Colobomatous Microphthalmia and Skeletal Dysplasia Syndrome via the MAB21L2 Gene

Anophthalmia (A; absence of a globe in the orbit) and microphthalmia (M; reduced size of the globe) are severe and rare developmental defects of the globe with an estimated incidence of 0.2–0.4/10,000 and ~1.5/10,000 live births, respectively (Källén and Tornqvist. 2005. PubMed ID: 15971507). Both A/M may be unilateral or bilateral, and over 50% of A/M affected individuals have systemic abnormalities such as hypothalamic–pituitary disorder, mild dysmorphic facial features and short stature, urogenital anomalies, cryptorchidism and/or micropenis in males, developmental delay, seizures, oesophageal atresia or tracheoesophageal fistula and hearing loss (Ragge et al. 2005. PubMed ID: 15812812). However, only about 25% of affected individuals have distinct and well-defined syndromes (Bakrania et al. 2007. PubMed ID: 17522144). Unilateral A/M cases often have developmental anomalies of the other eye; including coloboma, lens, and optic nerve (Ragge et al. 2007. PubMed ID: 17914432).

MAB21L2-associated disorder is characterized by colobomatous microphthalmia, a distinctive skeletal dysplasia, and intellectual disability (Horn et al. 2015. PubMed ID: 26116559).

Pathogenic variants in MAB21L2 cause a spectrum of autosomal dominant (AD) and autosomal recessive (AR) syndromic eye malformations (Rainger et al. 2014. PubMed ID: 24906020; Deml et al. 2015. PubMed ID: 25719200). Mouse model studies suggested that Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud; exact function of the protein is still unknown. However, the the MAB21L2 protein binds to single stranded RNA, and this activity was lost in all altered forms of the protein. In vitro studies suggested that induced expression of of wild-type MAB21L2 increases phospho-ERK (pERK1/2) signaling (Rainger et al. 2014. PubMed ID: 24906020).

Heterozygous pathogenic variants are possibly acting in a dominant negative manner due to their increased stability and are probably associated with the abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells. This is a plausible pathogenic mechanism for the severe AD disorder. Homozygous variants in MAB21L2 might lead to complete loss of MAB21L2 RNA binding and result in a less severe AR disorder (Rainger et al. 2014. PubMed ID: 24906020). To date, only missense variants have been documented causative for the MAB21L2-associated disorder (Human Gene Mutation Database). Of note, a homozygous MAB21L2 frameshift protein truncating variant has been reported in a rare case of syndromic scrotal agenesis (Bruel et al. 2017. PubMed ID: 27103078).

Predicting clinical sensitivity for the MAB21L2 gene is challenging due to the limited number of MAB21L2-associated cases. Analytical sensitivity should be high because all pathogenic variants reported are detectable by sequencing.

This test provides full coverage of all coding exons of the MAB21L2 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).