Opitz G/BBB Syndrome Panel

Opitz G/BBB syndrome is a congenital condition characterized by multiple midline structure malformation of the body. There are two types of Opitz G/BBB syndrome, X-linked Opitz G/BBB syndrome (type 1) and autosomal dominant Opitz G/BBB syndrome (type 2). The main features include facial anomalies (hypertelorism, frontal bossing, broad nasal bridge, cleft lip and/or palate), laryngo-tracheo-esophageal abnormalities, cardiac defects and genitourinary abnormalities (imperforate anus, hypospadias). Developmental delay and intellectual disability is common. The expressivity of Opitz G/BBB syndrome is highly variable (Cox et al. 2000. PubMed ID: 11030761; Ferrentino et al. 2007. PubMed ID: 17221865; Kruszka et al. 2015. PubMed ID: 25412741).

In this panel, we sequence two Opitz G/BBB syndrome related genes (MID1, SPECC1L) and several other genes which present with overlapping clinical features. Opitz G/BBB syndrome is inherited via pathogenic variants either in an X-linked recessive manner (MID1 gene) or an autosomal dominant manner (SPECC1L gene). Frequently, Opitz syndrome is misdiagnosed in patients with FG syndromes, Mowat-Wilson syndrome and craniofrontonasal dysplasia which are caused by pathogenic variants in other genes.

MID1 encodes protein midline 1 which is a microtubule-associated protein that belongs to the tripartite motif family. Protein midline 1 contains an RBCC (RING finger motif, two B-box zinc finger motifs and a Coiled-Coil region) domain and a C terminal domain of unknown function (Cox et al. 2000. PubMed ID: 11030761). Midline 1 catalyzes the polyubiquitination of the catalytic subunit of protein phosphatase 2A (PP2Ac) which is a major serine/threonine phosphatase that regulates cellular processes associated with metabolism, cell-cycle progression, and apoptosis (Du et al. 2014. PubMed ID: 25207814; Wright et al. 2014. PubMed ID: 25216264).

SPECC1L encodes sperm antigen with calponin homology and coiled-coil domains 1-like protein which interacts with both microtubules and the actin cytoskeleton and is necessary for cell adhesion and migration (Kruszka et al. 2015. PubMed ID: 25412741).

Large deletions and duplications are relatively common in MID1, CASK , FLNA, ZEB2 and EFNB1 (Cox et al. 2000. PubMed ID: 11030761; Ferrentino et al. 2007. PubMed ID: 17221865; Human Gene Mutation Database).

See individual gene test descriptions for additional information on molecular biology of gene products and spectra of pathogenic variants.

MID1 is the only gene responsible for X-linked Opitz G/BBB syndrome. Sequence analysis detects pathogenic variants in 24-45% of males with clinically diagnosed Opitz G/BBB syndrome (Cox et al. 2000. PubMed ID: 11030761; Ferrentino et al. 2007. PubMed ID: 17221865; Fontanella et al. 2008. PubMed ID: 18360914; Kruszka et al. 2015. PubMed ID: 25412741). The sensitivity of this test is >50% in patients with Opitz G/BBB syndrome with X-linked inheritance (Meroni. 2018. PubMed ID: 20301502). Large deletions and duplications are relatively common in MID1, CASK, FLNA, ZEB2 and EFNB1 (Cox et al. 2000. PubMed ID: 11030761; Ferrentino et al. 2007. PubMed ID: 17221865; Human Gene Mutation Database).

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).