FeedbackMassively Parallel Sequencing
Use to evaluate for a molecular etiology of HPE in an affected individual
Massively Parallel Sequencing
Use to evaluate for a molecular etiology of HPE in an affected pregnancy
Polymerase Chain Reaction/Sequencing
- Use to assess for a familial sequence variant previously identified in a family member
- A copy of the relative's genetic laboratory report documenting the familial variant is required.
For chromosome analysis and CNV testing, see Related Tests.
Holoprosencephaly (HPE) is a brain malformation resulting from partial or complete failure of the forebrain (prosencephalon) to divide into hemispheres. This malformation originates from failed midline delineation during early embryonic development. There are multiple types of HPE, detailed in the table below, with variable degrees of severity depending on the level of abnormal division in the brain. This condition can be an isolated finding (nonsyndromic) or associated with a broader syndrome such as Smith-Lemli-Opitz or Kallman syndrome. HPE is associated with multiple etiologies, including structural or numerical chromosomal abnormalities, copy number variations (CNVs), pathogenic variants in single genes, and environmental and teratogenic factors. Additionally, emerging evidence indicates that genetic and environmental modifiers likely play a role in modulating phenotypes.
Testing Strategy
Chromosome analysis, with or without reflex to genomic microarray, should be performed as a first-tier test since more than 50% of individuals with HPE may have an associated chromosomal or CNV abnormality.
Clinical Features
- Microcephaly (macrocephaly may be seen in cases of hydrocephalus)
- Central nervous system (CNS) malformations
- Seizures
- Pituitary dysfunction
- Craniofacial abnormalities
- Cognitive disabilities ranging from mild to severe
- Developmental delays
Types of HPE
| Type | Range of Findings |
|---|---|
|
Alobar HPE |
|
|
Semilobar HPE |
|
|
Lobar HPE |
|
|
Middle interhemispheric fusion variant |
|
|
Microform HPE |
|
Genetics
Genes
Sequencing and deletion/duplication: CDON, FGFR1, GLI2, PTCH1, SHH, SIX3, TGIF1, ZIC2
Etiology
- Pathogenic variants in single genes
- Cytogenetic abnormalities
- Numerical or structural chromosome anomalies
- CNV anomalies
- Environmental and teratogenic factors
- Maternal diabetes mellitus
- Prenatal alcohol exposure
Prevalence
Inheritance
Dependent on etiology
For single gene variants: autosomal dominant with reduced penetrance and variable expressivity
Test Interpretation
Clinical Sensitivity
25% for molecular testing of genes included on this panel
Analytic Sensitivity
For massively parallel sequencing:
| Variant Class | Analytic Sensitivity (PPA) Estimatea (%) and 95% Credibility Region | Analytic Specificity (NPA) |
|---|---|---|
|
SNVs |
>99 (96.9-99.4) |
>99.9 |
|
Deletions 1-10 bpb |
93.8 (84.3-98.2) |
>99.9 |
|
Insertions 1-10 bpb |
94.8 (86.8-98.5) |
>99.9 |
|
Exon-levelc deletions |
97.8 (90.3-99.8) [2 exons or larger] 62.5 (38.3-82.6) [Single exon] |
>99.9 |
|
Exon-levelc duplications |
83.3 (56.4-96.4) [3 exons or larger] |
>99.9 |
|
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA). bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced. cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp. bp, base pairs; PPA, positive percent agreement; NPA, negative percent agreement; SNVs, single nucleotide variants |
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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
- SNVs and small deletions/insertions will not be called in the following exons due to technical limitations of the assay:
- FGFR1 (NM_001354367) exon(s) 18
- FGFR1 (NM_001354369) exon(s) 18
- FGFR1 (NM_001354370) exon(s) 17
- ZIC2 (NM_007129) partial exon(s) 3(Chr13:100637736-100637843)
- 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
- Large duplications less than 3 exons in size
- Single exon deletions/duplications in the following exons:
- FGFR1 (NM_001354367, NM_001354369) 18
- FGFR1 (NM_001354370) 17
- Noncoding transcripts
- Low-level somatic variants
- Certain other variants due to technical limitations in the presence of pseudogenes and/or repetitive or homologous regions
Genes Tested
| Gene | Alias Symbol(s) | MIM Number | Disorder |
|---|---|---|---|
|
CDON |
ORCAM, CDO, CDON1 |
608707 |
Holoprosencephaly 11 |
|
FGFR1 |
FLT2, KAL2, H2, H3, H4, H5, CEK, FLG, BFGFR, N-SAM, CD331 |
136350 |
Hypogonadotropic hypogonadism 2 with or without anosmia Hartsfield syndrome |
|
GLI2 |
THP2, HPE9, THP1 |
165230 |
Holoprosencephaly 9 Culler-Jones syndrome |
|
GLI3 |
GCPS, PHS, PAP-A, PAPA, PAPA1, PAPB, ACLS, PPDIV |
165240 |
Pallister-Hall syndrome |
|
PTCH1 |
NBCCS, PTCH, BCNS |
601309 |
Holoprosencephaly 7 |
|
SHH |
HPE3, HLP3, HHG1, SMMCI, TPT, TPTPS, MCOPCB5 |
600725 |
Holoprosencephaly 3 Solitary median maxillary central incisor |
|
SIX3 |
HPE2 |
603714 |
Holoprosencephaly 2 |
|
TGIF1 |
HPE4, TGIF |
602630 |
Holoprosencephaly 4 |
|
ZIC2 |
HPE5 |
603073 |
Holoprosencephaly 5 |
References
-
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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20104599
Orioli IM, Castilla EE. Epidemiology of holoprosencephaly: prevalence and risk factors. Am J Med Genet C Semin Med Genet. 2010;154C(1):13-21.
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29761639
Summers AD, Reefhuis J, Taliano J, et al. Nongenetic risk factors for holoprosencephaly: An updated review of the epidemiologic literature. Am J Med Genet C Semin Med Genet. 2018;178(2):151-164.
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29785796
Dubourg C, Kim A, Watrin E, et al. Recent advances in understanding inheritance of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018;178(2):258-269.
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29771000
Kruszka P, Martinez AF, Muenke M. Molecular testing in holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018;178(2):187-193.
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20104595
Roessler E, Muenke M. The molecular genetics of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010;154C(1):52-61.
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22310223
Roessler E, Vélez JI, Zhou N, et al. Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene×gene interactions. Mol Genet Metab. 2012;105(4):658-64.
30182442
Hu T, Kruszka P, Martinez AF, et al. Cytogenetics and holoprosencephaly: a chromosomal microarray study of 222 individuals with holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018;178(2):175-186.
See Testing Strategy