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Hydrocephalus Sequencing Panel with CNV Detection

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Exome with CNV

Test Code Test Copy GenesCPT Code Copy CPT Codes
7939 AKT3 81479,81479 Add to Order
AP1S2 81479,81479
CCDC88C 81479,81479
CCND2 81479,81479
CRB2 81479,81479
DNAI1 81479,81479
EML1 81479,81479
FLVCR2 81479,81479
HDAC6 81479,81479
L1CAM 81407,81479
MPDZ 81479,81479
P4HB 81479,81479
PIK3R2 81479,81479
POMT1 81406,81479
PTEN 81321,81323
WDR81 81479,81479
ZIC3 81479,81479
Full Panel Price* $890.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
7939 Genes x (17) $890.00 81321, 81323, 81406, 81407, 81479(x30) Add to Order
Pricing Comments

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.

Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 26 days.

Clinical Sensitivity

This panel focuses on isolated hydrocephalus. The sensitivity is variable depending on different disorders. For example, the most common heritable form is caused by pathgenic variants in L1CAM and accounts for up to 10% of males with X-linked isolated idiopathic hydrocephalus. In this panel, the most common causative genes are L1CAM, AP1S2, MPDZ and CCDC88C (Al-Jezawi et al. 2018. PubMed ID: 29499638).

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Clinical Features

Hydrocephalus is a complex condition influenced by both genetic and environmental factors. The genetic form of hydrocephalus can be caused by a group of heterogeneous disorders affecting the ventricular system of the brain with excessive accumulation of cerebrospinal fluid (CSF). It can present either in an isolated form (congenital or pure hydrocephalus) or in conjunction with other genetic anomalies. The symptoms of hydrocephalus vary with age, cause, and disease progression. In infancy, the major features of hydrocephalus are characterized by a rapid increase in head circumference or an unusually large head size, vomiting, sleepiness, irritability, downward deviation of the eyes and seizures. In older children, clinical features may include headache, vomiting, nausea, blurred vision, downward deviation of the eyes, gait disturbance, developmental delay, intellectual disability, etc. Cranial imaging techniques such as ultrasonography, CT, MRI, or pressure-monitoring techniques are useful in the diagnosis of patients with hydrocephalus (Shaheen et al. 2017. PubMed ID: 28556411; Al-Jezawi et al. 2018. PubMed ID: 29499638; Saugier-Veber et al. 2017. PubMed ID: 28460636; Ekici et al. 2010. PubMed ID: 21031079).

Genetics

The genetic etiology of the Hydrocephalus is extremely heterogeneous, ranging from monogenic causes with little or no influence from modifiers or environmental factors to genetically complex forms. In this panel, we mainly focus on familial, congenital hydrocephalus causative genes, as well as genes for other genetic disorders with presence of hydrocephalus. The selected genes involve in different cellular processes, such as neural cell adhesion (L1CAM), planar cell polarity (MPDZ), the Wingless/integrated WNT signaling pathway (CCDC88C), or vesicle transport within the cell (AP1S2), etc. (Shaheen et al. 2017. PubMed ID: 28556411; Al-Jezawi et al. 2018. PubMed ID: 29499638; Saugier-Veber et al. 2017. PubMed ID: 28460636; Ekici et al. 2010. PubMed ID: 21031079; Cacciagli et al. 2014. PubMed ID: 23756445). Hydrocephalus can be inherited in an autosomal dominant, autosomal recessive and X-linked manner or through complex inheritance.

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. 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

The Hydrocephalus panel is recommended for patients suspected to have isolated, congenital or pure hydrocephalus.

Genes

Official Gene Symbol OMIM ID
AKT3 611223
AP1S2 300629
CCDC88C 611204
CCND2 123833
CRB2 609720
DNAI1 604366
EML1 602033
FLVCR2 610865
HDAC6 300272
L1CAM 308840
MPDZ 603785
P4HB 176790
PIK3R2 603157
POMT1 607423
PTEN 601728
WDR81 614218
ZIC3 300265
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Band Heterotopia AR 600348
Chondrodysplasia with Platyspondyly, Distinctive Brachydactyly, Hydrocephaly, and Microphthalmia XL 300863
Ciliary Dyskinesia, Primary, 1 AR 244400
Cole-Carpenter Syndrome 1 AD 112240
Hydrocephalus, Nonsyndromic, 1 AR 236600
Hydrocephalus, Nonsyndromic, 3 AR 617967
Hydrocephalus, Nonsyndromic, Autosomal Recessive 2 AR 615219
Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 1 AD 603387
Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 2 AD 615937
Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 3 AD 615938
Pettigrew Syndrome XL 304340
Proliferative Vasculopathy And Hydranencephaly-Hydrocephaly Syndrome AR 225790
Vacterl Association With Hydrocephalus AR 276950
VACTERL Association With Hydrocephaly, X-Linked XL 314390
Ventriculomegaly with Cystic Kidney Disease AR 219730
Walker-Warburg Congenital Muscular Dystrophy AR 236670
X-Linked Hydrocephalus Syndrome XL 307000

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CONTACTS

Genetic Counselors
Geneticist
Citations
  • Al-Jezawi et al. 2018. PubMed ID: 29499638
  • Cacciagli et al. 2014. PubMed ID: 23756445
  • Ekici et al. 2010. PubMed ID: 21031079
  • Saugier-Veber et al. 2017. PubMed ID: 28460636
  • Shaheen et al. 2017. PubMed ID: 28556411
Order Kits
TEST METHODS

Exome Sequencing with CNV Detection

Test Procedure

For the PGxome we use Next Generation Sequencing (NGS) technologies to cover the coding regions of targeted genes plus ~10 bases of non-coding DNA flanking each exon. As required, genomic DNA is extracted from patient specimens. Patient DNA corresponding to these regions is captured using Agilent Clinical Research Exome hybridization probes. Captured DNA is sequenced on the NovaSeq 6000 using 2x150 bp paired-end reads (Illumina, San Diego, CA, USA). The following quality control metrics are generally achieved: >97% of target bases are covered at >20x, and mean coverage of target bases >120x. Data analysis and interpretation is performed by the internally developed software Titanium-Exome. In brief, the output data from the NovaSeq 6000 is converted to fastqs by Illumina Bcl2Fastq, and mapped by BWA. Variant calls are made by the GATK Haplotype caller and annotated using in house software and SnpEff. Variants are filtered and annotated using VarSeq (www.goldenhelix.com).

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

Analytical Validity

NextGen Sequencing: As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.

Copy Number Variant Analysis: The PGxome test detects most larger deletions and duplications including intragenic CNVs and large cytogenetic events; however aberrations in a small percentage of regions may not be accurately detected due to sequence paralogy (e.g., pseudogenes, segmental duplications), sequence properties, deletion/duplication size (e.g., 1-3 exons vs. 4 or more exons), and inadequate coverage. In general, sensitivity for single, double, or triple exon CNVs is ~70% and for CNVs of four exon size or larger is >95%, but may vary from gene-to-gene based on exon size, depth of coverage, and characteristics of the region.

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available. Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When sequencing does not reveal any heterozygous differences from the reference sequence, we cannot be certain that we were able to detect both patient alleles.

For technical reasons, the PGxome test is not 100% sensitive. Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies in the genome. Therefore, a small fraction of sequence variants will not be detected.

We sequence coding exons for most given transcripts, plus ~10 bp of flanking non-coding DNA for each exon. Unless specifically indicated, test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions, uncharacterized alternative exons, chromosomal rearrangements, repeat expansions, epigenetic effects, and mitochondrial genome variants.

In most cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient's nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during amplification.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes if taken from whole blood). Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Balanced translocations or inversions are only rarely detected.

Certain types of sex chromosome aneuploidy may not be detected.  

Our ability to detect CNVs due to somatic mosaicism is limited.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics. However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

A negative finding does not rule out a genetic diagnosis.

Genetic counseling to help to explain test results to the patients and to discuss reproductive options is recommended.

Order Kits

Ordering Options


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.
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.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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