Holoprosencephaly Panel

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).

Testing strategy:

Because clinical sensitivity of chromosome analysis may approach 50% for HPE, chromosome analysis should be performed before the HPE panel.

  • 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

  • 35-45% for familial holoprosencephaly    ,   
  • Unknown for sporadic cases

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
Hartsfield syndrome

FOXH1

FAST1

603621

  

GLI2

THP2, HPE9, THP1

165230

Holoprosencephaly 9
Culler-Jones syndrome

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
solitary median maxillary central incisor

SIX3

HPE2

603714

Holoprosencephaly 2

TGIF1

HPE4, TGIF

602630

Holoprosencephaly 4

ZIC2

HPE5

603073

Holoprosencephaly 5
    References