Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Karaj, Iran.
Department of Biology, Faculty of Basic Sciences, Semnan University, Semnan, Iran.
BMC Med Genomics. 2023 Feb 24;16(1):33. doi: 10.1186/s12920-023-01467-1.
SALL4, a member of the SALL genes family, encodes a zinc-finger transcriptional factor that either activates or represses gene transcription depending on cell type during embryonic development. SALL4 mutations cause extremely variable conditions including Duane-radial ray (DRR), Okihiro, Holt-oram, Acro-renal ocular and IVIC syndromes, all with autosomal dominant inheritance pattern. However, all these syndromes with different terminologies are actually the same entity termed SALL4 related disorders.
Herein, we examine an Iranian patient suspected to DRR syndrome which has not been previously described in the population. Whole-exome sequencing (WES) was performed to examine pathogenic genes in the proband. Subsequently, Sanger sequencing was used to confirm the mutation found. To elucidate the effects of the identified mutation, clinical data of patient was collected. Morever, the possible impact of the mutation found on the corresponding protein was evaluated using bioinformatics tools. WES identifed a novel de novo heterozygous nonsense mutation in exon 2 of SALL4 gene (c.712 C > T:p.Q238X). Subsequently, segregation and phenotype-genotype correlation analysis as well as in-silico approaches confirmed the autosomal dominance inheritance and disease-causing nature of the identified mutation. In addition, studied patient had features not described previously, including kyphoscoliosis, dimple presacral sinus, barrel chest and artric disc (C6-C7). These manifestations could be additional characteristics of the growing phenotypic spectrum of SALL4 related disorders.
Our findings could extend the pathogenic mutations and phenotypic spectrum of SALL4 related disorders. Such reports can also aid to conduct genetic counseling, prenatal diagnosis and clinical management for individuals at high risk of SALL4 related disorders.
SALL4 是 SALL 基因家族的成员，编码一种锌指转录因子，在胚胎发育过程中根据细胞类型激活或抑制基因转录。SALL4 突变导致多种不同的病症，包括 Duane-radial 射线（DRR）、Okihiro、Holt-oram、acro-renal 眼和 IVIC 综合征，均为常染色体显性遗传。然而，所有这些具有不同术语的综合征实际上都是同一实体，称为 SALL4 相关疾病。
本文中，我们检查了一名伊朗患者，怀疑患有 DRR 综合征，该患者在该人群中以前尚未描述过。对先证者进行全外显子组测序（WES）以检查致病基因。随后，使用 Sanger 测序来确认发现的突变。为了阐明鉴定突变的影响，收集了患者的临床数据。此外，使用生物信息学工具评估了发现的突变对相应蛋白的可能影响。WES 在 SALL4 基因的外显子 2 中发现了一个新的从头杂合无义突变（c.712C>T:p.Q238X）。随后，分离和表型-基因型相关性分析以及计算机模拟方法证实了鉴定突变的常染色体显性遗传和致病性质。此外，研究患者具有以前未描述的特征，包括脊柱后凸侧凸、骶前凹窝、桶状胸和颈椎间盘（C6-C7）。这些表现可能是 SALL4 相关疾病不断增长的表型谱的附加特征。
我们的研究结果可以扩展 SALL4 相关疾病的致病突变和表型谱。此类报告还可以帮助对 SALL4 相关疾病高风险个体进行遗传咨询、产前诊断和临床管理。
