Baraitser-Winter Syndrome Type 1 via the ACTB Gene

Baraitser-Winter syndrome 1 (BRWS1) is a rare syndromic form of intellectual disability characterized by intellectual deficits and developmental delays ranging from mild to severe. A majority of individuals with BRWS1 have epilepsy and reduced brain sulcation (agyria, pachygyria, lissencephaly), with the age of onset and intensity of seizures correlating with the severity of brain malformations. Facial features of Baraitser-Winter patients comprise a unique facial gestalt that can aid diagnosis. These include trigonocephaly, arched eyebrows, long palpebral fissures, hypertelorism, ptosis, short nose, anteverted nares, wide nasal tip, long philtrum, macrostomia, thin upper lip, and prominent lower lip. Importantly, the facial features change significantly with age - beginning as a rounded and flattened appearance to the face in infancy, followed by gradual coarsening. Other common physical features include postnatal short stature, microcephaly, microphthalmia, coloboma (of iris, retina, or eyelid), dysplastic ears, short webbed neck, and pectus deformities. Sensorineural hearing loss, dysplastic corpus callosum, facial clefting, pterygia, contractures, abnormal spine curvature, congenital heart defects, hydronephrosis, hernias, and kidney dysplasia are additional common features of patients with Baraitser-Winter syndrome type 1 (Rivière et al. 2012. PubMed ID: 22366783; Verloes et al. 2015. PubMed ID: 25052316; Yates et al. 2017. PubMed ID: 27625340). Childhood-onset progressive dystonia has been reported for one family, and it remains to be determined whether this is unique to the family, or a common feature of BRWS1 (Procaccio et al. 2006. PubMed ID: 16685646).

While missense variants cause the typical BRWS1 phenotype described above, loss of function ACTB alterations cause a variation with many overlapping features, yet several notable differences. These patients often have prenatal growth deficiencies (in addition to postnatal short stature), and significant feeding difficulties after birth. Brain abnormalities are observed in a majority of these patients (widely variable in type, but notably lacking the pachygyria-lissencephaly spectrum typical for BRWS1), and seizures are rare. Finally, the facial gestalt of these patients is also unique, often including interrupted wavy eyebrows, dense eyelashes, and a prominent chin. Intellectual disability and developmental delay are present in all patients identified to date, but additional behavioral features are described for patients with loss of function variants - such as autism, attention deficit hyperactivity disorder, and a notably social-empathetic personality (Cuvertino et al. 2017. PubMed ID: 29220674).

A third distinct phenotype exists for pathogenic variation in the last two exons of the ACTB gene. These alterations in exons 5-6 (both missense and loss of function changes) lead to a form of BRWS1 that has significant overlap with the other two variations described above, but tends to have a milder clinical course, and includes the additional phenotype of thrombocytopenia (Latham et al. 2018. PubMed ID: 30315159).

No direct treatments are available for Baraitser-Winter syndrome; however, patients and their families may benefit from a molecular diagnosis for prognostic information, early identification and treatment of symptoms, or for connecting with Baraitser-Winter support groups. A confirmed de novo occurrence in the proband (undetectable in parents) dramatically reduces the risk of recurrence, and thus may ease concerns for reproductive planning.

Pathogenic variants in the ACTB gene cause Baraitser-Winter syndrome type 1 (BRWS1), an autosomal dominant disorder typically caused by a de novo pathogenic variant in the proband (Yates et al. 2017. PubMed ID: 27625340). ACTB pathogenic variant types include missense, nonsense, frameshift, small in-frame deletions, and gross deletion variants, as well as a small number of large duplications. Initially, a gain-of-function or dominant negative mechanism was proposed for the BRWS1 phenotype resulting from ACTB missense variation; yet the significant phenotypic overlap now described in patients with loss of function mutations calls this theory into question (Cuvertino et al. 2017. PubMed ID: 29220674; Yates et al. 2017. PubMed ID: 27625340). Genotype-phenotype correlations for ACTB include distinct phenotypes for missense alterations as compared to loss of function alterations (nonsense, frameshift, large deletions)(see "Clinical Features" section above). Additionally, missense variation in the 5' region of the protein tend to cause a more severe presentation of BRWS1, whereas missense and loss of function variation in the 3' end of the protein (exons 5-6) cause a less severe form of BRWS1 that additionally includes thrombocytopenia (Latham et al. 2018. PubMed ID: 30315159; Cuvertino et al. 2017. PubMed ID: 29220674; Yates et al. 2017. PubMed ID: 27625340). Several pathogenic missense changes are recurrent, and one particularly commonly altered residue is p.Arg196. ACTB BRWS1 is thought to be fully penetrant, but has widely variable severity, even for individuals with the same alteration. While most pathogenic variants arise de novo, a handful of cases inherited from affected parents have been described, and inheritance may be more common for the less severe form of the disease resulting from alterations in exons 5-6 (Cuvertino et al. 2017. PubMed ID: 29220674; Yates et al. 2017. PubMed ID: 27625340; Latham et al. 2018. PubMed ID: 30315159). Pathogenic variation in the ACTG1 gene (coding for γ-actin) causes autosomal dominant Baraitser-Winter syndrome type 2 (BRWS2), which has a strongly overlapping phenotype to BRWS1, and should be considered in the differential diagnosis.

The ACTB gene is on chromosome 7p22.1, contains 6 exons, and creates a 375 amino acid protein. The protein created is β-actin - one of six cytoskeletal actins, and one of two cytoplasmic actins (along with γ-actin - coded by the ACTG1 gene). These cytoplasmic actins are ubiquitously expressed, highly-conserved, and implicated in nearly all cellular processes - including cell size and shape, cell movement, cell division, maintenance of intracellular environment, and regulation of gene expression (Cuvertino et al. 2017. PubMed ID: 29220674). As such, Actb null mice are embryonic lethal, whereas neural specific knockouts show brain defects comparable to those observed in humans with BRWS1 (Yates et al. 2017. PubMed ID: 27625340).

The proportion of syndromic intellectual disability caused by pathogenic variants in ACTB is predicted to be very low (<0.1%). Yet, accurate phenotyping, including use of a program such as Face2Gene (https://www.face2gene.com/) to compare facial gestalt, will increase the clinical sensitivity of this test. It is important to note the high clinical and genetic heterogeneity of intellectual disability, and the improved diagnostic yields that result from testing large panels of genes as well as testing parents along with the patient using a trio approach (Vissers et al. 2016. PubMed ID: 26503795). The analytical sensitivity of this test is expected to be very high, as it will detect all types of ACTB pathogenic variants identified to date, including sequence variants and large deletions and duplications (CNVs).

This test provides full coverage of all coding exons of the ACTB 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

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).