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H3-3A Related Neurodevelopmental Delay via the H3-3A 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
H3-3A 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
13367H3-3A81479 81479,81479 $990 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 platform).

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

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

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks 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

  • Renee Bend, PhD

Clinical Features and Genetics

Clinical Features

H3-3A (H3F3A) syndrome is an autosomal dominant neurodevelopmental disorder characterized by developmental delay and intellectual disability, manifesting early during postnatal development. It affects both males and females. Affected individuals are typically identified in infancy due to global motor and language delays along with other variable congenital abnormalities. To date, all known pathogenic changes have arisen de novo. Regarding the severity of delays, cognitive deficits are frequently more severe than physical. For example, over half of these patients achieve independent walking; however, a majority of patients remain completely nonverbal throughout life. While neurodevelopmental delays are the only feature seen in all patients, other frequently observed phenotypes include brain malformations identified on magnetic resonance imaging (70%), hypotonia (60%), oculomotor abnormalities (60%, primarily strabismus), seizures (50%), skeletal abnormalities (30%), short stature (30%), gastroesophageal reflux and feeding problems (25%), microcephaly (21%), chronic constipation (30%) and congenital heart defects (20%). Joint laxity, hearing loss, eczema, laryngomalacia, and digit abnormalities are also seen in less than 20% of patients. In addition to the hypotonia that is frequent in early life, a smaller portion of patients are born with or develop contractures or spasticity. Genital abnormalities (particularly cryptorchidism) are common in males (40%), but not observed in affected females. Other than this difference, males and females appear to be equally affected by the disorder in terms of severity, yet a slightly higher proportion of identified patients are male. While undergrowth and microcephaly are observed in over 20% of patients, a small subset of affected individuals present with the opposite phenotype— overgrowth, obesity, and macrocephaly. There is no recognizable facial gestalt; however, common craniofacial abnormalities include a prominent forehead, hypertelorism, and abnormal skull shape (Bryant et al. 2020. PubMed ID: 33268356). 

H3-3A syndrome is a rare disorder. While there is no treatment for this disorder, advantages of testing may include prognostic information, early identification and treatment of symptoms such as seizures and feeding problems, and the ability to join relevant family support groups. Because all known pathogenic variants in this gene are sporadic, a confirmed de novo finding (implicating lower recurrence risk) may ease anxiety for reproductive planning.

Genetics

H3-3A syndrome is an autosomal dominant disorder caused by de novo alterations in the H3-3A gene. All identified pathogenic changes in H3-3A are missense alterations, and the significance of loss of function changes in humans is currently unknown. Indeed, on the whole, the gene is intolerant to missense variation but the intolerance to loss of function changes is less clear (Genome Aggregation Database).

Pathogenic variants are spread widely throughout the H3-3A protein and do not appear to cluster in any specific domains. Several of the pathogenic alterations identified are recurrent. The most commonly observed changes are p.Thr46Ile observed in four unrelated patients, and p.Gln125Arg, observed in three unrelated patients (NM_002107.5). Full penetrance is expected based on the current literature and gnomAD data for this gene. No inherited pathogenic changes have been observed, and none of the known pathogenic alterations are present in the gnomAD database of individuals without severe pediatric diseases.

H3-3A (previously called H3F3A) codes for an H3.3-type histone protein, which consists of three exons, and creates a 136 amino acid protein. Histone proteins help to package DNA neatly into chromatin, which creates chromosomes. The multiple different classes of histones are differentially regulated both by tissue type and developmental time. Other histone proteins that cause similar diseases to H3-3A syndrome in humans include H3-3B (H3-3B syndrome), H1-4 (Rahman Syndrome), and H4C3 (H4C3 syndrome). Of note, the H3-3B gene also codes for a H3.3 class histone. Its mature protein product is identical to H3-3A but has a different expression profile. Still, the neurodevelopmental syndrome caused by these two genes is nearly identical (Bryant et al. 2020. PubMed ID: 33268356). Of these four histone diseases, H3-3A syndrome is the most common.

Double knockout of both H3f3a and H3f3b in mice causes early embryonic lethality, and more minor reductions of expression of individual H3.3’s cause phenotypes of growth retardation, sterility, and increased early mortality. Similarly in Drosophila, complete disruption of both genes causes sterility and increased lethality, but individual knockouts are tolerated. Studies in yeast test the effects of various missense alterations, thus more closely mimicking the relevant human variant type. Finally, studies in zebrafish have also tested the effects of individual missense changes, and phenotypes may more closely mimic those observed in humans (Jang et al. 2015. PubMed ID: 26159997; Bush et al. 2013. PubMed ID: 23570311; Sakai et al. 2009. PubMed ID: 19781938; Lim et al. 2015. PubMed ID: 26369364; Bryant et al. 2020. PubMed ID: 33268356).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in H3-3A are expected to account for <0.1% of cases of early neurodevelopmental delays. In this context, it is important to note the extraordinarily broad genetic heterogeneity for neurodevelopmental delay phenotypes (McRae et al. 2017. PubMed ID: 28135719; Bowling et al. 2017. PubMed ID: 28554332). Testing a large panel of genes as well as using a trio approach (testing parents) is known to have higher diagnostic yield due to the extreme clinical and genetic heterogeneity of these phenotypes (Vissers et al. 2016. PubMed ID: 26503795).

Single nucleotide variants (SNVs) are the only variant type known to cause H3-3A syndrome (Bryant et al. 2020. PubMed ID: 33268356; Human Gene Mutation Database), therefore this test’s analytical sensitivity for H3-3A pathogenic changes is expected to be very high. In summary, this test is expected to detect all currently identified variant types in H3-3A.

Testing Strategy

This test is performed using Next-Generation sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the H3-3A 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. 

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

This test is appropriate for patients with neurodevelopmental delays, seizures, and other minor congenital abnormalities, who are negative for chromosomal abnormalities, copy number variations, and Fragile-X syndrome. Yet this gene is more commonly tested as part of a larger panel, exome, or genome test. Targeted testing is indicated for family members of patients who have a known pathogenic variant in H3-3A.

Gene

Official Gene Symbol OMIM ID
H3-3A 601128
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID

Citations

  • Bowling et al. 2017. PubMed ID: 28554332
  • Bryant et al. 2020. PubMed ID: 33268356
  • Bush et al. 2013. PubMed ID: 23570311
  • Genome Aggregation Database (gnomAD).
  • Human Gene Mutation Database (Biobase).
  • Jang et al. 2015. PubMed ID: 26159997
  • Lim et al. 2015. PubMed ID: 26369364
  • McRae et al. 2017. PubMed ID: 28135719
  • Sakai et al. 2009. PubMed ID: 19781938
  • Vissers et al. 2016. PubMed ID: 26503795

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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

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2) Select Additional Test Options

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