Bohring-Opitz Syndrome via the ASXL1 Gene

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD).

Bohring-Opitz syndrome (BOPS), also known as Oberklaid-Danks syndrome or C-like syndrome, is a form of syndromic ID that is caused by the deficiency of a transcription regulator, Additional Sex Combs Like 1 (ASXL1) protein. Clinical features of BOPS vary and may include (but may not be limited to) developmental delay, speech and language delay, intellectual disability, seizures, epilepsy, hypotonia, structural brain malformations such as Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum, short stature, intrauterine growth retardation, failure to thrive, feeding difficulties, gastroesophageal reflux, microcephaly, coarse facies, dysmorphic features including brachycephaly, triangular and hypotonic face, micrognathia, prominent forehead, retrognathia, facial hemangioma, low-set posteriorly rotated ears, hypertelorism, epicanthus, upslanting palpebral fissures and other abnormalities of the head, neck, chest, skin, nails, hair, ocular, cardiovascular, genitourinary and skeletal systems (Bohring et al. 2006. PubMed ID: 16691589, Pierron et al. 2009. PubMed ID: 19606480, Avila et al. 2013. PubMed ID: 23704076, Magini et al. 2012. PubMed ID: 22419483). Of note, early childhood deaths have been reported in severely affected individuals (Hoischen et al. 2011. PubMed ID: 21706002).

Bohring-Opitz syndrome (BOPS) is an autosomal dominant disorder, caused by heterozygous pathogenic variants (primarily de novo) in ASXL1. ASXL1 consists of 14 coding exons and maps to chromosome 20q11.21, encoding a 1541 amino acid polypeptide. ASXL1 is a putative polycomb group protein and acts on homeobox (Hox) genes as a repressor as well as an enhancer, and is important for development. Although the function of the ASXL-gene family in human development is largely unknown, in Drosophila Asx regulation is highly variable and tightly controlled directly after fertilization (Russell and Graham. 2013. PubMed ID: 23672984). ASXL1 is known to repress the transcription of a subset of adipogenic genes and to regulate adipogenesis primarily via peroxisome proliferator-activated receptor (PPAR)-gamma (Park et al. 2011. PubMed ID: 21047783). Of note, complete knock out mice model of Asxl1 showed embryonic lethality (~80%) during late gestation as well as developmental abnormalities, dwarfism, anophthalmia and similar features of myelodysplastic syndrome (MDS) (Wang et al. 2014. PubMed ID: 24255920). To date, nonsense, missense, frameshift and splice site pathogenic variants have been reported and there are also reports of gross duplications involving ASXL1 (Human Gene Mutation Database). The disease transmission pattern is consistent with autosomal dominant inheritance.

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795). We expect the analytical sensitivity for detection of nucleotide substitutions and small insertions or deletions to be high.

To date, three gross duplications involving ASXL1 have been reported (Avila et al. 2013. PubMed ID: 23704076).

This test provides full coverage of all coding exons of the ASXL1 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).