FeedbackMassively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Testing strategy:
Because clinical sensitivity of chromosome analysis may approach 50% for HPE, chromosome analysis should be performed before the HPE panel.
Polymerase Chain Reaction/Sequencing
- Recommended test for a known familial sequence variant previously identified in a family member.
- A copy of the family member’s test result documenting the known familial variant is required.
For chromosome analysis testing, see Related Tests
Holoprosencephaly (HPE) is a brain malformation resulting from incomplete separation of the forebrain at 3-5 weeks postconception. Diagnosis is confirmed by brain magnetic resonance imaging (MRI) or computed tomography (CT) imaging. Genetic testing helps families understand the cause of HPE and the risk for recurrence.
Disease Overview
Associated Findings
- Microcephaly (or macrocephaly due to hydrocephalus)
- Central nervous system (CNS) malformations
- Seizures
- Pituitary dysfunction
- Craniofacial abnormalities
- Intellectual disabilities ranging from mild to severe
Types of HPE
Based on degree of brain separation:
- Alobar
- Semilobar
- Lobar
- Middle interhemispheric fusion variant
- Microform HPE
Etiology
Multifactorial, with both genetic and environmental contributions:
- Maternal diabetes mellitus is known environmental risk factor
- Numerical or structural chromosome abnormalities ~25-50%
- Pathogenic single-gene variants
Prevalence
1/250 embryos and 1/10,000-16,000 live births
Inheritance
Dependent on etiology
- Autosomal dominant for all genes tested on HPE panel
Genotype-Phenotype Correlation
- Reduced penetrance
- Variable expressivity depending on gene and variant
Test Description
See Genes Tested table for genes included in the panel.
Clinical Sensitivity
Limitations
- A negative result does not exclude a heritable form of holoprosencephaly.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be affected if the individual has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the targeted genes
- Regulatory region variants and deep intronic variants
- Breakpoints of large deletions/duplications
- Deletions/duplications in CDON, FGFR1, and GLI3
- Noncoding transcripts
- The following exons are not sequenced due to technical limitations of the assay: ZIC2 (NM_007129) 3
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Deletions/duplications less than 1kb in the targeted genes by array
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level somatic variants
- Single exon deletions/duplications in the following exons:
- FGF8 (NM_033163) 1; PTCH1 (NM_001083602) 1; SHH (NM_001310462) 2
Analytical Sensitivity
For massively parallel sequencing:
| Variant Class | Analytical Sensitivity (PPA) Estimatea (%) | Analytical Sensitivity (PPA) 95% Credibility Regiona (%) |
|---|---|---|
|
SNVs |
99.2 |
96.9-99.4 |
|
Deletions 1-10 bp |
93.8 |
84.3-98.2 |
|
Deletions 11-44 bp |
100 |
87.8-100 |
|
Insertions 1-10 bp |
94.8 |
86.8-98.5 |
|
Insertions 11-23 bp |
100 |
62.1-100 |
|
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants |
||
Genes Tested
| Gene | Alias Symbol(s) | MIM Number | Disorder |
|---|---|---|---|
|
CDON |
ORCAM, CDO, CDON1 |
608707 |
Holoprosencephaly 11 |
|
DISP1 |
DISPA, MGC13130, DKFZP434I0428, MGC16796 |
607502 |
Holoprosencephaly 10, microform |
|
FGF8 |
AIGF |
600483 |
Hypogonadotropic hypogonadism 6 with or without anosmia |
|
FGFR1 |
FLT2, KAL2, H2, H3, H4, H5, CEK, FLG, BFGFR, N-SAM, CD331 |
136350 |
Hypogonadotropic hypogonadism 2 with or without anosmia |
|
FOXH1 |
FAST1 |
603621 |
|
|
GLI2 |
THP2, HPE9, THP1 |
165230 |
Holoprosencephaly 9 |
|
GLI3 |
GCPS, PHS, PAP-A, PAPA, PAPA1, PAPB, ACLS, PPDIV |
165240 |
Pallister-Hall syndrome |
|
NODAL |
601265 |
Nodal-related holoprosencephaly |
|
|
PTCH1 |
NBCCS, PTCH, BCNS |
601309 |
Holoprosencephaly 7 |
|
SHH |
HPE3, HLP3, HHG1, SMMCI, TPT, TPTPS, MCOPCB5 |
600725 |
Holoprosencephaly 3 |
|
SIX3 |
HPE2 |
603714 |
Holoprosencephaly 2 |
|
TGIF1 |
HPE4, TGIF |
602630 |
Holoprosencephaly 4 |
|
ZIC2 |
HPE5 |
603073 |
Holoprosencephaly 5 |
References
-
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Edison R, Muenke M. The interplay of genetic and environmental factors in craniofacial morphogenesis: holoprosencephaly and the role of cholesterol. Congenit Anom (Kyoto). 2003;43(1):1-21.
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18566978
Leoncini E, Baranello G, et al. Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: searching for population variations. Birth Defects Res A Clin Mol Teratol. 2008;82(8):585-591.
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594909
Matsunaga E, Shiota K. Holoprosencephaly in human embryos: epidemiologic studies of 150 cases. Teratology. 1977;16(3):261-272.
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10441331
Odent S, Atti-Bitach T, Blayau M, et al. Expression of the Sonic hedgehog (SHH ) gene during early human development and phenotypic expression of new mutations causing holoprosencephaly. Hum Mol Genet. 1999;8(9):1683-1689.
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11857543
Orioli IM, Vieira AR, Castilla EE, et al. Mutational analysis of the Sonic hedgehog gene in 220 newborns with oral clefts in a South American (ECLAMC) population. Am J Med Genet. 2002;108(1):12-15.
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10556296
Nanni L, Ming JE, Bocian M, et al. The mutational spectrum of the Sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet. 1999;8(13):2479-2488.
PubMed -
8896572
Roessler E, Belloni E, Gaudenz K, et al. Mutations in the human Sonic hedgehog gene cause holoprosencephaly. Nat Genet. 1996;14(3):357-360.
PubMed -
9302262
Roessler E, Belloni E, Gaudenz K, et al. Mutations in the C-terminal domain of Sonic hedgehog cause holoprosencephaly. Hum Mol Genet. 1997;6(11):1847-1853.
PubMed -
11285244
Brown LY, Odent S, David V, et al. Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Hum Mol Genet. 2001;10(8):791-796.
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9771712
Brown SA, Warburton D, Brown LY, et al. Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet. 1998;20(2):180-183.
PubMed
Indications for ordering:
To determine etiology of holoprosencephaly (HPE) or determine if parents of an affected individual are carriers (the affected individual should be tested first, if possible).