ClinGen Dosage Sensitivity Curation Page

ESPN

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.