Objective: The article aims to provide genetic counseling to a family with two children who were experiencing growth and developmental delays.Methods: Clinical information of the proband was collected. Peripheral blood was collected from core family members to identify the initial reason for growth and developmental delays by whole exome sequencing (WES) and Sanger sequencing. To ascertain the consequences of the newly discovered variants, details of the variants detected were analyzed by bioinformatic tools. Furthermore, we performed in vitro experimentation targeting SNX14 gene expression to confirm whether the variants could alter the expression of SNX14.Results: The proband had prenatal ultrasound findings that included flattened frontal bones, increased interocular distance, widened bilateral cerebral sulci, and shortened long bones, which resulted in subsequent postnatal developmental delays. The older sister also displayed growth developmental delays and poor muscle tone. WES identified compound heterozygous variants of c.712A>T (p.Arg238Ter) and .2744A>T (p.Gln915Leu) in the SNX14 gene in these two children. Both are novel missense variant that originates from the father and mother, respectively. Sanger sequencing confirmed this result. Following the guideline of the American College of Medical Genetics and Genomics (ACMG), the SNX14 c.712A>T (p.Arg238Ter) variant was predicted to be pathogenic (P), while the SNX14 c.2744A>T (p.Gln915Leu) variant was predicted to be a variant of uncertain significance (VUS). The structural analysis revealed that the c.2744A>T (p.Gln915Leu) variant may impact the stability of the SNX14 protein. In vitro experiments demonstrated that both variants reduced SNX14 expression.Conclusion: The SNX14 gene c.712A>T (p.Arg238Ter) and c.2744A>T (p.Gln915Leu) were identified as the genetic causes of growth and developmental delay in two affected children. This conclusion was based on the clinical presentations of the children, structural analysis of the mutant protein, and in vitro experimental validation. This discovery expands the range of SNX14 gene variants and provides a foundation for genetic counseling and guidance for future pregnancies in the affected children’s families.

中文翻译：

---

SNX14 基因复合杂合突变导致常染色体隐性遗传脊髓小脑共济失调 20

目的：本文旨在为一个有两个孩子的生长发育迟缓的家庭提供遗传咨询。方法：收集先证者的临床信息。从核心家庭成员采集外周血，通过全外显子组测序（WES）和桑格测序来确定生长和发育延迟的最初原因。为了确定新发现的变异的后果，通过生物信息学工具分析了检测到的变异的详细信息。此外，我们还进行了体外实验目标SNX14基因表达以确认变体是否可以改变SNX14结果：先证者产前超声检查结果包括额骨扁平、眼距增大、双侧脑沟增宽、长骨缩短，导致出生后发育迟缓。姐姐还表现出生长发育迟缓和肌张力差。 WES 鉴定了 c.712A>T (p.Arg238Ter) 和 .2744A>T (p.Gln915Leu) 的复合杂合变体SNX14这两个孩子的基因。两者都是新颖的错义变体，分别源自父亲和母亲。桑格测序证实了这一结果。遵循美国医学遗传学和基因组学学院 (ACMG) 的指导方针，SNX14c.712A>T (p.Arg238Ter) 变体被预测为致病性 (P)，而SNX14c.2744A＞T(p.Gln915Leu)变体被预测为意义不确定的变体(VUS)。结构分析表明，c.2744A>T (p.Gln915Leu) 变体可能影响稳定性SNX14蛋白质。体外实验表明，两种变体都减少了SNX14结论：SNX14基因c.712A>T (p.Arg238Ter)和c.2744A>T (p.Gln915Leu)被确定为两个受影响儿童生长和发育迟缓的遗传原因。这一结论是基于儿童的临床表现、突变蛋白的结构分析以及体外实验验证。这一发现扩大了范围SNX14基因变异，并为受影响儿童家庭的未来怀孕提供遗传咨询和指导奠定基础。