ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
15286153 Naz et al. 2004 identified a family with a 4-bp deletion that segregated in an autosomal recessive (AR) inheritance pattern in a family with 4 affected/2 unaffected and a published LOD score of 3.4. The variant NM_031475.2:c.1988_1991del, (p.Lys663ThrfsX2) causes a stop codon in exon 9 and is predicted to cause nonsense mediated decay and haploinsufficiency. Inheritance of this variant in a homozygous state, as was the case in this consanguineous family caused vestibular areflexia and prelingual sensorineural hearing impairment.
18973245 Boulouiz et al. 2008 reported a NM_031475.2:c.1756dup (p.Ala586GlyfsX73) variant that causes a stop codon in exon 9/13 and is predicted to cause nonsense mediated decay of the transcript. The variant segregated with hearing loss without vestibular dysfunction in 6 individuals in the consanguineous Moroccan family. In a homozygous state, as was the case in this consanguineous family, the variant caused severe to profound hearing loss w/o vestibular involvement.

Haploinsufficiency phenotype comments:

The ESPN gene has been associated with autosomal dominant (AD) hearing loss (ADHL) as well as autosomal recessive (AR) hearing loss (ARHL). Within the context of autosomal recessive hearing loss, there have been 2 convincing loss of function (LOF) variants reported in the literature by Naz 2004 and Boulouiz 2008, as described above. Additionally, Naz et al. 2017 identified a NM_031475.2:c.2019dup (p.Leu674AlafsX72) variant that causes a stop codon in exon 10/13 of a transcript that is predicted to undergo nonsense mediated decay. However, there were 2 nonsegregations in this ARHL family (2 affected siblings were heterozygous for the variant). The publication suggests locus heterogeneity or environmental factors to be the cause of this. Also, Naz et al. 2004 identified another 4bp deletion, NM_031475.2:c.2470_2473del, which takes place in the last exon and causes a frameshift and a stop codon in the last exon (p.Ser824ArgfsTer22). This is not a convincing LOF variant Furthermore, there have been two other not convincing LOF variants published in the literature causing HL in an AR inheritance pattern: NM_031475.2:c.2519G>A p.Trp840Ter identified by Wang et al. 2017 and NM_031475.2:c.2440C>T (p.Gln814Ter) identified by Sloan-Heggen et al. 2015. Both stop codons occur in the last exon and may escape nonsense mediated decay and therefore cannot be counted towards the haploinsufficiency score. Despite the surprising number of unconvincing LOF variants that take place in the last exon, the ESPN gene was found to be definitively associated with ARHL and therefore should be given the hapolinsufficiency score of 30. It is important to also note that non-LOF variants in this gene have also been shown to cause ADHL (Donaudy 2006). The ClinGen Hearing Loss Working Group has determined that, given the overall evidence, ESPN, when altered, does Within the context of autosomal dominant hearing loss, non-LOF variants have been reported in ESPN in individuals with hearing loss. However, the overall evidence that ESPN, when altered, causes ADHL has been classified as LIMITED after primary curation by the ClinGen Hearing Loss Working Group. This indicates that, at this time, there is not a convincing amount of evidence to suggest that variation within EPSN can cause ADHL. In contrast, the overall evidence does support a DEFINITIVE association between ESPN and ARHL.

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

Triplosensitivity phenotype comment:

There have not been any reports to suggest triplosensitivity of ESPN causing disease in humans.