Noonan Syndrome via the A2ML1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
10655 A2ML1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
10655A2ML181479 81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View 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

Clinical Features and Genetics

Clinical Features

Noonan Syndrome (NS) is characterized by dysmorphic facial features, growth and congenital heart defects, and musculoskeletal abnormalities. Cardiac abnormalities are found in up to 80% of patients and include pulmonary valve stenosis, atrial septal defect, atrioventricular canal defect, and hypertrophic cardiomyopathy. Musculoskeletal abnormalities include short stature, chest deformity with sunken or raised sternum, and short webbed neck. Several additional abnormalities have been described and include renal, genital, hematological, neurologic, cognitive, behavioral, gastrointestinal, dental, and lymphatic findings. Intelligence is usually normal; however, learning disabilities may be present. NS is characterized by extensive clinical heterogeneity, even among members of the same family. Diagnosis is often made in infancy or early childhood. Symptoms often change and lessen with advancing age. Infants with NS are at risk of developing juvenile myelomonocytic leukemia (JMML). The prevalence of NS is estimated at 1 in 1,000 to 1 in 2,500 births worldwide (Allanson. 1987. PubMed ID: 3543368; Romano et al. 2010. PubMed ID: 20876176; Smpokou et al. 2012. PubMed ID: 23165751; Cao et al. 2017. PubMed ID: 28643916).

Clinical features of Noonan syndrome overlap with those of Cardio-Facio-Cutaneous syndrome (Gripp et al. 2007. PubMed ID: 17551924; Rauen 2016. PubMed ID: 20301365), and Costello syndrome (Gripp and Lin. 2012. PubMed ID: 20301680).

Genetics

Noonan and Noonan-like syndromes are caused by pathogenic variants in PTPN11, SOS1, RAF1, KRAS, SHOC2, BRAF, NRAS, CBL, KAT6B, RIT1, SOS2, LZTR1, MAP3K8, SPRY1, NF1, RRAS, RASA2, and A2ML1 (Human Gene Mutation Database).

Pathogenic variants in the A2ML1 gene have been identified in patients presenting with features within the Noonan-spectrum disorders. Clinical features include broad and high forehead, hypertelorism, low set and posteriorly rotated ears, webbed neck, pulmonary valve stenosis, broad thorax, pectus excavaum, short stature, pigmented naevi, esy bruising, prenatal polydydramnios, intellectual disability and hearing loss (Vissers et al. 2015. PubMed ID: 24939586).

To date, three pathogenic missense variants in the A2ML1 gene have been identified, via whole exome sequencing, in patients with Noonan syndrome (Vissers et al. 2015. PubMed ID: 24939586). Evidence for pathogenicity include: (1) de novo origin of one variant in the sporadic case and co-segregation of two variants with the phenotype in the familial cases; (2) Functional characterization of the missense variants in zebrafish led to abnormalities similar to those seen in Noonan syndrome, including cardiac malformations, a broad head, and blunted face.

The A2ML1 gene encodes the secreted protease inhibitor α-2-macroglobulin-like-1, capable of activating the MAPK cascade (Galliano et al. 2006. PubMed ID: 16298998; Justino et al. 2015. PubMed ID: 24896146). It has been hypothesized that A2ML1 may act upstream of the signaling pathways that have been implicated in Noonan spectrum disorders (Vissers et al. 2015. PubMed ID: 24939586).

Clinical Sensitivity - Sequencing with CNV PG-Select

Pathogenic variants in the A2ML1 gene appear to be a rare cause of Noonan syndrome. They are expected to account for less than 0.5 % of patients clinically diagnosed with a Noonan spectrum disorder (Vissers et al. 2015. PubMed ID: 24939586).

Testing Strategy

This test provides full coverage of all coding exons of the A2ML1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for this test are patients with clinical features within the Noonan spectrum disorders.

Gene

Official Gene Symbol OMIM ID
A2ML1 610627
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID

Citations

  • Allanson. 1987. PubMed ID: 3543368
  • Cao et al. 2017. PubMed ID: 28643916
  • Galliano et al. 2006. PubMed ID: 16298998
  • Gripp and Lin. 2012 PubMed ID: 20301680
  • Gripp et al. 2007. PubMed ID: 17551924
  • Human Gene Mutation Database (Bio-base).
  • Justino et al. 2015. PubMed ID: 24896146
  • Rauen. 2016. PubMed ID: 20301365
  • Romano et al. 2010. PubMed ID: 20876176
  • Smpokou et al. 2012. PubMed ID: 23165751
  • Vissers et al. 2015. PubMed ID: 24939586

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.

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

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ORDER OPTIONS

View Ordering Instructions

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.

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