ClinGen Dosage Sensitivity Curation Page

PQBP1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
20950397 Germanaud et al. (2011) report 13 male patients from 7 families who had syndromic intellectual disability and either frameshift or nonsense mutations. Carrier females were normal. The authors provided detailed clinical descriptions adding to the growing spectrum of features included in what is now considered collectively as Renpenning syndrome.
17033686 Martinez-Garay et al (2007) report two male cousins with syndromic intellectual disability, including microphthalmia, who had a frameshift mutation. Carrier mothers were normal.
21315190 Rejeb et al (2011) report three brothers with syndromic intellectual disability and a frameshift mutation. Their carrier mother was normal. They also provide a review of all previous cases reported.

Haploinsufficiency phenotype comments:

Several families have been reported with loss of function mutations in PQBP1. While the phenotypes described in these families have historically received various names, these are now considered to be within the spectrum of features that are known currently as Renpenning syndrome. Additional evidence includes: Cho RY et al., 2020 (PMID:31840929) describe an affected female with a de novo LOF variant (c.459_462delAGAG/p.R153fs193X ). The authors noted "streaky hypopigmentation of the skin... supporting a hypothesized presence of an actively expressed, PQBP1 mutation-bearing X-chromosome in some cells. X-inactivation studies on peripheral blood cells demonstrated complete skewing in both the proband and her mother with preferential inactivation of the maternal X chromosome in the child. [They] demonstrated expression of the PQBP1 mutant transcript in leukocytes of the affected girl." Lenski C et al., 2004. (PMID 15024694) describe 2 LOF variants in two families, including the originally described Renpenning family. Kalscheuer et al., 2003 (PMID 14634649) report 5 families with frameshift variants involving exon 4. Three of these families are described in additional detail in Kleefstra et al., 2004 (PMID: 15355434). Additional LOF variants are described in: Stevenson, R. E et al., 2005 [PMID 15782410], Mart?nez-Garay I et al., 2006 [PMID 17033686], Sheen VL et al., 2010 [PMID 20886605], Germanaud D et al., 2011 [PMID 20950397], Mameesh et al. 2019 [31718390] etc.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There have been no reports of focal duplications of PQBP1. Some individuals with syndromic intellectual disability have been reported with large duplications that include PQBP1 and several other genes: PMID:21204222, 20613765, 16900295.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.