X-linked Lenz Microphthalmia Syndrome and Lethal Ogden Syndrome via the NAA10 Gene

Lenz microphthalmia syndrome (LMS) is a X-linked disorder characterized by unilateral or bilateral microphthalmia accompanied by multiple congenital extraocular abnormalities. Extraocular symptoms include developmental delay, skeletal abnormalities, genitourinary malformations, cleft lip and palate, digital anomalies, and anomalies of the ears and teeth. Mild to severe intellectual disability and seizures are seen in about 60% of affected males (Traboulsi et al. 1988; Esmailpour et al. 2014).

Ogden syndrome (OS) is an X-linked lethal disorder in infancy with severe developmental delays and a unique combination other symptoms including facial dysmorphic features, skin, skeletal, cardiac, genital and neurological abnormalities (Rope et al. 2011; Myklebust et al. 2015). X-chromosome inactivation was analyzed in heterozygous, affected OS women and all four women showed skewed X-inactivation (Myklebust et al. 2015).

Besides lethality, a distinct difference between MLS and OS is microphthalmia or anophthalmia, which only present in MLS. Reduced expressivity of the symptoms have been reported in female carriers (Rope et al. 2011; Esmailpour et al. 2014).

Hemizygous variants in NAA10 have been reported to be causative for allelic disorders LMS and OS. The mutation spectrum cannot be precisely described due to the limited number of documented cases. So far, only a missense (p.Ser37Pro) and a splice-site variant (c.471+2T>A) have been reported to be causative (Rope et al. 2011; Esmailpour et al. 2014). The splice-site variant in NAA10 has been shown to affect the retinoic acid signaling pathway that is is important for normal eye development and resulted in LMS. Whereas the missense variant was shown to reduce N-terminal acetyltransferase activity and resulted in severe phenotype OS (Rope et al. 2011; Esmailpour et al. 2014).

NAA10-encoded N-terminal acetyltransferase (NAT) is a ubiquitously expressed protein, which is involved in protein N-terminal acetylation (NTA). Recently, NAT has been shown to be involved in post-translational NTA, lysine acetylation, and NAT/KAT-independent functions (Dörfel and Lyon 2015). NTA is a commonly occurring protein modification in eukaryotes that has an important role in the modulation of protein-protein interaction, protein degradation, complex formation, subcellular targeting, and protein folding (Aksnes et al. 2015; Dörfel and Lyon 2015). NAT was also shown to be involved in the retinoic acid signaling pathway and normal eye development (Esmailpour et al. 2014).

LMS is genetically heterogeneous; NAA10 (MCOPS1 locus) and BCOR (MCOPS2 locus) are the only two genes so far identified (Ng 2014).

Clinical sensitivity cannot be precisely estimated for Lenz microphthalmia and Ogden syndrome patients as they are rare disorders with a limited number of documented cases. Analytical sensitivity should be high because all NAA10 pathogenic variants reported are detectable by sequencing. No gross deletions or duplications have been reported so far (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the NAA10 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).