Opitz G/BBB Syndrome Type 1 via the MID1 Gene

Opitz G/BBB syndrome type 1, X-linked, is a congenital disorder characterized by multiple midline structure malformation (Cox et al 2000). The manifestations include facial anomalies (hypertelorism, frontal bossing, broad nasal bridge, cleft lip and/or palate), laryngo-tracheo-esophageal abnormalities, genitourinary abnormalities (imperforate anus, hypospadias) and cardiac defects. Developmental delay and intellectual disability are common and present in half of affected males. The expressivity of Opitz G/BBB syndrome is highly variable. Almost all patients who harbor pathogenic variants in MID1 have hypertelorism, laryngo-tracheo-esophageal defects and hypospadias, while other less frequent signs are cleft lip and/or palate, cardiac and anal defects (Cox et al 2000; Ferrentino et al. 2007).

The clinical phenotype of Opitz G/BBB syndrome type , X-linked, is presented in male patients, while female carriers usually present with only hypertelorism and occasionally other minor signs (Ferrentino et al. 2007).

Opitz G/BBB syndrome is inherited in X-linked recessive manner and is caused by pathogenic variants in the MID1 gene encoding protein midline 1. Pathogenic variants reported in the MID1 gene include missense, nonsense, splicing, small deletions and small duplications (Ferrentino et al. 2007; Fontanella et al. 2008). Large deletions and duplication are also relatively common (Cox et al 2000; Ferrentino et al. 2007). 

Protein midline 1 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). 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 (Short et al. 2002; Du et al. 2014; Wright et al. 2014).

MID1 is the only gene responsible for X-linked Opitz G/BBB syndrome. Sequence analysis detects pathogenic variants in 15 - 45% of males with clinically diagnosed Opitz G/BBB syndrome (Cox et al. 2000; Ferrentino et al. 2007; Fontanella et al. 2008). The sensitivity of this test is >50% in patients of Opitz G/BBB syndrome with X-linked inheritance (Meroni et al 2011).

Large deletions and duplications are not rare in the patients with X-linked Opitz G/BBB syndrome and have been reported in many cases (Ferrentino et al 2007).

This test provides full coverage of all coding exons of the MID1 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).