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Autosomal Dominant Lower Extremity-Predominant Spinal Muscular Atrophy Type 2 via the BICD2 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
12633 BICD2 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
12633BICD281479 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

  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Spinal Muscular Atrophies (SMAs) are a diverse group of genetic disorders characterized by neurodegeneration and muscle weakness. SMAs are clinically and genetically heterogeneous disorders that are categorized into different forms based on onset, severity of symptoms, and inheritance pattern (Neveling et al. 2013. PubMed ID: 23664116). The most common form of SMA is due to homozygous deletions or pathogenic variants of the survival of motor neuron 1 (SMN1) gene localized to 5q13.2. This type of SMA accounts for up to 95% of cases of SMA (Oates et al. 2013. PubMed ID: 23664120; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). The functional loss of SMN1 leads to this autosomal recessive form of SMA that is divided into different types based on the age of onset and severity of the symptoms. Other forms of SMA have been identified that are not linked to the SMN1 gene and include autosomal dominant lower extremity-predominant spinal muscular atrophy 1, caused by pathogenic variants in the DYNC1H1 gene, and autosomal dominant lower-extremity predominant spinal muscular atrophy 2A, Childhood Onset and 2B, Prenatal Onset, caused by pathogenic variants in the BICD2 gene.

Autosomal dominant lower extremity-predominant spinal muscular atrophy 2 (SMALED2) is a rare condition with unknown prevalence. It is caused by heterozygous pathogenic variants in the BICD cargo adaptor 2 (BICD2) gene. Overall, patients with SMALED2 experience nonprogressive muscle weakness and atrophy of the proximal lower limbs (Neveling et al. 2013. PubMed ID: 23664116; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). About 5-29% of patients with BICD2 pathogenic variants experience fasciculations, hip contractures, hip dysplasia, hyperlordosis, hyperreflexia, knee flexion contracture, scapular winging, and spasticity. Additional symptoms may include Achilles tendon contracture, areflexia, axial muscle weakness, difficulty running, gowers sign, hyporeflexia, motor delay, spinal muscular atrophy, talipes equinovarus, toe walking, and waddling gait (Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138; Rudnik-Schoneborn et al. 2016. PubMed ID: 26998597). Molecular genetic testing is advantageous to establish a diagnosis for individuals with muscular weakness lacking deletions or pathogenic variants in SMN1. Current treatment is supportive care.

There are two forms of SMALED2, both caused by variants in BICD2, which differ only in the age of onset and the severity of the symptoms. SMALED2 type A is characterized by early childhood onset of muscle weakness and atrophy, however adult onset has also been reported (Neveling et al. 2013. PubMed ID: 23664116; Oates et al. 2013. PubMed ID: 23664120; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). There is very limited to no disease progression observed in this disorder (Neveling et al. 2013. PubMed ID: 23664116). SMALED2 type B is a severe neuromuscular disorder with onset in utero and death occurring in early childhood. Symptoms at birth may include congenital contractures, severe hypotonia, muscle atrophy, and respiratory insufficiency due to muscle weakness (Storbeck et al. 2017. PubMed ID: 28635954).

Genetics

SMALED2 is an autosomal dominant disorder that results from heterozygous pathogenic variants in BICD2. To date, about fifteen missense variants have been reported in patients with SMALED2 (Neveling et al. 2013. PubMed ID: 23664116; Peeters et al. 2013. PubMed ID: 23664119; Oates et al. 2013. PubMed ID: 23664120; Synofzik et al. 2013. PubMed ID: 24336790; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138; Rossor et al. 2015. PubMed ID: 25497877; Rudnik-Schoneborn et al. 2016. PubMed ID: 26998597; Fiorillo et al. 2016. PubMed ID: 27000979). These variants have not been reported in population databases or have been reported at very low frequencies.

BICD2 (9q22.31) encodes the Bicaudal D Homolog 2 protein. This protein is considered to be a golgin and is a resident protein of the Golgi apparatus where it works to help maintain the structure of the Golgi and is involved in regulation of vesicle transport via interaction with the dynein complex (Neveling et al. 2013. PubMed ID: 23664116; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). All of the reported BICD2 missense variants in SMALED2 patients have been determined to exert a gain of function effect (Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138). Increased activity of the BICD2 protein leads to aberrant function as the protein is unable to properly bind with the dynein complex and regulate vesicle transport. In addition, the altered protein is unable to properly maintain the structure of the Golgi apparatus, leading to its destruction. The exact mechanism of the cause of disease remains to be elucidated as variants have been found throughout the gene and lack a strong correlation with disease onset or severity (Storbeck et al. 2017. PubMed ID: 28635954).

The BICD2 gene is highly conserved and is homologous to the Drosophila Bicaudal D (BicD) gene and to the murine Bicaudal D 2 (Bicd2) gene. Flies with mutant BicD showed reduced larvae locomotion, and the complete absence of BicD resulted in lethality during early development (Ran et al. 1994. PubMed ID: 8026332; Li et al. 2010. PubMed ID: 20111007; Neveling et al. 2013. PubMed ID: 23664116; Jaarsma et al. 2014. PubMed ID: 24614806; Martinez-Carerra et al. 2018. PubMed ID: 29528393). Mouse models with heterozygous loss of Bicd2 did not have pathological effects; however the complete absence resulted in lethality early in post-natal life (Ran et al. 1994. PubMed ID: 8026332; Jaarsma et al. 2014. PubMed ID: 24614806; Martinez-Carerra et al. 2018. PubMed ID: 29528393). No motor neuron abnormalities were observed in mice such as seen in patients with SMALED2, suggesting that missense pathogenic variants with a gain of function effect lead to disease in humans (Jaarsma et al. 2014. PubMed ID: 24614806). In vitro studies of BICD2 variants in HeLa cells and primary fibroblasts from SMALED2 patients showed increased fragmentation of the Golgi apparatus as a result of aberrant BICD2 protein function (Neveling et al. 2013. PubMed ID: 23664116; Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138).

Clinical Sensitivity - Sequencing with CNV PGxome

The great majority of cases of SMA (~95%) are due homozygous deletions/variants of SMN1 localized to 5q13.2 (aka 5q SMA). The remaining ~5% of cases of SMA are non-5q SMA and are very rare. These disorders are clinically and genetically heterogeneous and are usually classified based on their inheritance pattern (AD, AR, or X-linked). Of the non-5q SMA disorders, a small percentage is inherited in an autosomal dominant manner. Of these autosomal dominantly inherited SMAs, SMALED1 and SMALED2, only ~30% have detectable pathogenic variants (Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138).

Testing Strategy

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

This test provides full coverage of all coding exons of the BICD2 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 coverage as ≥20X NGS reads or Sanger reads.

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

Candidates for this test are patients showing features consistent with SMALED2, such as early childhood onset of muscle weakness and non progressive atrophy predominantly affecting the proximal and distal muscles of the lower extremities. Candidates should also be negative for homozygous deletions/variants in SMN1. We will also sequence any single exon (Test #100) in family members of patients with a known pathogenic variant or to confirm research results.

Gene

Official Gene Symbol OMIM ID
BICD2 609797
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Fiorillo et al. 2016. PubMed ID: 27000979
  • Jaarsma et al. 2014. PubMed ID: 24614806
  • Li et al. 2010. PubMed ID: 20111007
  • Martinez-Carerra and Wirth. 2015. PubMed ID: 26594138
  • Martinez-Carerra et al. 2018. PubMed ID: 29528393
  • Neveling et al. 2013. PubMed ID: 23664116
  • Oates et al. 2013. PubMed ID: 23664120
  • Peeters et al. 2013. PubMed ID: 23664119
  • Ran et al. 1994. PubMed ID: 8026332
  • Rossor et al. 2015. PubMed ID: 25497877
  • Rudnik-Schoneborn et al. 2016. PubMed ID: 26998597
  • Storbeck et al. 2017. PubMed ID: 28635954
  • Synofzik et al. 2013. PubMed ID: 24336790

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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