Usher Syndrome Type IJ and Deafness, Autosomal Recessive 48 (DFNB48) via the CIB2 Gene

Usher syndrome is a clinically heterogeneous disorder characterized by progressive retinitis pigmentosa (RP) and sensorineural hearing impairment, with or without vestibular abnormalities. Three types are recognized based on the age of onset, severity of symptoms and the vestibular involvement. Usher syndrome type 1 is the most common type. It is distinguished by congenital onset of hearing loss, RP in the first decade of life, and abnormal vestibular function (Cohen et al. 2007). Features of RP include night blindness progressing to constriction of the peripheral visual field with eventually loss of central vision, abnormal fundus with bone-spicule deposits/attenuated retinal vessels, and abnormal electroretinographic (ERG) findings (Daiger et al. 2007). The vestibular abnormality results in development delay in sitting and walking.

Hereditary or familial hearing loss (HL) and deafness can be prelingual (before language develops) or postlingual (after language develops) and may be conductive, sensorineural, or a combination of both. Causes for hereditary HL can be syndromic (associated with malformations of the external ear or other organs or with medical problems involving other organ systems) or nonsyndromic (no associated visible abnormalities of the external ear or any related medical problems). Familial forms of hearing loss must be distinguished from acquired (non-genetic) causes of hearing loss (such as environmental effects or mechanical stress) and are diagnosed by otologic, audiologic, and physical examination, family history, ancillary testing (e.g., CT examination of the temporal bone), and molecular genetic testing. Molecular genetic testing is possible for many types of syndromic and nonsyndromic deafness and plays a prominent role in diagnosis and genetic counseling (Smith et al. 2013).

Nonsyndromic hearing loss and deafness is characterized by childhood-onset, progressive, moderate-to-severe sensorineural hearing impairment. The audioprofile may vary significantly, even among family members. Affected individuals have no other associated medical findings (Smith et al. 2013).

Autosomal recessive deafness 48 (DFNA48) is a pre-lingual onset profound nonsyndromic hearing loss that affects all frequencies (Ahmad et al. 2005).

Variants in the calcium and integrin binding family member 2 (CIB2) gene cause both autosomal recessive Usher syndrome type 1 (USH1J) and autosomal recessive nonsyndromic deafness 48 (DFNB48). A homozygous missense variant in CIB2 (c.272T>C; p.Phe91Ser) was found in 54 DFNB48 Pakistani families. A second missense variant in CIB2 (c.297C>G; p.Cys99Trp) was found in 2 different DFNB48 Pakistani families. A third missense variant in CIB2 (c.368T>C; p.Ile123Thr) was found in a Turkish DFNB48 family. A fourth missense variant in CIB2 (c.192G>C; p.Glu64Asp) was found to be homozygous in a USH1J Pakistani family (Riazuddin et al. 2012). A fifth and sixth missense and nonsense variant in CIB2 (c.196C>T; p.Arg66Trp and c. 97C>T; p.Arg33*) were found in families of Dutch origin with nonsyndromic hearing loss (Seco et al. 2015). A seventh missense variant in CIB2 (c.556C>T; p.Arg186Trp) was homozygous in two individuals with nonsyndromic hearing loss in a Caribbean Hispanic family (Patel et al. 2015).

CIB2 binds calcium and magnesium ions and interacts with integrin (Huang et al. 2012). CIB2 is expressed widely in human and mouse, including the inner ear and retina (Riazuddin et al. 2012). Transfection experiments using COS-7 cells found that five of the known CIB2 pathogenic missense variant significantly affected the ability of CIB2 to decrease ATP-induced calcium release from the cell (Riazuddin et al. 2012; Patel et al. 2015). These results suggest that CIB2 has an important role in calcium ion regulation of the mechanotransduction process in the inner ear and photoreceptor maintenance in the eye.

In unaffected Pakistani individuals the frequency of the c.272T>C and c.297C>G CIB2 variants were reported to be 0.09% and 0.47%, respectively (Riazuddin et al. 2012). This suggests clinical sensitivity of this test in patients with Pakistan ancestry may be relatively high. Overall, clinical sensitivity is difficult to estimate because pathogenic variants have been documented only in a small number of patients outside of Pakistan. Analytical sensitivity should be high because all reported variants are detectable by sequencing.

This test provides full coverage of all coding exons of the CIB2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).