Tenorio Syndrome via the RNF125 Gene

Tenorio syndrome, known as overgrowth, macrocephaly and intellectual disability syndrome, is one genetic cause of a group of overgrowth syndromes in which all parameters of growth and physical development are above the mean for age and sex. Major features include overgrowth, macrocephaly, intellectual disability, hypotonia, seizures and psychomotor impairment. Patients also present abnormality in skin, skeletal, cardiovascular and immune systems. Laboratory findings are hypoglycemia and hypoinsulinemia. MRI reveals structural brain abnormalities including cortical atrophy and ventricular asymmetry (Tenorio et al. 2014. PubMed ID: 25196541).

Tenorio syndrome is inherited in an autosomal dominant manner and is caused by pathogenic variants in the RNF125 gene, which encodes RING finger protein 125. RNF125 is a RING finger E3 ubiquitin ligase with a RING domain, three zinc fingers and a ubiquitin interacting motif. RNF125 is an important ligase in cell ubiquitination which regulates almost every cellular process either through the destruction of target proteins or the spatial or temporal alteration of their functions. A study demonstrated that loss of function of RNF125 leads to dysregulation of the RIG-I-IPS1, PI3K-AKT, and interferon pathways, however, the exact pathogenic mechanism is unclear (Bijlmakers et al. 2016. PubMed ID: 27411375; Tenorio et al. 2014. PubMed ID: 25196541).

Reported pathogenic point variants in RNF125 are only missense. One large deletion involving the RNF125 locus has also been reported in Tenorio syndrome (Human Gene Mutation Database).

In study of overgrowth syndrome, 4 out of 270 families were found to have a pathogenic variant in RNF125 (Tenorio et al. 2014. PubMed ID: 25196541).

This test provides full coverage of all coding exons of the RNF125 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).