Septo-optic Dysplasia Spectrum Panel

Septo-optic dysplasia spectrum (SOD) is a rare congenital developmental abnormality characterized by two or more features of the classical triad: hypoplasia of the optic nerves (unilateral or bilateral), pituitary hypoplasia and midline defects of brain. The majority of patients (96%) have optic nerve hypoplasia on MRI imaging (Cemeroglu et al. 2015. PubMed ID: 25879316). Hormonal dysfunction such as combined hypopituitarism and precocious puberty is present in 78% of cases. Other less frequent symptoms include developmental delay, seizures, visual impairment, sleep disturbance, obesity, anosmia, sensorineural hearing loss and cardiac anomalies. MRI imaging can reveal hypoplasia of the optic nerves and optic chiasm, agenesis of the septum pellucidum, abnormalities of the corpus callosum and hypothalamopituitary axis. The incidence is approximately 1 in 10,000 live births. Onset of the disorder can be at birth or later when growth failure occurs in a child (Webb and Dattani. 2010. PubMed ID: 19623216; Koizumi et al. 2017. PubMed ID: 28458461; Ganau et al. 2019. PubMed ID: 31695544).

SOD can be caused by defects in several genes with variable and overlapping presentations. It can be difficult to diagnose by clinical manifestations, laboratory findings and image studies alone. An accurate molecular diagnosis is critical for treatment, prognosis, prediction of recurrence risk, as well as future family plans. Of note, hormonal insufficiencies should be treated as early as possible, as untreated hormonal abnormalities affect neurodevelopment, and increase the risk for visual impairment, hypoglycaemia, adrenal crises and consequent death (Webb and Dattani. 2010. PubMed ID: 19623216).

This panel for SOD spectrum contains 7 genes: GLI2, HESX1, PAX6, PROP1, OTX2, SOX2 and SOX3. SOD is inherited in an autosomal recessive manner in PROP1, an autosomal dominant manner in four genes (GLI2, PAX6, OTX2 and SOX2), and an X-linked manner in SOX3. HESX1 pathogenic variants can be inherited in either an autosomal dominant or recessive manner.

Pathogenic variants are detected more commonly in HESX1, SOX2, SOX3, and OTX2 compared to the other genes (Ganau et al. 2019. PubMed ID: 31695544). A wide variety of causative variants in these genes have been reported including missense, nonsense, splicing, small insertions/deletions and large deletions/duplications (Human Gene Mutation Database). De novo pathogenic variants are common in SOX2 (Dennert et al. 2017. PubMed ID: 27862890).

HESX1 is a homeobox gene expressed in ES cells. It encodes a transcriptional repressor involved in the development of forebrain and pituitary.

PAX6 encodes paired box gene 6, a transcriptional regulator involved in oculogenesis and other development.

PROP1 encodes prop paired-like homeobox 1, a paired-like homeodomain transcription factor required for normal pituitary development.

OTX2 codes for orthodenticle Drosophila, homolog of. This protein is a transcriptional factor involved in brain, craniofacial and sensory organ development.

SOX2 and SOX3 encode SRY-box 2 and SRY-box 3 respectively. Both are members of the SOX family of transcription factors involved in the regulation of embryonic development and determination of cell fate.

GLI2 encodes GLI-KRUPPEL family member 2, a transcription factor involved in SHH signal transduction.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical sensitivity is about 4% for SOD and 10% for defects in pituitary development (Cerbone et al. 2020. PubMed ID: 32140665).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 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).