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Holoprosencephaly-3 (Autosomal Dominant Nonsyndromic) via the SHH 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
8619 SHH 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8619SHH81479 81479(x2) $890 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. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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).

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

For Sanger Sequencing click here.

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; OMIM 236100) is a common developmental anomaly of the human forebrain and midface that affects 1 in 16,000 live births (Muenke and Gropman. GeneReviews 2008) and approximately 1 in 200 spontaneous abortions (Orioli et al., Hum Genet 109:1-6, 2001). HPE results from failure of the developing forebrain to divide into two hemispheres and ventricles and causes a continuum of structural brain malformations ranging from alobar HPE to semilobar HPE to lobar HPE. In addition to the structural brain abnormality, patients with HPE may exhibit variable craniofacial anomalies including cyclopia, ocular hypotelorism, structurally and positionally abnormal proboscis, bilateral cleft lip, anophthalmia or microophthalmia, absent nasal septum, flat nose, or single central incisor. Because incomplete penetrance is a feature of dominantly-inherited HPE, relatively normal facial appearance can be seen in individuals who have causative gene variants and affected first degree relatives. Developmental delay is a nearly constant clinical manifestation of HPE. Other findings include short stature, failure to thrive, seizures, feeding problems, and hypothalamic and brain stem dysfunction. Severely affected newborns with alobar HPE, cyclopia, and ethmocephaly usually do not live beyond the first week of life (Croen et al. Am J Med Genet. 64:465-472, 1996), but survival is greater in those cases with less severe craniofacial anomalies (Barr and Cohen. Am J Med Genet. 89:116-120, 1999). More 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. Am J Med Genet. 73:217-226, 1997; Barr and Cohen, 1999).

Genetics

Holoprosencephaly has both genetic and non-genetic causes. The most common non-genetic cause is maternal diabetes, which confers a risk of 1% to infants of diabetic mothers (Barr et al., J Pediatr. 102:565-568, 1983). Chromosome aneuploidy and structural abnormality is the overall single most common cause accounting for 25%-50% of all cases; while another 18%-25% of all cases occur as part of syndromes resulting from single gene variants (Muenke and Gropman; GeneReviews, 2008). Both autosomal recessive and dominant syndromes with HPE as a feature are known. 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, Teratology 40:211-35, 1989). Seven causative loci, including five proven genes and one candidate gene (TMEM1), have been identified as causes of autosomal dominant nonsyndromic HPE. The five HPE genes are SHH, ZIC2, SIX3, TGIF, and PTCH1. Another gene, GLI2, is associated with facial features typical of HPE but does not cause typical CNS findings. Over 50 SHH variants, mostly missense, have been documented as causative for HPE3 (OMIM 142945).

Clinical Sensitivity - Sequencing with CNV PGxome

SHH variants have been reported to account for 30%-40% of autosomal dominant nonsyndromic HPE and <5% of simplex cases (Nanni et al., Hum Mol Genet 8:2479-2488, 1999; Muenke and Gropman; GeneReviews, 2008).

Testing Strategy

This test provides full coverage of all coding exons of the SHH 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 full 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.

Gene

Official Gene Symbol OMIM ID
SHH 600725
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Holoprosencephaly 3 AD 142945

Related Tests

Name
Autosomal Dominant, Non-Syndromic Holoprosencephaly via the GAS1 Gene
Holoprosencephaly, Autosomal Dominant, Nonsyndromic, Panel
Holoprosencephaly-2 (Autosomal Dominant, Nonsyndromic) via the SIX3 Gene
Holoprosencephaly-4 (Autosomal Dominant, Nonsyndromic) via the TGIF1 Gene
Holoprosencephaly-7 (Autosomal Dominant, Nonsyndromic) via the PTCH1 Gene

Citations

  • Barr, M., Jr., Cohen, M. M., Jr. (1999). "Holoprosencephaly survival and performance." Am J Med Genet 89(2): 116-20. PubMed ID: 10559767
  • Barr, M., Jr., et.al. (1983). "Holoprosencephaly in infants of diabetic mothers." J Pediatr 102(4): 565-8. PubMed ID: 6834191
  • Cohen, M. M., Jr. (1989). "Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology." Teratology 40(3): 211-35. PubMed ID: 2688166
  • Croen, L. A., et.al. (1996). "Holoprosencephaly: epidemiologic and clinical characteristics of a California population." Am J Med Genet 64(3): 465-72. PubMed ID: 8862623
  • Maximilian Muenke, Andrea Gropman (2008). "Holoprosencephaly Overview."
  • Nanni, L., et.al. (1999). "The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly." Hum Mol Genet 8(13): 2479-88. PubMed ID: 10556296
  • Olsen, C. L., et.al. (1997). "Epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York State, 1984-1989." Am J Med Genet 73(2): 217-26. PubMed ID: 9409876
  • Orioli, I. M., et.al. (2001). "Identification of novel mutations in SHH and ZIC2 in a South American (ECLAMC) population with holoprosencephaly." Hum Genet 109(1): 1-6. PubMed ID: 11479728

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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