ClinGen Dosage Sensitivity Curation Page

Gene Information

• id: ISCA-26477
• Date last evaluated: 2016-08-22
• Issue Type: ClinGen Gene Curation
• Gene type: protein-coding
• Entrez Gene: https://www.ncbi.nlm.nih.gov/gene/25861
• OMIM: https://omim.org/entry/611383
• Gene Reviews: https://www.ncbi.nlm.nih.gov/books/NBK1341/?term=DFNB31

Location Information

• 9q32
• GRCh37/hg19 chr9: 117,164,360-117,267,736

Evidence for Loss Phenotypes

• Loss of function score: Gene associated with autosomal recessive phenotype
• Strength of Evidence: Gene associated with autosomal recessive phenotype
• Haploinsufficiency phenotype: DEAFNESS, AUTOSOMAL RECESSIVE 31; DFNB31

Evidence for loss of function phenotype

PubMed ID	Description
12833159	Mburu et al. 2003 identified a consanguineous family from Jordan with 5 autosomal recessive segregations with profound prelingual deafness (6 affected, 11 unaffected). The variant was NM_015404.3:c.2332C>T (p.Arg778Ter) which causes a stop codon in exon 10/12 and therefore leads to absent or truncated protein.
15841483	Tilili et al. 2005 identified a consanguineous family with profound prelingual deafness. The NM_015404.3:c.2423delG (p.Gly808fsX12) variant segregated with disease 3 times. Of note, this variant occurs in the second to last exon (11/12) though the stop codon that it produces does occur more than 50 bp from the final intron. It is unclear as to whether the product of this transcript will undergo nonsense mediated decay. However, this variant still provides support for this gene being associated with autosomal recessive prelingual profound deafness.

• Loss of function phenotype comments: There have been 2 families with autosomal recessive nonsyndromic profound prelingual deafness associated with loss of function variants segregating in WHRN. There have also been experimental studies conducted by Ebrahim et al. 2016 and Zou et al. 2014. Ebrahim 2016 generated a mouse model, Whrn which have a spontaneous deletion including exons 6-10 of the gene. The mice are profoundly deaf and exhibit headbobbing and circling characteristics of vestibular dysfunction. These mice also have abnormally short inner hair cells and outer hair cells (OHC) have irregular spacing. Whrn (tm1b/tm1b) mice have an exon 4 deletion and cassette including lacZ inserted into intron 3, and do not exhibit vestibular dysfunction. The (tm1b/tm1b) mice have OHC phenotype but not the shortened stereocilia. Zou 2014 found that WHRN colocalizes with PDZD7 at the base of hair bundles and that knockout of PDZD7 seemed to prevent WHRN localization. PDZD7 is associated with autosomal recessive hearing loss as well. In summary, WHRN is associated with autosomal recessive nonsyndromic profound prelingual sensorineural deafness. Variation in WHRN has been reported in individuals with Usher Syndrome 2 (USH2) and ARNSHL. Furthermore, the association between WHRN and USH2 has been expert reviewed by the ClinGen Hearing Loss Working Group and classified as DEFINITIVE. However, the overall evidence that WHRN, when altered, causes ARNSHL was classified as MODERATE after primary curation.

Evidence for Triplosenstive Phenotype

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

• Triplosensitivity phenotype comment: There has not been a distinct phenotype associated with triplosensitivity of WHRN.

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.