Li Ming, Lin Jingqi, Fei Hongjun, Liu Jinyu, Chen Yiyao, Han Xu, Wang Yanlin, Wang Jian, Hua Renyi, Li Shuyuan, Li Niu
The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China.
Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, 200030, China.
Orphanet J Rare Dis. 2025 Feb 3;20(1):48. doi: 10.1186/s13023-024-03510-5.
To determine the pathogenicity of a novel splicing variant in the SMARCC2 gene identified from a pair of adult male monozygotic twins with neurodevelopmental disorder, and to investigate the genotype-phenotype characteristics associated with SMARCC2 variants.
Whole-exome sequencing (WES) was conducted on the proband, and candidate variants were validated using Sanger sequencing within the family. The effect of the identified splicing variant on SMARCC2 mRNA processing was analyzed using reverse transcription PCR (RT-PCR) and TA-clone sequencing using samples derived from the proband. The clinical features of the twins were collected and compared with the previously reported patients.
The twin adult males displayed comparable phenotypes, characterized by moderate developmental delay, intellectual and language delays, dense hair, craniofacial anomalies, scoliosis, cryptorchidism, hypotonia, behavioral abnormalities, allergic purpura and eczema, and drug allergies. WES unveiled a previously unreported heterozygous splice variant of the SMARCC2 gene (NM_003075.3: c.1496 + 1G > T). Sanger sequencing confirmed that the variant was de novo in both patients. TA-clone sequencing of the RT-PCR fragments showed that the canonical splicing variant resulted in two distinct aberrant splicing events in SMARCC2 mRNA. Specifically, approximately 80% of the mutant clones resulted from the in-frame insertion of 126 bases in intron 16, while the remaining 20% showed an in-frame deletion of exon 16 (c.1383_1496del). Crystal structure analysis showed that both in-frame alterations hindered the proper formation of the alpha helix structure within the SMARCC2 protein. An analysis of genotype-phenotype correlations indicated that our patients displayed neurological phenotypes of greater severity than those observed in patients with truncating variants, instead aligning more closely with the characteristics of the missense/in-frame variant group.
We identified and reported a pair of twins suffering from syndromic neurodevelopmental disorders caused by a novel splicing variant of SMARCC2. Our findings further reinforce the notion that individuals harboring missense/in-frame variants in SMARCC2 are prone to experiencing more severe neurological phenotypes.
为确定从一对患有神经发育障碍的成年男性同卵双胞胎中鉴定出的SMARCC2基因新型剪接变体的致病性，并研究与SMARCC2变体相关的基因型-表型特征。
对先证者进行全外显子组测序（WES），并在家族内使用桑格测序法验证候选变体。使用逆转录PCR（RT-PCR）和来自先证者的样本进行TA克隆测序，分析鉴定出的剪接变体对SMARCC2 mRNA加工的影响。收集双胞胎的临床特征，并与先前报道的患者进行比较。
这对成年男性双胞胎表现出相似的表型，其特征为中度发育迟缓、智力和语言发育迟缓、毛发浓密、颅面畸形、脊柱侧弯、隐睾、肌张力减退、行为异常、过敏性紫癜和湿疹，以及药物过敏。WES揭示了SMARCC2基因一个先前未报道的杂合剪接变体（NM_003075.3: c.1496+1G>T）。桑格测序证实该变体在两名患者中均为新发。RT-PCR片段的TA克隆测序表明，该典型剪接变体在SMARCC2 mRNA中导致了两种不同的异常剪接事件。具体而言，约80%的突变克隆是由于内含子16中126个碱基的框内插入，而其余20%则显示外显子16的框内缺失（c.1383_1496del）。晶体结构分析表明，这两种框内改变均阻碍了SMARCC2蛋白内α螺旋结构的正确形成。基因型-表型相关性分析表明，我们的患者表现出比截短变体患者更严重的神经学表型，而是与错义/框内变体组的特征更密切相关。
我们鉴定并报告了一对由SMARCC2新型剪接变体引起的综合征性神经发育障碍双胞胎。我们的发现进一步强化了这样一种观点，即SMARCC2中携带错义/框内变体的个体更容易出现更严重的神经学表型。
