背景:Alström综合征(ALMS),由ALMS1突变引起的一种罕见的隐性遗传性纤毛病,其特征是视网膜营养不良,儿童肥胖,感觉神经性听力损失,和2型糖尿病。ALMS1中的大多数致病变体是无义和移码突变,这将导致蛋白质过早截断,而拷贝数变异很少报道。
方法:这里,我们为一名10岁的中国女孩提供ALMS。通过全基因组测序证实了潜在的致病遗传变异,实时定量PCR分析,还有Sanger测序.此外,进行断点分析以确定大缺失的确切断点位点并阐明其可能的形成机制。
结果:该患者具有三房内阴险(CTS)结构。遗传分析确定了患者的新型复合杂合变体,由移码变体c.4414_4415delGT组成(p。ALMS1中的V1472Nfs*26)和chr2:73,612,355-73,626,339处的新的大缺失,包括ALMS1基因的外显子1。此外,断点分析显示,由于在断点两端观察到的6bp微同源性(TCCTTC),大缺失可能是通过微同源性介导的末端连接(MMEJ)机制形成的。
结论:在这项研究中,在具有CTS结构的ALMS患者中鉴定出ALMS1基因中的新型复合杂合变体。这些变体的分子确认扩展了ALMS1的突变谱,而患者中ALMS的表现提供了对该综合征的其他临床见解。
BACKGROUND: Alström syndrome (ALMS), a rare recessively inherited ciliopathy caused by mutations in ALMS1, is characterized by retinal dystrophy, childhood obesity, sensorineural hearing loss, and type 2 diabetes mellitus. The majority of pathogenic variants in ALMS1 are nonsense and frameshift mutations, which would lead to premature protein truncation, whereas copy number variants are seldom reported.
METHODS: Herein, we present a 10-year-old Chinese girl with ALMS. The potential causative genetic variant was confirmed through whole genome sequencing, quantitative real-time PCR analysis, and Sanger sequencing. Additionally, breakpoint analysis was performed to determine the exact breakpoint site of the large deletion and elucidate its probable formation mechanism.
RESULTS: The patient had a cor triatriatum sinister (CTS) structure. Genetic analysis identified novel compound heterozygous variants in the patient, consisting of a frameshift variant c.4414_4415delGT (p.V1472Nfs*26) in ALMS1 and a novel large deletion at chr2:73,612,355-73,626,339, which encompasses exon 1 of the ALMS1 gene. Moreover, breakpoint analysis revealed that the large deletion probably formed through the microhomology-mediated end joining (MMEJ) mechanism due to the 6-bp microhomologies (TCCTTC) observed at both ends of the breakpoints.
CONCLUSIONS: In this study, novel compound heterozygous variants in the ALMS1 gene were identified in an ALMS patient with a CTS structure. The molecular confirmation of these variants expands the mutational spectrum of ALMS1, while the manifestation of ALMS in the patient provides additional clinical insights into this syndrome.