Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas Qilin Zhang, Cheng Peng,

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Germline Mutations in CDH23, Encoding Cadherin-Related 23, Are Associated with Both Familial and Sporadic Pituitary Adenomas Qilin Zhang, Cheng Peng, Jianping Song, Yichao Zhang, Jianhua Chen, Zhijian Song, Xuefei Shou, Zengyi Ma, Hong Peng, Xuemin Jian, Wenqiang He, Zhao Ye, Zhiqiang Li, Yongfei Wang, Hongying Ye, Zhaoyun Zhang, Ming Shen, Feng Tang, Hong Chen, Zhifeng Shi, Chunjui Chen, Zhengyuan Chen, Yue Shen, Ye Wang, Shaoyong Lu, Jian Zhang, Yiming Li, Shiqi Li, Ying Mao, Liangfu Zhou, Hai Yan, Yongyong Shi, Chuanxin Huang, Yao Zhao The American Journal of Human Genetics Volume 100, Issue 5, Pages 817-823 (May 2017) DOI: 10.1016/j.ajhg.2017.03.011 Copyright © 2017 American Society of Human Genetics Terms and Conditions

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. The American Journal of Human Genetics 2017 100, 817-823DOI: (10.1016/j.ajhg.2017.03.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Three Additional Families Affected by CDH23 Mutations (A–C) Pedigrees of three families carrying CDH23 mutations. 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. (D) Sanger sequencing showing CDH23 mutations in three affected individuals from different families. The black arrows indicate the mutated nucleotides. The mutations and amino acid substitutions are shown on the left. The American Journal of Human Genetics 2017 100, 817-823DOI: (10.1016/j.ajhg.2017.03.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 CDH23 Mutations in a Large PA Cohort (A) The frequency of CDH23 mutations in familial PAs, sporadic PAs, and local healthy control individuals. (B) Mutant CDH23 variant sites in familial and sporadic PAs. All 14 EC domains with detected amino acid substitutions are shown. The ordinal of each EC domain is shown on the left. Corresponding EC domains are indicated to the left of the lineup. Light gray indicates conserved residues. Highly conserved calcium-binding elements are in gray and boxed. The residue in red indicates the mutant site discovered in family 1, and other variants are marked in blue. (C) Percentages of individuals with invasions in both wild-type (WT) and mutant (MT) groups. The p values were calculated by Pearson’s χ2 test. (D–F) Maximal tumor diameters of the WT and MT groups (D), ages at diagnosis of the WT and MT groups (E), and the clinical course of each person in the WT and MT groups (F). Each symbol represents an individual case. Error bars show the mean and standard errors of the data. The p values were calculated by the Mann-Whitney U test (∗p < 0.05 considered significant). The American Journal of Human Genetics 2017 100, 817-823DOI: (10.1016/j.ajhg.2017.03.011) Copyright © 2017 American Society of Human Genetics Terms and Conditions