The relationship between PCDH15 and autosomal recessive nonsyndromic hearing loss (ARNSHL) was evaluated using the ClinGen Clinical Validity Framework as of 12/8/2017. The PCDH15 gene has previously been classified as Definitive for Usher syndrome by the ClinGen Hearing Loss Expert Panel. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, we have split curations for the disease entities of Usher syndrome and non-syndromic hearing loss. Variants in PCDH15 were first reported in humans with this disease as early as 2003 (Ahmed et al., PMID 14570705). There are many cases in the literature claiming non-syndromic hearing loss with PCDH15 variants however many of the variants were not scored due to lack of convincing evidence of pathogenicity or lack of information of phase. However, at least 4 unique variants (missense, in-frame indel, truncating nonsense, frameshift) with sufficient evidence to score reported in humans with sufficient electroretinography or age-dependent phenotyping to rule out Usher syndrome. These variants were detected in a large Pakistani family with non-syndromic hearing loss with no history of retinitis pigmentosa (RP) (age range 13-44) (Ahmed 2003 14570705); a Chinese family that was claimed to be non-consanguineous with non-syndromic HL (18 year old proband and 28 year old brother w/ HL) (Zhan 2015 25930172); a 21 y.o. male noted to have no other symptoms (Wang 2017 28281779). There were some patients described to have no ERG's conducted so Usher syndrome could not be ruled out (Yang 2013 23767834). This gene-disease association is supported by expression studies and protein interaction studies (PMIDs: 25467981, 16807332, 11138007, 28263850, 14570705). However, many of the cases do not provide ages for individuals which makes this scoring susceptible to including cases that may develop late-onset RP. Therefore, the association between PCDH15 and ARNSHL is Limited. This classification was approved by the ClinGen Hearing Loss Working Group on 6/19/2018.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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