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Helsmoortel-Van der Aa Syndrome via the ADNP Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8123 ADNP 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8123ADNP81479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Greg Fischer, PhD

Clinical Features and Genetics

Clinical Features

Helsmoortel-Van der Aa syndrome (HVDAS) is a syndromic form of Autism Spectrum Disorders (ASD) that is associated with mild to severe intellectual disability (ID). To date all HVDAS patients present with ID and ASD, while a majority present with a thin upper lip (90%), prominent forehead with high hairline (75%) and ear malformations (70%). Hand abnormalities, vision defects, hypotonia, congenital heart defects, broad nasal bridge, smooth/long philtrum, mood disorders and seizures have been reported but vary among individuals (Krajewska-Walasek et al. 2016; Helsmoortel et al. 2014; Pescosolido et al. 2014).

ASD encompasses several neurodevelopmental disorders (such as HVDAS) characterized by varying degrees of social impairment, communication ability, and propensity for restricted interests and repetitive behavior(s) which usually present by age 3. Diagnosis is based on the degree and severity of symptoms and behaviors (Diagnostic and Statistical Manual of Mental Disorders (DSM-5); Levy et al. 2009; McPartland et al. 2016). Comorbidities occur in more than 70% of cases and include ID, epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi 2016).

ADNP (activity-dependent neuroprotective protein) is a transcriptional regulator that interacts with components of BAF (BRG1-associated factors) complexes to mediate chromatin remodeling and gene expression. Specifically, the C-terminal region of the ADNP protein interacts with the BAF complex proteins ARID1A, SMARCA4 and SMARCC2 (Helsmoortel et al. 2014; Mandel & Gozes 2007). Chromatin remodeling complexes like BAFs are essential for activity-dependent dendritic outgrowth and axonal development, a phenomenon that occurs in all neurons (Lessard et al. 2007).

Genetics

Helsmoortel-Van der Aa is an autosomal dominant disorder resulting from almost exclusively de novo truncating variants that cause disease through a dominant-negative or haploinsufficient mechanism (Vandeweyer et al. 2014). The ADNP gene consists of 5-6 exons (depending on the transcript), but only the last 3 are translated. There are 9 zinc finger domains, a NAP domain which encodes a neuroprotectant peptide influencing neurodegeneration, DNA-binding homeobox domain, P*V*L motif that indirectly recognizes histone modifications through HP1α, and a C-terminal region which directly interacts with BAF complex proteins (Helsmoortel et al 2014; Vandeweyer et al. 2014).

To date, all truncating variants result in at least the loss of the last 166 residues from the ADNP C-terminus (Helsmoortel et al. 2014; Vandeweyer et al. 2014). One frameshift variant inherited from an unaffected parent has been reported in the NHLBI Exome Sequencing Project database. However, this variant truncates only the 5 carboxy terminal residues of the ADNP protein and likely does not disrupt the region involved in BAF complex interactions (Vandeweyer et al. 2014).

Genetic aberrations are reported to be responsible for 50-90% and 15-50% of ASD and ID cases, respectively (Larsen et al. 2016; Karam et al. 2015). Incidence of ASD is approximately 1 in 68 individuals with a male-to-female ratio of 4:1 (Center for Disease Control 2014). De novo missense and likely gene disrupting variants are 15% and 75% more frequent in ASD patients than unaffected controls, respectively (Iossifov et al. 2014). To date, 17 individuals with truncating variants in ADNP have been described in autism cohorts totaling ~7,000 individuals (Deciphering Developmental Disorders 2015; Helsmoortel et al. 2014; Krajewska-Walasek et al. 2016).

Clinical Sensitivity - Sequencing with CNV PGxome

Currently, the contribution of de novo and inherited factors to Autism Spectrum Disorders risk is estimated to be approximately 50-60% (Krumm et al. 2015). ADNP is classified in the Simons Foundation Autism Research Initiative (SFARI) Database as a gene with ‘high confidence’ regarding ASD risk (https://gene.sfari.org/GeneDetail/ADNP). However, more than 700 genes total have been associated with ASD features (Bourgeron 2016). ADNP is estimated to be disrupted in 0.17% of all ASD cases, making it one of the most frequently implicated ASD genes to date (Helsmoortel et al. 2014).

Testing Strategy

This test provides full coverage of all coding exons of the ADNP gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Individuals presenting with features similar to Helsmoortel-Van der Aa syndrome that have ASD and mild to moderate intellectual disability are good candidates for this test.

Gene

Official Gene Symbol OMIM ID
ADNP 611386
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Helsmoortel-van der Aa Syndrome AD 615873

Citations

  • Bourgeron T. 2016. Comptes Rendus Biologies. 339: 300-7. PubMed ID: 27289453
  • Center for Disease Control and Prevention. 2014. Morbidity and Mortality Weekly Report. 63: 1-21. PubMed ID: 24670961
  • Deciphering Developmental Disorders Study. 2015. Nature. 519: 223-8. PubMed ID: 25533962
  • Helsmoortel C. et al. 2014. Nature Genetics. 46: 380-4. PubMed ID: 24531329
  • Iossifov I. et al. 2014. Nature. 515: 216-21. PubMed ID: 25363768
  • Karam S.M. et al. 2015. American Journal of Medical Genetics. Part A. 167: 1204-14. PubMed ID: 25728503
  • Krajewska-Walasek M. et al. 2016. American Journal of Medical Genetics. Part A. 170: 1647-50. PubMed ID: 27031564
  • Krumm N. et al. 2015. Nature Genetics. 47: 582-8. PubMed ID: 25961944
  • Larsen E. et al. 2016. Molecular Autism. 7: 44. PubMed ID: 27790361
  • Lessard J. et al. 2007. Neuron. 55: 201-15. PubMed ID: 17640523
  • Levy S.E. et al. 2009. Lancet. 374: 1627-38. PubMed ID: 19819542
  • Mandel S., Gozes I. 2007. The Journal of Biological Chemistry. 282: 34448-56. PubMed ID: 17878164
  • McPartland J.C. et al. 2016. Encyclopedia of Mental Health. 2: 124-130.
  • Pescosolido M.F. et al. 2014. Journal of Medical Genetics. 51: 587-9. PubMed ID: 25057125
  • Sztainberg Y., Zoghbi H.Y. 2016. Nature Neuroscience. 19: 1408-17. PubMed ID: 27786181
  • Vandeweyer G. et al. 2014. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics. 166C: 315-26. PubMed ID: 25169753

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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