Holoprosencephaly, Autosomal Dominant, Nonsyndromic, Panel
Summary and Pricing
Test MethodExome Sequencing with CNV Detection
|Test Code||Test Copy Genes||Gene CPT Codes Copy CPT Codes|
|10317||CDON||81479,81479||Order Options and Pricing|
|Test Code||Test Copy Genes||Panel CPT Code||Gene CPT Codes Copy CPT Code||Base Price|
|10317||Genes x (14)||81479||81479||$890||Order Options and Pricing|
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 PGxome Custom Panel tool.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
18 days on average for standard orders or 14 days on average for STAT orders.
Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
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).
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).
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.
Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).
Indications for Test
Individuals with clinical presentations in the HPE spectrum.
Individuals with clinical presentations in the HPE spectrum.
|Official Gene Symbol||OMIM ID|
|Kallmann Syndrome 6||AD||612702|
- 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
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.
- 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.