Otopalatodigital Spectrum Disorders, Periventricular Nodular Heterotopia and Cardiac Valvular Dystrophy via the FLNA 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
4641 FLNA 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4641FLNA81479 81479(x2) $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 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

Geneticists

  • Angela Gruber, PhD
  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Mutations in FLNA cause X-linked myxomatous cardiac valvular dystrophy, periventricular nodular heterotopia and otopalatodigital spectrum disorders. Otopalatodigital spectrum disorders are primarily characterized by skeletal dysplasia and include otopalatodigital syndrome type I (OPD1) and type II (OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and terminal osseous dysplasia with pigmentary skin defects (TOPD). OPD1 usually manifests at birth with females presenting with similar severity as related affected males. Symptoms include skeletal dysplasia, deafness, cleft palate, characteristic facial features, and oligohypodontia. In OPD2, males are severely affected and typically die within the first year of birth from pulmonary insufficiency while females typically have a subclinical phenotype. OPD2 features include skeletal dysplasia, cardiac septal defects, CNS abnormalities, and developmental delay. Males with MNS have a phenotype that is indistinguishable from OPD2. In FMD, females are less severely affected than related affected males. Females present with characteristic facial features found in FMD males. FMD males have skeletal dysplasia, oligohypodontia, deafness, and underdeveloped muscles around the shoulder girdle. Males with TOPD have not been described. Females have shortening and ossification of the carpals and metacarpals and characteristic facial findings. Periventricular nodular heterotopia is characterized by the presence of nodules on the surface of the lateral ventricles due to a failure in neuronal migration into the cerebral cortex. Affected females present with seizures in their teenage years. Females may also present with cardiovascular defects, such as patent ductus arteriosus, bicuspid aortic valve and dilation of the aorta. Males with periventricular nodular heterotopia show early lethality (Fox et al. Neuron 21(6):1315-1325, 1998). Myxomatous cardiac valvular dystrophy is characterized by mitral valve and/or aortic valve regurgitation. Only males are affected and carrier females are asymptomatic (Kyndt et al. Circulation 115(1):40-49, 2007). For more information, visit GeneReviews (Robertson. Otopalatodigital Spectrum Disorders, 2013).

Genetics

FLNA-related disorders are inherited in an X-linked manner. FLNA encodes for filamin A, which cross-links the actin cytoskeleton. Loss of function mutations in FLNA lead to defects in vascular function, connective tissues and neuronal migration. Missense mutations in FLNA cause a spectrum of mutations in multiple organ systems, especially the skeleton. Otopalatodigital spectrum disorders and periventricular nodular heterotopia are inherited in an X-linked dominant manner. Females with an FLNA causative mutation have a range of phenotypic expression. Cardiac valvular dysplasia is inherited in an x-linked recessive manner (Kyndt et al., 2007). The majority of mutations in MNS females are localized to exon 22 (Robertson et al. Nat Genet 33(4):487-491, 2003; Santos et al. Am J Med Genet A 152A:726-731, 2010). Mutations in OPD1 and OPD2 cluster in exons 3-5, but pathogenic mutations in other exons have been found (Robertson, 2013).

Clinical Sensitivity - Sequencing with CNV PG-Select

Robertson et al. (2003) found mutations in FLNA in 26 out of 41 patients with FLNA-related disorders (OPD1, OPD2, FMD, MNS) (Robertson et al. Nat Genet 33:487-491, 2003).

Gross deletions of the FLNA gene have been identified in patients with otopalatodigital spectrum disorders. One family with cardiac valvular dystrophy has been found to have a 1944bp deletion in FLNA (Kyndt et al. Circulation 115(1):40-49, 2007). One report found 3 out of 35 patients with periventricular heterotopia to have gross deletions in FLNA (Clapham et al. Neurology 78:269-278, 2012).

Testing Strategy

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

Indications for Test

Patients with clinical features consistent with otopalatodigital syndrome type I and type II, frontometaphyseal dysplasia, Melnick-Needles syndrome, terminal osseous dysplasia with pigmentary skin defect, periventricular nodular heterotopia and cardiac valvular dystrophy.

Gene

Official Gene Symbol OMIM ID
FLNA 300017
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

Name
Bleeding Disorders Panel
Opitz G/BBB Syndrome Panel

Citations

  • Clapham et al. (2012). "FLNA genomic rearrangements cause periventricular nodular heterotopia." Neurology 24:269-278. PubMed ID: 22238415
  • Fox et al. (1998).  "Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia." Neuron 21(6): 1315-1325. PubMed ID: 9883725
  • Kyndt et al. (2007). "Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy." Circulation 115(1): 40-49. PubMed ID: 17190868
  • Robertson et al. (2003). "Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans." Nat Genet 33(4):487-491. PubMed ID: 12612583
  • Robertson, S. (2013). "Otopalatodigital Spectrum Disorders." GeneReviews. PubMed ID: 20301567
  • Santos et al. (2010). "Mutational analysis of two boys with the severe perinatally lethal Melnick-Needles syndrome." Am J Med Genet A 152A:726-731. PubMed ID: 20186808

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

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


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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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