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Intellectual Disability/Autism Spectrum Disorders via the CHAMP1 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
12093 CHAMP1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
12093CHAMP181479 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

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 CHAMP1 have been implicated as a monogenic cause of intellectual disability and global developmental delay. Individuals with loss of function variants present with developmental delay, ID, impaired motor abilities, short stature, severe speech impairment, muscular (truncal) hypotonia and orofacial hypotonia, hypertelorism, microcephaly, stereotypy, decreased pain sensation, neonatal feeding difficulties, hyperopia, and various subtle dysmorphic features (short philtrum, tented and everted lips, long face, pointed chin, low-set ears, up or down-slanting palpebral fissures). Other features reported in a minority of individuals include autism spectrum disorder, epilepsy/seizure, apneic episodes, choanal atresia, intestinal malrotation, bicuspid aortic valve, ventricular septal defects, a decrease in brain volume and white matter, and hearing loss. De novo loss of function variants have exclusively been reported in affected individuals (Tanaka et al. 2016. PubMed ID: 27148580; Hempel et al. 2015. PubMed ID: 26340335).

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 (Center for Disease Control 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).

CHAMP1 pathogenic variants result in intellectual disability and global developmental delay symptoms in an autosomal dominant manner as all reported individuals are heterozygous for de novo loss of function variants. Copy number variants ranging in size from 966 kb to 12.77 Mb have been reported to encompass CHAMP1 with comparable clinical features. However, these copy number variants encompass multiple genes, and thus the specific role of CHAMP1 is unclear (Hempel et al. 2015. PubMed ID: 26340335).

The human CHAMP1 (chromosome alignment maintaining phosphoprotein 1) gene contains two 5’ untranslated exons and a third encoding an 812 amino acid protein. Specifically, the CHAMP1 protein consists of five C2H2 zinc finger domains (2 N-terminal and 3 C-terminal) flanking several SPE, WK, and FPE motifs. To date, de novo loss of function variants have been reported between the flanking N-terminal and C-terminal zinc finger domains (Tanaka et al. 2016. PubMed ID: 27148580). CHAMP1 expression has been observed in both fetal and adult tissue, with expression specifically reported during fetal brain development (Hawrylycz et al. 2012. PubMed ID: 22996553; Nagase et al. 2001. PubMed ID: 11347906; Tanaka et al. 2016. PubMed ID: 27148580).

CHAMP1 is important for proper chromosome alignment during metaphase. Specifically, the CHAMP1 FPE domains are necessary for the attachment of microtubules to the kinetochore complex, while the C-terminal zinc finger domains are important for protein localization to chromosomes and the mitotic spindle. CHAMP1 is also a component of the mitotic spindle assembly checkpoint complex, which monitors alignment of chromosomes at the metaphase plate and regulates the mitotic transition to anaphase (Itoh et al. 2011. PubMed ID: 21063390; Hempel et al. 2015. PubMed ID: 26340335; Tanaka et al. 2016. PubMed ID: 27148580). Defects in chromosome segregation resulting in variegated aneuploidies have been previously implicated in both syndromic and non-syndromic intellectual disability, microcephaly, and growth delay. Since all reported loss of function variants are predicted to disrupt the C-terminal zinc finger domains, disruption has been proposed as the mechanism behind dysmorphism and altered brain development observed in affected individuals (assuming a stable protein product is produced) (Hempel et al. 2015. PubMed ID: 26340335; Tanaka et al. 2016. PubMed ID: 27148580).

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).

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 the single coding exon of the CHAMP1 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

To date, all loss of function variants described in CHAMP1 have arose de novo. However, individuals with family members having known pathogenic CHAMP1 variants and/or presenting with impaired motor abilities, intellectual disability, global developmental delay, dysmorphic features, and severe speech impairment are candidates for this test.

Gene

Official Gene Symbol OMIM ID
CHAMP1 616327
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mental retardation, autosomal dominant 40 AD 616579

Citations

  • Bailey et al. 1995. PubMed ID: 7792363
  • Bourgeron. 2016. PubMed ID: 27289453
  • Centers for Disease Control and Prevention. 2014. PubMed ID: 24670961
  • Devlin and Scherer. 2012. PubMed ID: 22463983
  • Hawrylycz et al. 2012. PubMed ID: 22996553
  • Hempel et al. 2015. PubMed ID: 26340335
  • Hoang et al. 2017. PubMed ID: 28803755
  • Iossifov et al. 2014. PubMed ID: 25363768
  • Itoh et al. 2011. PubMed ID: 21063390
  • 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.
  • Nagase et al. 2001. PubMed ID: 11347906
  • Sztainberg and Zoghbi. 2016. PubMed ID: 27786181
  • Tanaka et al. 2016. PubMed ID: 27148580
  • 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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