SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.

SOX6属于 20 个SRY相关的含 HMG 盒 (SOX) 基因家族，这些基因编码在许多发育和成人过程中控制细胞命运和分化的转录因子。对于SOX6，这些过程包括但不限于神经发生和骨骼发生。一半 SOX 基因的变异已被证明会导致严重的发育和成人综合征，称为 SOXopathies。我们在此提供了SOX6变体也引起 SOXopathy 的证据。使用临床和遗传数据，我们确定了 19 名携带各种类型SOX6的个体改变和表现出发育迟缓和/或智力残疾；这些人来自17个无关的家庭。此外，不稳定的特征包括注意力缺陷/多动障碍 (ADHD)、自闭症、轻度面部畸形、颅缝早闭和多发性骨软骨瘤。所有变体都是杂合的。十四个是从头，一个是从马赛克父亲那里继承的，两个家庭的四个后代有一个父系遗传的变异。预计基因内微缺失、平衡结构重排、移码和无义变体会使SOX6失活变异等位基因。四种错义变体出现在进化上高度保守的残基和蛋白质区域。在 gnomAD 对照队列中未检测到这些变体，并且预计氨基酸替换会造成破坏。其中两个变体位于 HMG 结构域并在体外消除 SOX6 转录活性。没有发现明确的基因型-表型相关性。综上所述，这些发现一致认为SOX6单倍体不足会导致神经发育性 SOX 病变，通常包括 ADHD 和异常骨骼和其他特征。