Department of Neuropsychology, Kennedy Krieger Institute, 1750 E. Fairmount Ave, Baltimore, USA.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, USA.
Orphanet J Rare Dis. 2024 May 13;19(1):196. doi: 10.1186/s13023-024-03175-0.
KAT6A (Arboleda-Tham) syndrome is a Mendelian disorder of the epigenetic machinery caused by pathogenic variants in the lysine acetyltransferase 6 A (KAT6A) gene. Intellectual disability and speech/language impairment (e.g., minimally verbal) are common features of the disorder, with late-truncating variants associated with a more severe form of intellectual disability. However, much of the cognitive phenotype remains elusive given the dearth of research.
This study examined non-verbal and social skills of 15 individuals with molecularly-confirmed diagnoses of KAT6A syndrome (Mean age = 10.32 years, SD = 4.12). Participants completed select subtests from the DAS-II, the NEPSY-II, and the Beery Buktenica Developmental Test of Visual Motor Integration 6th Edition, and their caregivers completed an assortment of behavior rating inventories.
Findings suggest global cognitive impairment with nonverbal cognition scores similar to those for receptive language. Autism-related features, particularly restricted interests and repetitive behaviors, and broad adaptive deficits were common in our sample juxtaposed with a relatively strong social drive and low frequency of internalizing and externalizing behavioral problems. A general trend of lower performance scores on nonverbal and receptive language measures was observed among those with protein-truncating variants vs. missense variants; however, no effect was observed on caregiver rating inventories of daily behaviors. Late and early truncating variants yielded comparable neuropsychological profiles.
Overall, study results show the cognitive phenotype of KAT6A syndrome includes equally impaired nonverbal cognition and receptive language functioning, paired with relatively intact social drive and strengths in behavior regulation. Emergent genotype-phenotype correlations suggest cognition may be more affected in protein-truncating than missense mutations although similar neurobehavioral profiles were observed.
KAT6A（Arboleda-Tham）综合征是一种表观遗传机制的孟德尔疾病，由赖氨酸乙酰转移酶 6A（KAT6A）基因的致病性变异引起。智力残疾和言语/语言障碍（例如，几乎不能说话）是该疾病的常见特征，具有晚期截断变异的个体与更严重形式的智力残疾相关。然而，由于研究匮乏，大部分认知表型仍然难以捉摸。
本研究检查了 15 名经分子确诊患有 KAT6A 综合征的个体的非言语和社交技能（平均年龄=10.32 岁，标准差=4.12）。参与者完成了 DAS-II、NEPSY-II 和 Beery Buktenica 视觉运动整合发展测试第 6 版的选择子测验，他们的照顾者完成了一系列行为评定量表。
研究结果表明存在整体认知障碍，非言语认知得分与接受性语言相似。在我们的样本中，自闭症相关特征，特别是受限的兴趣和重复行为，以及广泛的适应能力缺陷很常见，而社交驱动力相对较强，内化和外化行为问题的频率较低。与错义变异相比，具有蛋白质截断变异的个体在非言语和接受性语言测量上的表现得分呈下降趋势；然而，在日常行为的照顾者评定量表上没有观察到这种效应。晚期和早期截断变异产生了相似的神经心理学特征。
总的来说，研究结果表明 KAT6A 综合征的认知表型包括同样受损的非言语认知和接受性语言功能，同时伴有相对完整的社交驱动力和行为调节能力。新兴的基因型-表型相关性表明，在蛋白质截断变异中认知可能比错义突变受到更大影响，尽管观察到相似的神经行为特征。
