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Nonsyndromic Holoprosencephaly via the CRIPTO/TDGF1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
CRIPTO 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15465CRIPTO81479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Stela Berisha, PhD, FACMG

Clinical Features and Genetics

Clinical Features

Nonsyndromic holoprosencephaly (HPE) is a structural anomaly of the brain in humans resulting from incomplete cleavage of the prosencephalon (forebrain) into right and left hemispheres between the third to fourth weeks of gestation (Martinez et al. 2018. PubMed ID: 29761634). Nonsyndromic HPE can be divided into four types according to the degree of brain division. Alobar HPE is the most severe form, with a single monoventricle and no interhemispheric fissure. Partial separation of the lobes is observed in semilobar HPE, with the interhemispheric fissure only present posteriorly. In lobar HPE, the right and left ventricles are separated, but incomplete separation of the frontal lobes occurs. Middle interhemispheric fusion variant (MIHF/MIHV or syntelencephaly) is a milder subtype, characterized by abnormal midline union of the posterior frontal and parietal lobes with variable fusion of thalami (Dubourg et al. 2007. PubMed ID: 17274816; Tekendo-Ngongang et al. 2000. PubMed ID: 20301702). In addition to the structural brain abnormality, patients with nonsyndromic HPE may have a distinctive pattern of facial features. The most severe affected individuals often have one central eye (cyclopia) and a tubular nasal structure (proboscis) located above the eye. In the less severe HPE forms, a small head (microcephaly), abnormally small eyes (microphthalmia), absent eyes (anophthalmia), a close set of eyes (hypotelorism), and cleft lip or palate may be observed (Solomon et al. 2010. PubMed ID: 20104594).

Nonsyndromic HPE accounts for approximately 25 to 50 percent of all cases of HPE, which affects an estimated 1 in 10,000 newborns and 1 in 250 fetuses (Martinez et al. 2018. PubMed ID: 29761634). Nonsyndromic HPE is inherited in an autosomal dominant pattern with incomplete penetrance. Therefore, the phenotype of affected individuals is extremely variable, ranging from alobar HPE with cyclopia to clinically normal (Solomon et al. 2010. PubMed ID: 19955556; Solomon et al. 2010. PubMed ID: 20104608; Dubourg et al. 2018. PubMed ID: 29785796). The most severely affected newborns usually do not survive beyond the first week of life, while a significant proportion of more mildly affected individuals survive the first year of life. Some individuals with various HPE subtypes, including severe subtypes, can survive until adulthood (Croen et al. 1996. PubMed ID: 8862623; Levey et al. 2010. PubMed ID: 20104615; Weiss et al. 2018. PubMed ID: 30182446). Variants in CRIPTO/TDGF1 are also associated with tumorigenesis and congenital heart defects (Wang et al. 2011. PubMed ID: 19853938; Geng et al. 2014. PubMed ID: 25516202).

Currently, there are no treatments for nonsyndromic HPE. However, genetic testing may provide advantages, including prognostic information, such as reported genotype-phenotype correlations, which assist in predicting the expected severity of the disorder for a given patient. Early identification and treatment of symptoms such as seizures and feeding difficulties and prenatal testing or pre-implantation genetic diagnosis for future pregnancies may also be possible. Knowledge of a de novo variant may decrease anxiety for future reproductive planning due to reduced recurrence risk.


Nonsyndromic HPE is inherited as an autosomal dominant manner with incomplete penetrance and intrafamilial variable expression. Fourteen genes have been associated with nonsyndromic HPE: CDON, CRIPTO, DISP1, DLL1, FGF8, FOXH1, GAS1, GLI2, NODAL, PTCH1, SHH, SIX3, TGIF1, and ZIC2. Of those, SHH, SIX3, ZIC2, and TGIF1 are common monogenic causes, representing approximately 24% of all cases with known etiology. Pathogenic variants in the SHH gene are the most common cause of nonsyndromic HPE; the frequency of pathogenic variants in the other genes, including CRIPTO, are unknown or rare (Tekendo-Ngongang et al. 2020. PubMed ID: 20301702; Martinez et al. 2018. PubMed ID: 29761634).

CRIPTO (crypto growth factor (CRGF)) is part of the EGF-CFC gene family that encodes a highly conserved epidermal growth factor-like domain (EGF) and a second cysteine-rich region called the CFC domain. Recent findings indicate that members of this gene family act as essential cofactors for Nodal, a member of the transforming growth factor β (TGF-β) family. They also play a crucial role in regional and cellular differentiation during embryonic development, especially in the specification of the endomesoderm, whose derivatives participate in the division of the eye field and brain (Minchiotti et al. 2002. PubMed ID: 11992720; de la Cruz et al. 2002. PubMed ID: 12073012).

CRIPTO is relatively tolerant to loss of function variants (Genome Aggregation Database). Gene function studies in zebrafish and mouse models indicate a role for CRIPTO in human midline and forebrain development (Minchiotti et al. 2002. PubMed ID: 11992720; de la Cruz et al. 2002. PubMed ID: 12073012; Shen and Schier. 2000. PubMed ID: 10858660). Genetic analysis of this gene is complicated by its pseudogenes found on chromosomes 2, 3, 6, 19, and X (Dono et al. 1991. PubMed ID: 1882841; Scognamiglio et al. 1999. PubMed ID: 10393436). Overall, CRIPTO has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

Clinical Sensitivity - Sequencing with CNV PGxome

The clinical sensitivity in CRIPTO is expected to be very low since variants in CRIPTO have rarely been reported in individuals with nonsyndromic HPE (Tekendo-Ngongang et al. 2020. PubMed ID: 20301702).

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the CRIPTO gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger reads.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Candidates for this test are patients with holoprosencephaly (HPE), other brain malformations, anophthalmia, and cyclopia. Targeted testing is indicated for family members of patients who have a known pathogenic variant in CRIPTO.


Official Gene Symbol OMIM ID
CRIPTO 187395
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID

Related Test

Holoprosencephaly, Autosomal Dominant, Nonsyndromic, Panel


  • Croen et al. 1996. PubMed ID: 8862623
  • de la Cruz et al. 2002. PubMed ID: 12073012
  • Dono et al. 1991. PubMed ID: 1882841
  • Dubourg et al. 2007. PubMed ID: 17274816
  • Dubourg et al. 2018. PubMed ID: 29785796
  • Geng et al. 2014. PubMed ID: 25516202
  • Genome Aggregation Database (gnomAD).
  • Levey et al. 2010. PubMed ID: 20104615
  • Martinez et al. 2018. PubMed ID: 29761634
  • Minchiotti et al. 2002. PubMed ID: 11992720
  • Online GEne Essentiality Database (OGEE).
  • Scognamiglio et al. 1999. PubMed ID: 10393436
  • Shen and Schier. 2000. PubMed ID: 10858660
  • Solomon et al. 2010. PubMed ID: 20104594
  • Solomon et al. 2010. PubMed ID: 19955556
  • Solomon et al. 2010. PubMed ID: 20104608
  • Tekendo-Ngongang et al. 2020. PubMed ID: 20301702
  • Wang et al. 2011. PubMed ID: 19853938
  • Weiss et al. 2018. PubMed ID: 30182446


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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