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Aicardi-Goutières Syndrome 7 and Singleton-Merton Syndrome 1 via the IFIH1 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
11383 IFIH1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11383IFIH181479 81479(x2) $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

  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Aicardi-Goutières Syndrome 7 is a phenotypically heterogeneous inflammatory disorder linked to inappropriate upregulation of Type I interferon. The symptoms can appear similar to those of neonatal Aicardi-Goutières Syndrome 1, which include irritability, hepatomegaly with elevated liver enzymes, and thrombocytopenia. In one alternate form of the disease, developmental progress is normal until 13-15 months of age, at which point rapid neurological regression occurs. A third type of the condition involves only spastic paraparesis, with adult patients displaying normal neuroimaging (Rice et al. 2014). A heightened state of inflammation affecting blood vessels, teeth and bones is present in Singleton-Merton syndrome 1 (SMS1). This rare autosomal dominant disorder can cause severe childhood aortic and valvular calcification, dental anomalies and skeletal abnormalities such as osteoporosis and osteolysis. Less commonly, affected individuals may have generalized muscle weakness, psoriasis, early onset glaucoma, and particular facial features. (Feigenbaum et al. 2013).

Genetics

An atypical form of Aicardi-Goutieres Syndrome (Aicardi-Goutieres 7) and SMS1 are both caused by autosomal dominant pathogenic variants in IFIH1. This gene encodes a cytoplasmic protein that senses double-stranded viral RNAs and mediates an immune activation. Heterozygous IFIH1 missense variants have been detected in 15 individuals from 13 families with atypical Aicardi-Goutieres syndrome (Crow et al. 2015; Rice at al. 2009; Oda et al. 2014). Most IFIH1 variants are located within the Hel1 and Hel2 helicase domains of the IFIH1 protein. Functional studies indicate that the variants are gain of function variants because they confer an induction of interferon activity that is consistently higher than in mutation-negative family members. Testing of parental samples demonstrated that the pathogenic variants arose de novo in the majority of patients. In one family, a mutation positive father with an affected son was not clinically affected, a finding that indicates that IFIH1 pathogenic variants may not be fully penetrant.

Whole exome sequencing identified a unique IFIH1 missense variant in a patient with SMS1. This variant was also located in the Hel2 helicase domain, displayed an autosomal dominant mode of transmission, and was linked to upregulation of interferon. Sanger sequencing identified the presence of this variant in additional family members of the proband and in two other SMS1 families. In one family, the IFIH1 pathogenic variant appeared to have arisen de novo. In two other SMS1 families, no unaffected member was found to possess the pathogenic variant, and the pathogenic variant segregated with the disorder, though disease symptoms and severity differed among affected family members. (Rutch et al 2015). The clinical variability in Aicardi-Goutières Syndrome 7 and SMS1 families suggests that external factors such as differential pathogen exposure or other genetic or epigenetic influences may modify the penetrance of IFIH1 pathogenic variants. A separate clinical disorder, Singleton-Merton syndrome 2, shares many clinical features with SMS1 but is linked to pathogenic variants in DDX58. The protein product of DDX58 also functions as an double-stranded RNA sensor that up regulates type 1 interferon through the same pathway as IFIH1 (Jang et al. 2015).

The observation of the inflammatory nature of IFIH1 gain of function pathogenic variants suggests that the pathology of the associated disorders is progressive. Early treatment may therefore result in disease attenuation. Antibodies targeted against interferon alpha subtypes and the type I interferon receptor are in clinical trials for a related immune disorder (Crow et al. 2013).

Clinical Sensitivity - Sequencing with CNV PGxome

Approximately 3% of Aicardi-Goutières Syndrome is due to heterozygous missense variants in the IFIH1 gene (Crow et al. 2015). It is difficult to estimate the clinical sensitivity of sequencing for Singleton-Merton Syndrome 1. It is a rare disorder with only three index cases reported in the literature. For these cases, the causative variants were all detectable by sequencing. Due to the heterogeneity of clinical features, the prevalence of IFIH1 pathogenic variants in the population is currently unknown.

Testing Strategy

This test provides full coverage of all coding exons of the IFIH1 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

Patients with clinical features consistent with AGS, chronic leukocytosis, and increased interferon-alpha (INF-a) and neopterin in Cerebrospinal fluid.

Gene

Official Gene Symbol OMIM ID
IFIH1 606951
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Aicardi-Goutieres Syndrome 7 AD 615846
Singleton-Merten Syndrome 1 AD 182250

Citations

  • Crow Y.J. et al. 2014. Clinical and Experimental Immunology. 175: 1-8. PubMed ID: 23607857
  • Crow Y.J. et al. 2015. American Journal of Medical Genetics. Part A. 167A: 296-312. PubMed ID: 25604658
  • Feigenbaum A. et al. 2013. . American Journal of Medical Genetics. Part A. 161A: 360–70. PubMed ID: 23322711
  • Jang M.A. et al. 2015. American Journal of Human Genetics. 96: 266-74. PubMed ID: 25620203
  • Oda H. et al. 2014. American Journal of Human Genetics. 95: 121-5. PubMed ID: 24995871
  • Rice G.I. et al. 2014. Nature Genetics. 46: 503-9. PubMed ID: 24686847
  • Rutsch F. et al. 2015. American Journal of Human Genetics. 96: 275-82. PubMed ID: 25620204

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.
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