Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.
Birth Defects Res. 2022 Aug 1;114(13):759-767. doi: 10.1002/bdr2.2058. Epub 2022 Jun 18.
Xia-Gibbs syndrome (XGS) is a rare neurodevelopmental disorder caused by pathogenic variants in the AT-hook DNA-binding motif-containing 1 gene (AHDC1), encoding a protein with a crucial role in transcription and epigenetic regulation, axonogenesis, brain function, and neurodevelopment. AHDC1 variants possibly act through a dominant-negative mechanism and may interfere with DNA repair processes, leading to genome instability and impaired DNA translesion repair. Variants affecting residues closer to the N-terminal are thought to determine a milder phenotype with better cognitive performances. However, clean-cut genotype-phenotype correlations are still lacking.
In this study, we investigated five subjects with XGS in whom exome sequencing led to the identification of five novel de novo pathogenic variants in AHDC1. All variants were extremely rare and predicted to cause a loss of protein function. The phenotype of the reported patients included developmental delay, hypotonia, and distinctive facial dysmorphisms. Additionally, uncommon clinical features were observed, including congenital hypothyroidism and peculiar skeletal abnormalities.
In this study, we report uncommon XGS features associated with five novel truncating variants in AHDC, thus expanding the genotype and phenotypic spectrum of this complex condition. We also compared our cases to previously reported cases, discussing the current status of genotype-phenotype correlations in XGS.
Xia-Gibbs 综合征（XGS）是一种罕见的神经发育障碍，由 AT-hook DNA 结合基序包含 1 基因（AHDC1）的致病性变异引起，该基因编码一种在转录和表观遗传调控、轴突发生、大脑功能和神经发育中起关键作用的蛋白质。AHDC1 变异可能通过显性负性机制起作用，并可能干扰 DNA 修复过程，导致基因组不稳定和 DNA 跨损伤修复受损。影响更接近 N 端的残基的变异被认为决定了更温和的表型，具有更好的认知表现。然而，仍然缺乏明确的基因型-表型相关性。
在这项研究中，我们研究了五名患有 XGS 的受试者，外显子组测序导致在 AHDC1 中鉴定出五个新的从头致病性变异。所有变异都极为罕见，预计会导致蛋白质功能丧失。报告患者的表型包括发育迟缓、低张力和独特的面部畸形。此外，还观察到不常见的临床特征，包括先天性甲状腺功能减退和特殊的骨骼异常。
在这项研究中，我们报告了与五个新的截断变异相关的不常见 XGS 特征，从而扩展了这种复杂疾病的基因型和表型谱。我们还将我们的病例与以前报告的病例进行了比较，讨论了 XGS 中基因型-表型相关性的现状。
