Dias-Logan Syndrome via the BCL11A Gene

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).

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).

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.