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Autism Spectrum Disorders/Intellectual Disability via the NAA15 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
12091 NAA15 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
12091NAA1581479 81479,81479 $890 Order Options and Pricing

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).

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

Autism spectrum disorder (ASD) and intellectual disability (ID) are heterogeneous groups of neurodevelopmental disorders. ASD is characterized by varying degrees of social impairment, limited communication ability, propensity for repetitive behavior(s), and restricted interests (Levy et al. 2009. PubMed ID: 19819542). ID refers to significant impairment of cognitive and adaptive development (intelligence quotient, IQ<70) due to abnormalities of brain structure and/or function (American Association of Intellectual and Developmental Disabilities). ID is not a single entity, but rather a general symptom of neurologic dysfunction that is diagnosed before age 18 in 1%-3% of the population, irrespective of social class and culture (Kaufman et al. 2010. PubMed ID: 21124998; Vissers et al. 2016. PubMed ID: 26503795). In contrast, ASD symptoms usually present by age 3, and diagnosis is based on the degree and severity of symptoms and behaviors (McPartland et al. 2016). ASD and ID are highly comorbid, suggesting shared etiologies in many forms. For ASD specifically, comorbidities have been observed in more than 70% of cases, and include ID, epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi. 2016. PubMed ID: 27786181). Recent studies using whole exome trio studies have identified novel gene candidates, with familial and de novo variants from several hundred genes now implicated in the development of ASD and ID (Bourgeron. 2016. PubMed ID: 27289453).

Pathogenic variants in NAA15 have been implicated in the development of ASD and ID phenotypes. Individuals with pathogenic variants present with developmental delay, ID, ASD, impaired motor abilities, impaired or absent speech, and behavioral abnormalities. Other features reported in a minority of individuals include fine motor delay, mild ataxia, hypotonia, variable dysmorphic facial features, reduced birthweight and length, and cardiac anomalies.

Genetics

Genetic aberrations are reported to be responsible for 50%-90% and 15%-50% of ASD and ID cases, respectively, and inheritance overall is multifactorial (Larsen et al. 2016. PubMed ID: 27790361; Karam et al. 2015. PubMed ID: 25728503). Incidence of ASD is approximately 1 in 68 individuals with a male-to-female ratio of 4:1 (Centers for Disease Control and Prevention. 2014. PubMed ID: 24670961). De novo missense and loss of function variants are 15% and 75% more frequent in ASD patients than unaffected controls, respectively (Iossifov et al. 2014. PubMed ID: 25363768).

NAA15 pathogenic variants result in ASD and ID phenotypes in an autosomal dominant manner as all reported individuals are either heterozygous for de novo or familial likely loss of function variants. De novo causative variants are much more common than familial. Familial variants, however, have been reported to segregate with cognitive phenotypes. Large deletions ranging in size from 2.7 Mb to 24.3 Mb encompassing multiple genes including NAA15 have been reported in individuals with intellectual disability, dysmorphic features, motor delay, cardiac anomalies, and global developmental delay phenotypes. In some reports, The large deletions arose de novo. However, the phenotype-genotype correlation resulting from NAA15 disruption specifically is unclear (Cheng et al. 2018. PubMed ID: 29656860).

The human NAA15 (N-alpha-acetyltransferase 15) gene contains 20 exons encoding an 866 amino acid protein. The NAA15 protein contains a tetratricopeptide repeat domain and a putative bipartite nuclear localization signal. Likely loss of function variants (nonsense, frameshift and splicing) have been identified throughout the NAA15 gene. Lymphoblastoid cell lines derived from several patients support that the NAA15 variant transcript is degraded via nonsense mediated decay. As such, haploinsufficiency has been proposed as the mechanism of disease (Cheng et al. 2018. PubMed ID: 29656860). De novo missense variants have also been reported in at least two individuals with ASD and ID (Cheng et al. 2018. PubMed ID: 29656860).

The NAA15 protein in association with NAA10 forms an N-terminal acetyltransferase (known as the NatA complex). Disruption of the NatA complex in cell lines results in defects in cell cycle progression, cell growth, and apoptosis. Other genetic defects impacting the NatA complex have been associated with Ogden syndrome, Lenz microphthalmia, and intellectual disability with variable cardiac features. NAA15 is expressed in most adult tissue, however it is specifically upregulated within the occipital neocortex and anterior cingulate cortex at week 8 during human development. Downregulation appears to coincide with neuronal differentiation during postnatal development (Cheng et al. 2018. PubMed ID: 29656860).

Clinical Sensitivity - Sequencing with CNV PGxome

Genetic variants have been found responsible in 25-50% of Intellectual Disability (ID) cases, and this percentage increases proportionally with the severity of the phenotype (McLaren and Bryson. 1987. PubMed ID: 3322329). For autism spectrum disorders (ASD), while heritability estimates have been reported as high as 90% (Bailey et al. 1995. PubMed ID: 7792363; Lichtenstein et al. 2010. PubMed ID: 20686188), only 20% of cases can be explained to date using genetic approaches (Devlin and Scherer. 2012. PubMed ID: 22463983).

While NAA15 is categorized as a gene with ‘syndromic, high confidence’ regarding its association with Autism spectrum disorder (ASD) in the Simons Foundation Autism Research Initiative (SFARI) Database (https://gene.sfari.org/database/human-gene/NAA15), no single gene has been reported to account for more than 1% of all ASD cases to date (Hoang et al. 2018. PubMed ID: 28803755). Furthermore, large cohort studies of individuals with neurodevelopmental phenotypes have implicated hundreds of genes (Larsen et al. 2016. PubMed ID: 27790361; Bourgeron. 2016. PubMed ID: 27289453). Therefore, the clinical sensitivity of any single gene test with regard to a neurodevelopmental phenotype is expected to be low (≤1%).

Testing Strategy

This test provides full coverage of all coding exons of the NAA15 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

While the majority of reported pathogenic variants in NAA15 have been reported to occur de novo, familial variants have been reported to segregate with cognitive phenotypes. Individuals with family members having known pathogenic NAA15 variants and/or presenting with impaired motor abilities, intellectual disability, autism spectrum disorder, and delayed or absent speech are candidates for this test.

Gene

Official Gene Symbol OMIM ID
NAA15 608000
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mental Retardation, Autosomal Dominant 50 AD 617787

Citations

  • Bailey et al. 1995. PubMed ID: 7792363
  • Bourgeron. 2016. PubMed ID: 27289453
  • Centers for Disease Control and Prevention. 2014. PubMed ID: 24670961
  • Cheng et al. 2018. PubMed ID: 29656860
  • Devlin and Scherer. 2012. PubMed ID: 22463983
  • Hoang et al. 2017. PubMed ID: 28803755
  • Iossifov et al. 2014. PubMed ID: 25363768
  • Karam et al. 2015. PubMed ID: 25728503
  • Kaufman et al. 2010. PubMed ID: 21124998
  • Larsen et al. 2016. PubMed ID: 27790361
  • Levy et al. 2009. PubMed ID: 19819542
  • Lichtenstein et al. 2010. PubMed ID: 20686188
  • McLaren and Bryson. 1987. PubMed ID: 3322329
  • McPartland et al. 2016. Encyclopedia of Mental Health. 2: 124-130.
  • Sztainberg and Zoghbi. 2016. PubMed ID: 27786181
  • 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


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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