituitary gonadotropes, somatotropes, lactotropes, and thyrotropes. These developmental defects result in deficiencies of LH, which is needed for normal growth; FSH and GH, which both play a role in sexual development and fetility; TSH, which helps with thyroid gland function; prolactin, which stimulates the production of breast milk; and ACTH, which influences energy production in the body and maintains normal blood sugar and blood pressure levels (Kelberman et al. 2009).

PROP1-related CPHD is inherited in an autosomal recessive manner. At least 34 pathogenic variants in the PROP1 gene have been found to cause CPHD (Human Gene Mutation Database). The most common pathogenic variant in which three AG repeats are reduced to two AG repeats (c.301_302del) deletes two DNA building blocks in the PROP1 gene and accounts for 55% of alleles in familial cases and 12% of alleles in sporadic cases of CPHD ( de Graaff et al. 2014).

Testing Strategy

This test involves bidirectional Sanger sequencing of all coding exons of the PROP1 gene plus ~10 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Candidates for this test are patients with GH deficiency and at least one other pituitary hormone deficiency, and family members of patients with known pathogenic variants.


Official Gene Symbol OMIM ID
PROP1 601538
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Pituitary Hormone Deficiency, Combined 2 AR 262600

Related Tests

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Combined Pituitary Hormone Deficiency (CPHD) Sequencing Panel with CNV Detection
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Disorders of Sex Development and Infertility Sequencing Panel with CNV Detection
Disorders of Sex Development Sequencing Panel with CNV Detection
Female Infertility Sequencing Panel with CNV Detection
Hypogonadotropic Hypogonadism/Kallmann Syndrome Sequencing Panel with CNV Detection
Male Infertility Sequencing Panel with CNV Detection
Septo-optic Dysplasia Spectrum Sequencing Panel


Genetic Counselors
  • Abrão M.G. et al. 2006. Clinical Endocrinology 65: 294-300 PubMed ID: 16918947
  • Böttner A. et al. 2004. The Journal of Clinical Endocrinology and Metabolism. 89: 5256-65. PubMed ID: 15472232
  • Duquesnoy P. et al. 1998. Febs Letters. 437: 216-20. PubMed ID: 9824293
  • Flück C. et al. 1998. The Journal of Clinical Endocrinology and Metabolism. 83: 3727-34. PubMed ID: 9768691
  • Graaff L.C.G. 2014. PROP1-Related Combined Pituitary Hormone Deficiency. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301521
  • Human Gene Mutation Database (Bio-base).
  • Kelberman D. et al. 2009. Clinical Endocrinology. 70: 96-103. PubMed ID: 19128366
  • Turton J.P. et al. 2005. Clinical Endocrinology. 63: 10-8. PubMed ID: 15963055
  • Zhang H. et al 2010. Hormone Research in Pediatrics. 74:98-105 PubMed ID: 20395664
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all 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 for example 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 and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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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.
  • 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.


(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.


(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.


(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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