Goolam Saadiah, Carstens Nadia, Ross Mark, Bentley David, Lopes Margarida, Peden John, Kingsbury Zoya, Tsogka Eleni, Barlow Robyn, Carmichael Trevor R, Ramsay Michèle, Williams Susan E
Division of Ophthalmology, Department of Neurosciences, University of Witwatersrand, Johannesburg, South Africa.
Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, South Africa.
Mol Vis. 2018 Jun 9;24:407-413. eCollection 2018.
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.
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.
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 (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.
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 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 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. with its wide phenotypic associations and highly variable expression should be considered a candidate gene in the diagnostic screen for any ocular developmental abnormality.
报告对一个具有常染色体显性遗传性先天性白内障、缺损和眼球震颤的南非多代混合血统大家庭进行的临床和基因研究。
对来自同一个南非混合血统家庭的27名个体进行眼科检查。从所有27名个体的外周血或口腔拭子中采集DNA，并对6名个体进行全基因组测序。采用桑格测序法验证其余家庭成员中可能存在的突变。
该研究纳入了27名家庭成员，其中19名个体患病。主要表型为先天性白内障（14例）、后段缺损（17例）和眼球震颤（18例），表现高度可变。其他特征包括高度近视、小角膜和斜视。在（dbSNP rs757259413；HGMD CM930572；NM_000280.3:c.622G>A；NP_000271.1:p.Arg208Trp）中发现的R208W突变被确定为最可能的致病突变。在所有27名家庭成员中均证实该突变与表型共分离。
是正常眼发育所必需的高度保守基因，虽然该基因内的突变可能导致一系列眼部发育异常，但大多数与无虹膜及无虹膜相关的眼部缺陷有关。无虹膜表型主要与无义突变相关，而较轻的非无虹膜表型与错义突变相关，这一观察结果表明该基因可能存在特定的基因型-表型相关性。该家族中发现的R208W突变对这一理论提出了挑战，因为此前在三个无亲缘关系的家族中也有报道，且在这四个家族中与无虹膜和非无虹膜表型均相关。鉴于其广泛的表型关联和高度可变的表达，在任何眼部发育异常的诊断筛查中都应将其视为候选基因。
