Dudakova Lubica, Skalicka Pavlina, Ulmanová Olga, Hlozanek Martin, Stranecky Viktor, Malinka Frantisek, Vincent Andrea L, Liskova Petra
Research Unit for Rare Diseases, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 2, 128 08 Prague, Czech Republic.
Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, U Nemocnice 2, 128 08 Prague, Czech Republic.
J Ophthalmol. 2020 May 10;2020:6807809. doi: 10.1155/2020/6807809. eCollection 2020.
The aim of the study was to identify the molecular genetic cause of two different Mendelian traits with ocular involvement present in the members of a single consanguineous Czech Roma family.
We have performed ocular examination and review of medical records in two individuals diagnosed with nanophthalmos (proband and her father) and one individual followed for bilateral congenital cataract and microcornea (uncle of the proband). DNA of subjects with nanophthalmos was analysed by exome sequencing. Sanger sequencing was applied for targeted screening of potentially pathogenic variants and to follow segregation of identified variants within the family.
A homozygous variant c.1509G>C; p.(Met503Ile), in was found in the two individuals affected with nanophthalmos. The change was absent from the gnomAD dataset, but two out of 118 control Roma individuals were also shown to be heterozygous carriers. Analysis of single nucleotide polymorphisms in linkage disequilibrium with the c.1509G>C in suggested a shared chromosomal segment. The nanophthalmos phenotype, characterized in detail in the younger individual, encompassed bilateral corneal steepening, retinal folds, buried optic head drusen, and restricted visual fields, but no signs of retinal dystrophy. A known pathogenic founder variant c.863+389C>T in a homozygous state was identified in the other family member confirming the suspected diagnosis of congenital cataracts, facial dysmorphism, and demyelinating neuropathy syndrome.
Herein, we report the first occurrence of nanophthalmos in the Roma population. We have identified pseudodominant inheritance for this phenotype caused by a novel variant in , representing a possible founder effect. Despite advances in genetic technologies such as exome sequencing, careful phenotype evaluation in patients from an isolated population, along with an awareness of population-specific founder effects, is necessary to ensure that accurate molecular diagnoses are made.
本研究的目的是确定一个近亲通婚的捷克罗姆人家庭中两名患有眼部相关孟德尔性状个体的分子遗传学病因。
我们对两名被诊断为小眼球症的个体（先证者及其父亲）以及一名患有双侧先天性白内障和小角膜的个体（先证者的叔叔）进行了眼部检查并查阅了病历。对患有小眼球症的个体进行外显子组测序分析其DNA。采用桑格测序法对潜在致病变异进行靶向筛查，并追踪所鉴定变异在家族中的分离情况。
在两名患有小眼球症的个体中发现了一个纯合变异c.1509G>C；p.(Met503Ile)。gnomAD数据集中未出现该变异，但在118名罗姆对照个体中有两名也为该变异的杂合携带者。与该基因中c.1509G>C处于连锁不平衡状态的单核苷酸多态性分析表明存在一个共享的染色体片段。在较年轻个体中详细描述的小眼球症表型包括双侧角膜陡峭、视网膜皱褶、埋藏性视盘玻璃膜疣和视野受限，但无视网膜营养不良的迹象。在另一名家族成员中鉴定出一个已知的致病性始祖变异c.863+389C>T处于纯合状态，证实了先天性白内障、面部畸形和脱髓鞘性神经病综合征的疑似诊断。
在此，我们报告了罗姆人群中首次出现小眼球症。我们已确定该表型由该基因中的一个新变异导致的假显性遗传，这可能代表一种始祖效应。尽管外显子组测序等基因技术取得了进展，但对来自孤立人群的患者进行仔细的表型评估以及了解特定人群的始祖效应，对于确保做出准确的分子诊断是必要的。
