背景:WarburgMicro(WARBM)综合征是一种罕见的异质性隐性遗传性疾病,其特征是眼部,神经学,和内分泌问题。迄今为止,已经确定了四个基因的致病变异导致这种综合征;其中,RAB3GAP1变体是最常见的。对农村人口中的WARBM综合征知之甚少。
目的:本研究旨在调查普什图家族中WARBM综合征的遗传学基础,该家族有两名巴基斯坦患者。患者出现痉挛型双瘫,严重的智力残疾,小眼症,微角膜,先天性白内障,视神经萎缩,和性腺功能减退.
方法:磁共振成像(MRI)分析显示明显的脑萎缩,包括call体发育不全和多囊。外显子组测序和随后的过滤鉴定了一个新的纯合错义变体NM_001172435:c.2891A>G,p.Gln964Arg中的RAB3GAP1基因。该变体已得到验证,它的隔离得到了证实,通过Sanger测序。
结果:多种预测工具评估此变体具有破坏性,和蛋白质的结构分析表明,突变氨基酸残基影响与相邻原子的极性接触。它非常罕见,在所有公共数据库中都不存在。一起来看,这些观察结果表明,这种变异是我们家庭中Micro综合征的基础,对管理和计划生育极为重要。
结论:对这种极其罕见的变异体的鉴定扩展了微综合征的突变谱。筛选更多的家庭,尤其是在代表性不足的人群中,将有助于揭示这种综合征背后的突变谱。
BACKGROUND: Warburg Micro (WARBM) syndrome is a rare heterogeneous recessive genetic disorder characterized by ocular, neurological, and endocrine problems. To date, disease-causing variants in four genes have been identified to cause this syndrome; of these, RAB3GAP1 variants are the most frequent. Very little is known about WARBM syndrome in rural populations.
OBJECTIVE: This study aims to investigate the genetics underpinnings of WARBM syndrome in a Pashtun family with two patients from Pakistan. The patients presented with spastic diplegia, severe intellectual disability, microphthalmia, microcornea, congenital cataracts, optic atrophy, and hypogonadism.
METHODS: Magnetic resonance imaging (MRI) analysis revealed pronounced cerebral atrophy including corpus callosum hypoplasia and polymicrogyria. Exome sequencing and subsequent filtering identified a novel homozygous missense variant NM_001172435: c.2891A>G, p.Gln964Arg in the RAB3GAP1 gene. The variant was validated, and its segregation confirmed, by Sanger sequencing.
RESULTS: Multiple prediction tools assess this variant to be damaging, and structural analysis of the protein shows that the mutant amino acid residue affects polar contact with the neighboring atoms. It is extremely rare and is absent in all the public databases. Taken together, these observations suggest that this variant underlies Micro syndrome in our family and is extremely important for management and family planning.
CONCLUSIONS: Identification of this extremely rare variant extends the mutations spectrum of Micro syndrome. Screening more families, especially in underrepresented populations, will help unveil the mutation spectrum underlying this syndrome.