Holoprosencephaly, Autosomal Dominant, Nonsyndromic, Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10317 CDON 81479,81479 Order Options and Pricing
DISP1 81479,81479
DLL1 81479,81479
FGF8 81479,81479
FOXH1 81479,81479
GAS1 81479,81479
GLI2 81479,81479
NODAL 81479,81479
PTCH1 81479,81479
SHH 81479,81479
SIX3 81479,81479
TDGF1 81479,81479
TGIF1 81479,81479
ZIC2 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10317Genes x (14)81479 81479(x28) $890 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our Custom Panel tool.

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 backbone).

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

Turnaround Time

18 days on average for standard orders or 13 days 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.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Stela Berisha, PhD, FACMG

Clinical Features and Genetics

Clinical Features

Holoprosencephaly (HPE) is a relatively common developmental anomaly of the human forebrain affecting 1 in 10,000 live births and approximately 1 in 250 spontaneous abortions (Orioli and Castilla 2010). HPE results from failure of the developing forebrain to divide into two hemispheres and ventricles causing a continuum of structural brain malformations ranging from (in order of decreasing severity): alobar HPE to semilobar HPE to lobar HPE. In addition to the structural brain abnormality, patients with HPE may exhibit variable craniofacial anomalies including microcephaly, hypotelorism, cyclopia, proboscis, cleft lip/palate, anophthalmia or microophthalmia, absent nasal septum, flat nose, or single central incisor (Solomon et al. 2010). Because incomplete penetrance is a feature of dominantly inherited HPE, relatively normal facial appearance can be seen in individuals who have pathogenic variants and affected first degree relatives. Developmental delay is a nearly constant clinical manifestation of HPE. Severely affected newborns with alobar HPE and cyclopia and ethmocephaly usually do not live beyond the first week of life (Croen et al. 1996), but survival is greater in those cases with less severe craniofacial anomalies (Barr and Cohen 1999; Levey et al. 2010). Greater than half of all infants with semilobar or lobar HPE and no other major organ system involvement survive the first year of life (Olsen et al. 1997; Barr and Cohen 1999).

Genetics

Holoprosencephaly has both genetic and non-genetic causes. Chromosome aneuploidy and structural abnormality are the overall most common cause accounting for 25%-50% of all cases; another 18%-25% of all cases occur as part of syndromes resulting from single gene pathogenic variants (Solomon et al. 2013). Both autosomal recessive and dominant syndromes with HPE as a feature exist. Nonsyndromic HPE is inherited as an autosomal dominant disorder with incomplete penetrance and intrafamilial variable expression. It is estimated that approximately one-third of obligate carriers of autosomal dominant forms of HPE are asymptomatic with normal cognitive function (Cohen 1989). Fourteen genes have been identified as causes of autosomal dominant nonsyndromic HPE. The fourteen HPE genes are CDON, DISP1, DLL1, FGF8, FOXH1, GAS1, GLI2, NODAL, PTCH1, SHH, SIX3, TDGF1, TGIF1, and ZIC2 (Solomon et al. 2013). Pathogenic variants in these genes are thought to be inherited in an autosomal dominant manner. Pathogenic variants in the SHH gene are the most common cause of HPE (Roessler et al. 2009), followed by ZIC2, SIX3 and TGIF1. The prevalence of pathogenic variants in the other genes is unknown/rare (Solomon et al. 2013).

See individual gene test descriptions for information on molecular biology of gene products.

Clinical Sensitivity - Sequencing with CNV PGxome

The clinical sensitivity depends on whether the affected individual has a positive family history or is a simplex case. Clinical sensitivity for pathogenic variants in the SHH, ZIC2, SIX3 and TGIF1 genes in individuals with a family history are 30-40%, 5%, 1.3% and 1.3%, respectively. For simplex cases the clinical sensitivity for pathogenic variants in the SHH and ZIC2 genes are <5% and 2%, respectively. For all other genes the clinical sensitivity is expected to be very low (Solomon et al. 2013).

The clinical sensitivity of large deletions from most genes on this panel is expected to low. Deletions in only the DLL1, GLI2, SHH, SIX3, TGIF1, and ZIC2 genes have infrequently been reported in association with holoprosencephaly (Human Gene Mutation Database).

Testing Strategy

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

This panel typically provides 99.8% coverage of all coding exons of the genes 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 sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

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

Individuals with clinical presentations in the HPE spectrum.

Genes

Official Gene Symbol OMIM ID
CDON 608707
DISP1 607502
DLL1 606582
FGF8 600483
FOXH1 603621
GAS1 139185
GLI2 165230
NODAL 601265
PTCH1 601309
SHH 600725
SIX3 603714
TDGF1 187395
TGIF1 602630
ZIC2 603073
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Test

Name
PGxome®

Citations

  • Barr M. Jr., Cohen M.M. Jr. 1999. American Journal of Medical Genetics. 89: 116-20. PubMed ID: 10559767
  • Cohen M.M. Jr. 1989. Teratology. 40: 211-35. PubMed ID: 2688166
  • Croen L.A. et al. 1996. American Journal of Medical Genetics. 64: 465-72. PubMed ID: 8862623
  • Human Gene Mutation Database (Bio-base).
  • Levey E.B. et al. 2010. American Journal of Medical Genetics. Part C. 154C: 183-90. PubMed ID: 20104615
  • Olsen C.L. et al. 1997. American Journal of Medical Genetics. 73: 217-26. PubMed ID: 9409876
  • Orioli I.M., Castilla E.E. 2010. American Journal of Medical Genetics. Part C. 154C: 13-21. PubMed ID: 20104599
  • Roessler E. et al. 2009. Human Mutation. 30: E921-35. PubMed ID: 19603532
  • Solomon B.D. et al. 2010. American Journal of Medical Genetics. Part C. 154C: 3-7. PubMed ID: 20104594
  • Solomon B.D. et al. 2013. Holoprosencephaly Overview. 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: 20301702

Ordering/Specimens

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


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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