CIB2

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0010168

Submitter: ClinGen

CIB2 was first reported in relation to autosomal recessive Usher syndrome Type 1 in 2012 (Riazuddin et al., 23023331). One homozygous missense variants in this gene has been reported in at least one proband in one publication (Riazuddin et al. 2012, 23023331). Variants in this gene segregated with disease in 3 additional family members. One additional missense variant has been reported in heterozygosity in an affected individual, however the variant is frequent in population databases and no second pathogenic variant was identified (Fuster-Garcia et al. 2018, 30459346). Booth et al. 2017 (29112224) studied a multi-ethnic cohort of patients with CIB2-related-ARNSHL. All patients in this study have normal ocular phenotype and no vestibular dysfunction regardless of the variant impact. Booth et al. 2017 note that the p.Glu64Asp variant in the Riazuddin Usher family is only two amino acids away from the p.Arg66Trp variant that has been linked to ARNSHL in three families. Booth et al. argue that if CIB2 played a role in Usher syndrome, we would expect to see a retinal and vestibular phenotype in families segregating LOF variants. Michel et al. 2017 (29084757) described 2 families with CIB2-related-ARNSHL. Both families segregate LOF variants and have normal eye phneotype with no pigment deposits. In addition to the variants reported by Booth and Michel, 7 other variants have been linked solely to CIB2-related-ARNSHL (see the CIB2 and ARNSHL gene-disease pair). Michel et al. 2017 also described a CIB2 knockout mouse model. This mouse model displayed congenital profound deafness with no vestibular defect. It also exhibited normal cochlear hair bundle architecture up to postnatal day 7. This is in contrast with all other known USH1 mouse models, which display severe vestibular dysfunction and abnormal cochlear hair bundle architecture starting around postnatal day 3. Other CIB2-murine mutants (28663585 and 29255404) display an identical phenotype to that described by Michel et al. Additionally, it was shown that loss of known USH proteins like MYO7A, PCDH15, USH1C, WHRN, USH2A and PDZD7 does not affect the localization of CIB2, and vice versa. In summary, there is convincing evidence refuting the relationship between CIB2 and autosomal recessive Usher syndrome Type 1, which significantly outweighs the evidence supporting the relationship. This classification was approved by the ClinGen Hearing Loss Working Group on 02/19/2019.

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The CIB2 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/19/2017. This association was made using case-level data only. At least 9 variants (missense, in-frame indel, nonsense, frameshift) have been reported in humans. CIB2 was first associated with this disease in humans as early as 2012 (Riazuddin et al.). Association is seen in at least 9 probands in 6 publications (23023331, 26173970, 26473954, 27344577, 26226137, 26445815). Variants in this gene segregated with disease in 4 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence have been reached. This gene-disease association is supported by two mouse models (Giese et al. 2017) and a zebrafish model (Riazuddin et al. 2012). In summary, CIB2 is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 2/20/2018.

Inheritance Pattern: AR

Disease ID:MONDO:0012273

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: Unknown

Disease ID:MONDO:0013935

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013935

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012273

Submitter: G2P