背景:无眼症和小眼症是严重的发育性眼部疾病,影响眼球的大小,可以是单侧或双侧的。该疾病以综合征和非综合征形式存在。它是由染色体畸变引起的基因,拷贝数变异和单基因突变,以及非遗传因素,如病毒感染,维生素A缺乏和怀孕期间接触酒精或药物。迄今为止,30多个具有不同遗传模式的基因被鉴定为导致无眼和小眼症。
方法:在本研究中,对6名患有无眼和小眼症和/或其他智力障碍表型的患者进行了临床和遗传分析,巴基斯坦一个近亲家庭的发育迟缓和脑瘫。进行全外显子组测序,然后通过Sanger测序进行变体优先化和验证的数据分析,以鉴定致病变体。美国医学遗传学和基因组学学院(ACMG)指南用于对优先变体的临床解释进行分类。
结果:临床调查显示受影响的个体患有无眼炎。其中三名患者表现出智力障碍的额外表型,发育迟缓和其他神经系统症状。家族中受影响成员的DNA样品的全外显子组测序鉴定了所有受影响个体共有的叉头盒E3(FOXE3)基因中的新型纯合终止增益突变(NM_012186:c.106G>T:p.Glu36*)。此外,患者分离其他表型的痉挛性截瘫,智力残疾,听力损失和小头畸形在AP4M1中显示出额外的纯合序列变异(NM_004722:c.953G>A:p.Arg318Gln)。Sanger测序验证了受影响家族中鉴定的变体的正确分离。ACMG指南预测变体是致病性的。
结论:我们调查了第一例由FOXE3和AP4M1变异体引起的综合征性无眼。本发现有助于理解基因突变在无眼综合征形式中的病理作用。此外,这项研究表明,在具有不同表型的患者的家庭中寻找第二变异的鉴定。此外,这些发现将有助于临床遗传学家,遗传咨询师和受影响的家庭在产前检查方面,计划生育和遗传咨询。
BACKGROUND: Anophthalmia and microphthalmia are severe developmental ocular disorders that affect the size of the ocular globe and can be unilateral or bilateral. The disease is found in syndromic as well as non-syndromic forms. It is genetically caused by chromosomal aberrations, copy number variations and single gene mutations, along with non-genetic factors such as viral infections, deficiency of vitamin A and an exposure to alcohol or drugs during pregnancy. To date, more than 30 genes having different modes of inheritance patterns are identified as causing anophthalmia and microphthalmia.
METHODS: In the present study, a clinical and genetic analysis was performed of six patients with anophthalmia and microphthalmia and/or additional phenotypes of intellectual disability, developmental delay and cerebral palsy from a large consanguineous Pakistani family. Whole exome sequencing followed by data analysis for variants prioritization and validation through Sanger sequencing was performed to identify the disease causing variant(s). American College of Medical Genetics and Genomics (ACMG) guidelines were applied to classify clinical interpretation of the prioritized variants.
RESULTS: Clinical investigations revealed that the affected individuals are afflicted with anophthalmia. Three of the patients showed additional phenotype of intellectual disability, developmental delays and other neurological symptoms. Whole exome sequencing of the DNA samples of the affected members in the family identified a novel homozygous stop gain mutation (NM_012186: c.106G>T: p.Glu36*) in Forkhead Box E3 (
FOXE3) gene shared by all affected individuals. Moreover, patients segregating additional phenotypes of spastic paraplegia, intellectual disability, hearing loss and microcephaly showed an additional homozygous sequence variant (NM_004722: c.953G>A: p.Arg318Gln) in AP4M1. Sanger sequencing validated the correct segregation of the identified variants in the affected family. ACMG guidelines predicted the variants to be pathogenic.
CONCLUSIONS: We have investigated first case of syndromic anophthalmia caused by variants in the
FOXE3 and AP4M1. The present findings are helpful for understanding pathological role of the mutations of the genes in syndromic forms of anophthalmia. Furthermore, the study signifies searching for the identification of second variant in families with patients exhibiting variable phenotypes. In addition, the findings will help clinical geneticists, genetic counselors and the affected family with respect to prenatal testing, family planning and genetic counseling.