Renpenning Syndrome via the PQBP1 Gene

X-linked Intellectual Disability (XLID) contributes 10-15% of total intellectual disability (ID) in males. Renpenning Syndrome (RENS1) is a syndromic XLID that occurs exclusively in males. So far, there are no reports of affected females.

RENS1 is characterized by moderate to severe intellectual disability, developmental delay, and distinctive features of microcephaly, short stature, small testes, and dysmorphic facies (tall narrow face, up-slanting palpebral fissures, abnormal nasal configuration, cupped ears and short philtrum) (Stevenson et al. 1998). The affected individuals occasionally display additional features of cardiac malformations, muscular atrophy, cleft palate, anal anomalies and ocular colobomas.

Loss-of-function pathogenic variants in PQBP1 result in Renpenning syndrome (syndromic XLID). PQBP1 (~4.6 kb) maps to Xp11.23 and consists of 6 exons that encode a 265 amino acid polypeptide. PQBP1 is a highly conserved polyglutamine-binding nuclear protein and presumably functions as a scaffold protein, thereby playing a role in pre-mRNA splicing, transcription regulation and neuron development (Iwasaki et al. 2014; Wang et al. 2013). Using in vitro experiments, Zhang et al. have recently shown that mutant PQBP1 preferentially binds to non-phosphorylated fragile X mental retardation (FMRP) protein to promote its ubiquitin-mediated degradation, thus disrupting FMRP-dependent synaptic scaling (Zhang et al. 2017). Both nonsense and missense pathogenic variants as well as small and gross insertions/deletions have been reported in PQBP1. The disease transmission pattern is X-linked recessive.

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 100 genes have been identified in individuals with XLID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016). Analytical sensitivity should be high because most pathogenic variants reported to date are detectable by sequencing.

To date, among the total number of pathogenic variants reported involving this gene, almost 11% are large deletions or duplications (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the PQBP1 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).