Familial congenital cataract, coloboma, and nystagmus phenotype with variable expression caused by mutation in PAX6 in a South African family
Familial congenital cataract, coloboma, and nystagmus phenotype with variable expression caused by mutation in PAX6 in a South African family
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发表时间：
2018-06
期刊：
影响因子：
2.2
通讯作者：
S. Goolam;N. Carstens;M. Ross;D. Bentley;Margarida Lopes;J. Peden;Z. Kingsbury;Eleni Tsogka;R. B
中科院分区：
文献类型：
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作者：
S. Goolam;N. Carstens;M. Ross;D. Bentley;Margarida Lopes;J. Peden;Z. Kingsbury;Eleni Tsogka;R. B
目的报告南非一个多代混血家族常染色体显性先天性白内障、结肠瘤和眼球震颤的临床和遗传调查。方法对来自南非混血家族的27例患者进行眼科检查。从所有27人的外周血或口腔拭子中取样DNA，并对6人进行全基因组测序。使用Sanger测序来验证剩余家庭成员中可能的突变。结果共纳入27名家庭成员和19名患者。主要表型是先天性白内障（14例），后段结肠瘤（17例）和眼球震颤（18例），表达变化很大。其他特征包括高度近视、小角膜和斜视。PAX6的R208W突变(dbSNP rs757259413; HGMD CM930572; NM_000280.3:c.622G>A; NP_000271.1:p。Arg208Trp)是最可能的致病突变。在所有27个家族成员中证实了突变与表型的共分离。结论PAX6是一个高度保守的基因，对正常的眼部发育至关重要，尽管该基因的突变可能导致一系列眼部发育异常，但大多数与无虹膜和无虹膜相关的眼部缺陷有关。观察到PAX6无虹膜表型主要与无义突变和轻度非无虹膜表型与错义突变相关，这表明该基因可能存在特定的基因型-表型相关性。在这个家族中发现的PAX6中的R208W突变挑战了这一理论，因为之前在三个不相关的家族中报道过这种突变，并且在四个家族中与无虹膜和非无虹膜表型相关。PAX6具有广泛的表型关联和高度可变的表达，应被视为任何眼部发育异常诊断筛查的候选基因。
Purpose To report on a clinical and genetic investigation of a large, multigenerational South African family of mixed ancestry with autosomal dominant congenital cataracts, coloboma, and nystagmus. Methods Ophthalmic examination was performed in 27 individuals from the same admixed South African family. DNA was sampled from either peripheral blood or buccal swabs in all 27 individuals, and whole genome sequencing was performed in six individuals. Sanger sequencing was used to validate the probable mutation in the remaining family members. Results Twenty-seven family members with 19 affected individuals were included in the study. The predominant phenotype, with highly variable expression, was congenital cataract (14 individuals), posterior segment coloboma (17 individuals), and nystagmus (18 individuals). Other features present included high myopia, microcornea, and strabismus. An R208W mutation in PAX6 (dbSNP rs757259413; HGMD CM930572; NM_000280.3:c.622G>A; NP_000271.1:p.Arg208Trp) was identified as being the most probable pathogenic mutation. Cosegregation of the mutation with the phenotype was confirmed in all 27 family members. Conclusions PAX6 is a highly conserved gene crucial for normal oculogenesis, and although mutations within the gene may cause an array of ocular developmental abnormalities, most are associated with aniridia and aniridia-related ocular defects. The observation that PAX6 aniridia phenotypes are largely associated with nonsense mutations and milder non-aniridia phenotypes with missense mutations suggested that there may be specific genotype–phenotype correlations for the gene. The R208W mutation in PAX6 identified in this family challenges this theory as it has previously been reported in three unrelated families and is associated with aniridia and non-aniridia phenotypes across the four families. PAX6 with its wide phenotypic associations and highly variable expression should be considered a candidate gene in the diagnostic screen for any ocular developmental abnormality.