Compound Heterozygous Variants of the CPAMD8 Gene Co-Segregating in Two Chinese Pedigrees With Pigment Dispersion Syndrome/Pigmentary Glaucoma

Abstract

The molecular mechanisms underlying the pathogenesis of pigment dispersion syndrome and pigmentary glaucoma remain unclear. In pedigree-based studies, familial aggregation and recurrences in relatives suggest a strong genetic basis for pigmentary glaucoma. In this study, we aimed to identify the genetic background of two Chinese pedigrees with pigmentary glaucoma. All members of these two pedigrees who enrolled in the study underwent a comprehensive ophthalmologic examination, and genomic DNA was extracted from peripheral venous blood samples. Whole-exome sequencing and candidate gene verifications were performed to identify the disease-causing variants; in addition, screening of the CPAMD8 gene was performed on 38 patients of sporadic pigmentary glaucoma. Changes in the structure and function of abnormal proteins caused by gene variants were analyzed with a bioinformatics assessment. Pigmentary glaucoma was identified in a total of five patients from the two pedigrees, as were compound heterozygous variants of the CPAMD8 gene. No signs of pigmentary glaucoma were found in carriers of monoallelic CPAMD8 variant/variants. All four variants were inherited in an autosomal recessive mode. In addition to the 38 patients of sporadic pigmentary glaucoma, 13 variants of the CPAMD8 gene were identified in 11 patients. This study reported a possible association between CPAMD8 variants and pigment dispersion syndrome/pigmentary glaucoma.

Keywords: CPAMD8; autosomal recessive inheritance; compound heterozygous variant; pedigree; pigmentary glaucoma.

FIGURE 1

Ocular phenotypes of patients in two pigmentary glaucoma (PG) pedigrees associated with CPAMD8 variants. Clinical photography including slit-lamp biomicroscopy, gonioscopy, ultrasound biomicroscopy, and fundus photography. Representative signs of PG, such as Krukenberg’s spindle, TM pigmentation, and reverse pupillary block, were indicated by red arrows and white arrowheads, respectively. In pedigree 1, representative images were acquired from the right eye of patient II:5. In pedigree 2, representative images were acquired from the left eye of patient II:2 (slit-lamp biomicroscopy and fundus photography) and the right eye of patient II:3 (gonioscopy and ultrasound biomicroscopy).

FIGURE 2

Two PG pedigrees with CPAMD8 variants and Sanger sequencing results of the CPAMD8 gene. (A) The two PG pedigrees described from our research. Round symbols indicate female individuals; square symbols indicate male individuals; black symbols indicate PG patients; arrow marks indicate the proband; asterisks represent subjects involved in genetic research. The plus signs denote reference allele. (B) Sanger sequencing verification and segregation analysis of biallelic CPAMD8 variants in two PG pedigrees. Variants are denoted in red font. Two different compound heterozygous variants of CPAMD8 were identified in two PG pedigrees. Abbreviations: PG, pigmentary glaucoma.

FIGURE 3

Bioinformatics analyses of CPAMD8 variants in two PG pedigrees. (A) Schematic representations showing variant sites on the sequence of the CPAMD8 gene and CPAMD8 protein identified in our study and other studies of the association between CPAMD8 gene and inherited ocular disorders (Cheong et al., 2016; Hollmann et al., 2017; Alsaif et al., 2019; Bonet-Fernandez et al., 2020; Siggs et al., 2020; Li X. et al., 2021b). Each study was plotted in a distinct color. Domains were indicated according to the Pfam database (https://pfam.xfam.org/). Abbreviations: S, signal peptide; A2M, α-2-macroglobulin domain; A2M_BRD, α-2-macroglobulin bait region domain; A2MR, α-macroglobulin receptor binding domain; MG, macroglobulin domain of α-2-macroglobulin; M_FA, farnesoic acid O-methyl transferase domain; TED, α-macroglobulin thioester domain; K, kazal-2 serine protease inhibitor domain. (B) Sequence alignments of the CPAMD8 protein among different species. Four missense variants were highly conserved in various species. The positions of the variant amino acids are indicated by red arrows.