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Holoprosencephaly Panel, Nonsyndromic Sequencing and Deletion/Duplication, 11 Genes Indications for Ordering • Determine the etiology of holoprosencephaly (HPE) to aid in counseling and assessing recurrence risk • Determine if parents of an affected individual are carriers (the affected individual should be tested first, if possible) Test Description • Targeted capture of all coding exons and exon-intron junctions followed by massively parallel sequencing • Deletion/duplication analysis by the tiled, customdesigned comparative genomic hybridization (CGH) array • 11 gene panel covers most nonsyndromic HPE Tests to Consider Primary tests Holoprosencephaly Panel, Nonsyndromic, Sequencing and Deletion/Duplication, 11 Genes 2008848 • Preferred test for individuals with clinical phenotype of HPE and a normal karyotype Holoprosencephaly Sequencing, 11 Genes 2008853 • Acceptable test for individuals with clinical phenotype of HPE and a normal karyotype Holoprosencephaly, Nonsyndromic, Deletion/Duplication, 11 Genes 2008845 • Order if clinical suspicion is high, chromosome analysis is normal, and the Holoprosencephaly, Sequencing, 11 Genes test did not detect a pathogenic mutation Holoprosencephaly Panel, Nonsyndromic, Sequencing, and Deletion/Duplication, 11 Genes, Fetal 2008863 • Preferred test for fetuses with HPE not caused by a structural or numerical chromosome abnormality Related tests • Chromosome Analysis, Peripheral Blood 2002289 • Chromosome Analysis, Amniotic Fluid 2002293 • Chromosome Analysis, Chorionic Villus Sampling 2002291 • Chromosome Analysis, Products of Conception, with Reflex to Genomic Microarray 2005762 Disease Overview Incidence –1/250 embryos and 1/10,000-16,000 live births Classification – HPE is a brain malformation • Results from incomplete separation of the forebrain at 3to 5-weeks post conception • HPE classification − ranges from the most severe to the least severe depending on the degree of brain separation o Alobar variant o Semilobar variant o Lobar variant o Middle interhemispheric variant o Microform Symptoms Most common symptoms • Microcephaly • Macrocephaly in cases with hydrocephalus • Seizures • Pituitary dysfunction • Characteristic midline facial defects • Intellectual deficits − range from very mild to severe • Cardiac, gastrointestinal, urogenital, and skeletal malformations • Diabetes insipidus • Only 20-30% of infants with alobar HPE survive 1 year • MRI provides confirmation of the diagnosis Genetics Genes – DISP1, FGF8, FOXH1, GLI2, NODAL, PTCH1, SHH, SIX3, TDGF1, TGIF1, and ZIC2 Inheritance • Autosomal dominant – DISP1, FOXH1, GLI2, NODAL, PTCH1, SHH, SIX3, TDGF1, TGIF1, and ZIC2 genes • Autosomal recessive − FGF8 gene Penetrance – depends on the specific gene and mutation; higher penetrance for ZIC2 gene mutations Mutations • 25-50% of HPE caused by structural or numerical chromosomal abnormalities − best detected by chromosomal studies • 25% of HPE occur as part of a recognizable syndrome resulting from single gene mutations • 25% of HPE is nonsyndromic monogenic JUNE 2015 | © 2013 ARUP LABORATORIES | ARUP is a nonprofit enterprise of the University of Utah and its Department of Pathology. 500 Chipeta Way, Salt Lake City, UT 84108 | (800) 522-2787 | (801) 583-2787 | www.aruplab.com | www.arupconsult.com Test Interpretation Limitations • Only the following genes are tested − DISP1, FGF8, FOXH1, GLI2, NODAL, PTCH1, SHH, SIX3, TDGF1, TGIF1, and ZIC2 • Structural and numeric chromosomal abnormalities will not be detected • Diagnostic errors can occur due to rare sequence variations • Deep intronic and regulatory region mutations will not be evaluated • Breakpoints for large deletion/duplications will not be determined Sensitivity/specificity • Clinical sensitivity – unknown • Analytical sensitivity/specificity – 99% Results • Positive o Detection of a pathogenic HPE gene mutation in a symptomatic individual confirms etiology and aids in recurrence risk counseling o Detection of a pathogenic gene mutation in an asymptomatic individual indicates the individual has a 50% risk of passing the mutation on to their offspring • Inconclusive o Variants of unknown clinical significance may be identified Gene Symbol SHH ZIC2 SIX3 TGIF1 GLI2 PTCH1 FGF8 FOXH1 NODAL TDGF1 DISP1 Gene Description NM Number Sonic hedgehog (Drosophila) homologue 000193 Zic family member 2 (odd-paired 007129 Drosophila homologue) Sine oculis homeobox (drosophila 005413 homolog 3) Transforming growth factor beta induced 173208 factor homeobox 1– OMIM Number 600725 603073 Inheritance Disorder Frequency Autosomal dominant Autosomal dominant HPE HPE 30-40% 5% 603714 Autosomal dominant HPE 1% 602630 Autosomal dominant HPE 1% Stalk interruption syndrome GLI - Kruppel family member GLI2 Transcriptional factor mediating hedgehog signalling Patched (Drosophila) homologue Fibroblast growth factor 8 (androgeninduced) Forkhead box H1 Nodal, mouse, homologue of establishment Teratocarcinoma-derived growth factor 1 Dispatched homolog 1 (Drosophila) 005270 165230 Autosomal dominant HPE Unknown 000264 033163 601309 600483 Autosomal dominant Autosomal recessive HPE HPE Rare Rare 003923 018055 603621 601265 Autosomal dominant Autosomal dominant HPE HPE Rare Rare 003212 005270 187395 607502 Autosomal dominant Autosomal dominant HPE HPE Unknown Unknown JUNE 2015 | © 2013 ARUP LABORATORIES