Figure 1.

CDH23 Mutations Identified in Familial PA

(A) Pedigree of family 1, who has familial PA. Two affected (II-4 and III-8) and two unaffected (II-3 and III-12) individuals were selected for exome sequencing. Black filled shapes represent affected siblings. White shapes represent asymptomatic subjects. White shapes with a black dot represent asymptomatic carriers of CDH23 mutations. Symbols crossed with a diagonal line indicate deceased relatives. The age of each member is indicated under each symbol. Family members with available clinical data and DNA samples are indicated with E− or E+ under their symbols. E− indicates that the person had a negative evaluation for PA, and E+ indicates that the individual has PA.

(B) MRI data of two individuals with PA (II-4 and III-8) and one unaffected person (III-12) who were included for exome sequencing. Yellow arrows mark tumors.

(C) Filters applied to variants and indels detected by exome sequencing in this family.

(D) Sequencing chromatograms of CDH23 in two individuals with PA (II-4 and III-8) and one unaffected person (III-12). All heterozygous variants were verified by Sanger sequencing (indicated by the black arrow). The mutation and amino acid substitution are shown on the top.

(E) Alignment of the CDH23 EC13 domain shows evolutionary conservation at the site of the identified nucleic acid changes (indicated by the black arrow).

(F) Protein pathogenicity prediction of wild-type and p.Arg1379Leu (c.4136G>T) CDH23 proteins. The pink model represents the homologous template for the EC domain (PDB: 2WHV). The blue model shows the structure of wild-type CDH23. The green model shows the structure of p.Arg1379Leu CDH23.