Dias-Logan Syndrome via the BCL11A 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
15233 BCL11A 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
15233BCL11A81479 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

Geneticist

  • Greg Fischer, PhD

Clinical Features and Genetics

Clinical Features

Dias-Logan syndrome is a syndromic form of intellectual disability (ID) that results in 30% of Dias-Logan syndrome patients also having features of Autism Spectrum Disorder. A hallmark feature of the condition is persistence of fetal hemoglobin, which has been observed in all individuals to date. Individuals also present with global delay in developmental milestones, particularly speech and language, mild to severe intellectual disability, repetitive behavior, sensory anomalies, and physical features such as joint laxity (87%), strabismus (100%), microcephaly (55%), and external ear abnormalities (62%) which tend to be more severe in those with truncating variants (Dias et al. 2016).

ASD encompasses several neurodevelopmental disorders (such as Dias-Logan syndrome) characterized by varying degrees of social impairment, communication ability, and propensity for restricted interests and repetitive behavior(s) which usually present by age 3. Diagnosis is based on the degree and severity of symptoms and behaviors (Diagnostic and Statistical Manual of Mental Disorders (DSM-5); Levy et al. 2009; McPartland et al. 2016). Comorbidities occur in more than 70% of cases and include ID, epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi 2016). ID specifically 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, AAIDD). 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 (Kaufman et al. 2010; Vissers et al. 2016).

Genetics

Dias-Logan syndrome is an autosomal dominant condition resulting from de novo variants in BCL11A. The BCL11A gene is composed of 5 protein-coding exons that are alternatively splice to form three different transcripts, all of which have been identified in fetal brain tissue: BCL11A-XL (5.8 kb, NM_022893.3), BCL11A-L (3.8 kb, NM_018014.3), and BCL11A-S (1.5 kb, NM_138559.1). All three isoforms contain exons 1-3, while the longest isoform includes exon 4 (BCL11A-XL). Alternative splicing within exon 4 to a fifth exon yields the other two shorter transcripts (BCL11A-L and BCL11A-S) (Satterwhiteet al. 2001). To date, no variants have been reported in exon 5 that have been implicated in Dias-Logan phenotypes (Dias et al. 2016).

BCL11A (also known as CTIP1 and EVI9) is a transcription factor with a C2H2 zinc finger and DNA binding motif well-known for its roles in malignancy and hematopoiesis, but specifically acts as a transcriptional repressor of fetal hemoglobin (Dias et al. 2016; Sankaran et al. 2008). BCL11A is a component of the mammalian BAF swi/snf chromatin remodeling complex, which has been implicated in over 1% of neurodevelopmental disorders (Dias et al. 2016).

De novo missense, nonsense, and frameshift variants have been reported in individuals with Dias-Logan syndrome. Missense pathogenic variants to date all occur in an N-terminal dimerization domain of the BCL11A protein (exon 2). Individuals with these missense variants have milder phenotypes, but still have some degree of developmental delay and persistence of fetal hemoglobin. The N-terminal region of BCL11A is critical for protein dimerization, and variants in this region are hypothesized to impact the protein-protein interactions necessary for fetal hemoglobin repression (Dias et al. 2016). Individuals with nonsense and frameshift variants have more severe microcephaly, facial dysmorphism, external ear abnormalities, and in several cases, present with blue sclerae in infancy (Dias et al. 2016). Gross deletions within the 2p15p16.1 region that encompasses several genes (including BCL11A) have been associated with a syndromic from of ID (Balci et al. 2015). One de novo 0.2 Mb heterozygous deletion affecting BCL11A exclusively has been reported in an individual presenting with mild intellectual delay, apraxia of speech, hypotonia, and gross motor delay, but without microcephaly, growth retardation, organ defects, ASD-features, or skeletal anomalies (Peter et al. 2014).

Clinical Sensitivity - Sequencing with CNV PG-Select

Currently, the contribution of de novo and inherited factors to Autism Spectrum Disorders risk is estimated to be approximately 50-60% (Krumm et al. 2015) and 25-50% for Intellectual Disability, with the percentage increasing proportionately with phenotypic severity (McLaren and Bryson 1987). BCL11A is classified in the Simons Foundation Autism Research Initiative (SFARI) Database as a gene with ‘strong evidence’ regarding ASD risk (https://gene.sfari.org/database/human-gene/BCL11A). However, more than 700 genes have been associated with ASD features (Bourgeron 2016). At least 11 patients with developmental delay having variants within BCL11A have been reported in the literature to date (Dias et al. 2016; Iossifov et al. 2012).

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 BCL11A 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.

Indications for Test

Individuals with family members known to have pathogenic variants within the BCL11A gene and/or persistence of fetal hemoglobin are particularly good candidates for this test. Additional features including blue sclerae, microcephaly, external ear dysplasia, ASD and ID-like features with fetal hemoglobin abnormalities are supporting indications for testing as well.

Gene

Official Gene Symbol OMIM ID
BCL11A 606557
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Dias-Logan Syndrome AD 617101

Citations

  • Balci T.B. et al. 2015. European Journal of Medical Genetics. 58: 351-4. PubMed ID: 25979662
  • Bourgeron T. 2016. Comptes Rendus Biologies. 339: 300-7. PubMed ID: 27289453
  • Dias C. et al. 2016. American Journal of Human Genetics. 99: 253-74. PubMed ID: 27453576
  • Iossifov I. et al. 2012. Neuron. 74: 285-99. PubMed ID: 22542183
  • Kaufman L. et al. 2010. Journal of Neurodevelopmental Disorders. 2: 182-209. PubMed ID: 21124998
  • Krumm N. et al. 2015. Nature Genetics. 47: 582-8. PubMed ID: 25961944
  • Levy SE et al. 2009. Lancet. 374: 1627-38. PubMed ID: 19819542
  • McLaren J. & Bryson S.E. 1987. American Journal of Mental Retardation. 92: 243-54. PubMed ID: 3322329
  • McPartland J.C. et al. 2016. Encyclopedia of Mental Health. 2: 124-130.
  • Peter B. et al. 2014. American Journal of Medical Genetics. Part A. 164A: 2091-6. PubMed ID: 24810580
  • Sankaran V.G. et al. 2008. Science. 322: 1839-42. PubMed ID: 19056937
  • Satterwhite E. et al. 2001. Blood. 98: 3413-20. PubMed ID: 11719382
  • Sztainberg Y. & Zoghbi H.Y. 2016. Nature Neuroscience. 19: 1408-17. PubMed ID: 27786181
  • Vissers L.E. et al. 2016. Nature Reviews. Genetics. 17: 9-18. 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

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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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