Dias-Logan Syndrome via the BCL11A Gene
- Summary and Pricing
- Clinical Features and Genetics
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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).
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).
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).
This test involves bidirectional Sanger sequencing using genomic DNA of exons 1-4 of the BCL11A gene (BCL11A-XL) plus ~20 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) in family members of patients with a known pathogenic variant or to confirm research results. To date, pathogenic variants have only been reported in exons 1-4 of the BCL11A gene (Dias et al. 2016).
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.
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|Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection|
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- Greg Fischer, PhD - email@example.com
- 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
Bi-Directional Sanger Sequencing
Nomenclature for sequence variants was from the Human Genome Variation Society (http://www.hgvs.org). As required, DNA is extracted from the patient specimen. PCR is used to amplify the indicated exons plus additional flanking non-coding sequence. After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions. In nearly all cases, the full coding region of each exon as well as 20 bases of non-coding DNA flanking the exon are sequenced.
As of March 2016, we compared 17.37 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.
Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).
In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.
Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.
In most cases, only the indicated exons and roughly 20 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.
In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.
Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.
Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.
Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.
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.
- 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.
(Delivery accepted Monday - Saturday)
- Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
- For small babies, we require a minimum of 1 ml of blood.
- Only one blood tube is required for multiple tests.
- Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
- During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
- In cold weather, include an unfrozen ice pack in the shipping container as insulation.
- At room temperature, blood specimen is stable for up to 48 hours.
- If refrigerated, blood specimen is stable for up to one week.
- Label the tube with the patient name, date of birth and/or ID number.
(Delivery accepted Monday - Saturday)
- Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
- For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
- DNA may be shipped at room temperature.
- Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
- We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.
(Delivery preferred Monday - Thursday)
- PreventionGenetics should be notified in advance of arrival of a cell culture.
- Culture and send at least two T25 flasks of confluent cells.
- Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
- Send specimens in insulated, shatterproof container overnight.
- Cell cultures may be shipped at room temperature or refrigerated.
- Label the flasks with the patient name, date of birth, and/or ID number.
- We strongly recommend maintaining a local back-up culture. We do not culture cells.