In a screen of CDH23 in 107 individuals with Usher Syndrome (69) or non-syndromic deafness (38) this variant was found homozygously in one individual with Usher Syndrome. The authors note that Usher Syndrome is usually caused by a null allele, and the presentation of this case was “atypical.” Ancestry is not reported and “adequate clinical information could not be obtained.” Additionally, the authors did not directly sequence all 69 exons for each individual. This variant was not seen in 96 control samples.
In a study of 76 probands assessing digenic inheritance of Usher Syndrome between CDH23 and PCDH15, this variant was found in a homozygous state together with 5601delAAC in PCDH15. This patient was a 43yo African-American female with congenital deafness, balance problems at 29yo, retinitis pigmentosa at 30yo and night blindness at 40yo. The authors note that this phenotype is more severe than that of Astuto et al., possibly due to a modifier effect from PCDH15. This variant is in a functionally important, conserved domain and was not seen in 100 unrelated controls.
In developing a microarray for Usher Syndrome, testing of 370 Caucasian cases (140 with Usher Syndrome I) this variant was found heterozygously in 1/20 individuals with Atypical Usher Syndrome.
In silico data suggest that this variant causes aberrant splicing (assessed with ESE finder) and would explain why it is one of only four CDH23 missense mutations causing Usher Syndrome. This variant is conserved in mouse, chicken and zebrafish. A mini-gene assay showed no difference in splicing when compared with wildtype. The authors conclude that due to the work of Astuto and Zheng pathogenicity is likely, but it is still possible that additional mutations were missed.