O'Connell Mia, Harstad Elizabeth, Aites Jennifer, Hayes Katheryn, Arnett Anne B, Scotellaro Julia, Patel Soleha, Brewster Stephanie J, Barbaresi William, Doan Ryan N
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Division of Genetics & Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
Am J Med Genet A. 2025 Jan;197(1):e63851. doi: 10.1002/ajmg.a.63851. Epub 2024 Aug 20.
Attention-deficit/hyperactivity disorder (ADHD) belongs to a phenotypically broad class of mental health disorders impacting social and cognitive functioning. Despite heritability estimates of 77%-88% and a global prevalence of up to 1 in 20 children, most of the underlying genetic etiology of the disorder remains undiscovered, making it challenging to obtain a clinical molecular genetic diagnosis and to develop new treatments (Biological Psychiatry, 2005, 57, 1313; Psychological Bulletin, 2009, 135, 608; Psychological Medicine, 2014, 44, 2223). Here we report the identification of a novel ultra-rare heterozygous loss-of-function (p.Q1625*) variant in a child with complex ADHD (i.e., comorbid mild intellectual disability [ID]) and a missense (p.G1748R) variant (allele frequency of 4.7 × 10) in a child with primary ADHD (i.e., absence of comorbid autism spectrum disorder [ASD], ID, or syndromic features) both in the SPTBN1 gene. Missense variants in SPTBN1 have been reported in individuals with developmental disorders, language and communication disorders, and motor delays in recent publications (Nature Genetics, 2021, 53, 1006; American Journal of Medical Genetics Part A, 2021, 185, 2037) and ClinVar, though most variants in ClinVar have uncertain disease associations. The functional impact of these 135 variants, including from the current study, were further assessed using prediction scores from the recently developed AlphaMissense tool and benchmarked against published functional studies on a subset of the variants. While heterozygous SPTBN1 variants have recently been associated with neurodevelopmental disorders characterized by global developmental delay, intellectual disability, and behavioral abnormalities, the two patients in the current study expand the phenotypic spectrum to include ADHD in the absence of more severe neurodevelopmental disorders, such as ASD and moderate to severe ID. Furthermore, the culmination of these data with existing reported cases suggests that variation including loss of function and missense events underlie a broader clinical spectrum than previously understood.
注意缺陷多动障碍（ADHD）属于一类表型广泛的心理健康障碍，会影响社会和认知功能。尽管该疾病的遗传度估计为77%-88%，全球患病率高达每20名儿童中就有1名，但该疾病的大多数潜在遗传病因仍未被发现，这使得获得临床分子遗传学诊断和开发新的治疗方法具有挑战性（《生物精神病学》，2005年，第57卷，第1313页；《心理学期刊》，2009年，第135卷，第608页；《心理医学》，2014年，第44卷，第2223页）。在此，我们报告在一名患有复杂ADHD（即合并轻度智力障碍[ID]）的儿童中鉴定出一种新的超罕见杂合功能丧失（p.Q1625*）变异，以及在一名原发性ADHD（即不存在合并自闭症谱系障碍[ASD]、ID或综合征特征）的儿童中鉴定出一种错义（p.G1748R）变异（等位基因频率为4.7×10），这两种变异均在SPTBN1基因中。最近的出版物（《自然遗传学》，2021年，第53卷，第1006页；《美国医学遗传学杂志A辑》，2021年，第185卷，第2037页）以及ClinVar中报道了SPTBN1中的错义变异与发育障碍、语言和沟通障碍以及运动发育迟缓的个体有关，尽管ClinVar中的大多数变异与疾病的关联尚不确定。使用最近开发的AlphaMissense工具的预测分数进一步评估了这些135种变异的功能影响，并与已发表的关于一部分变异的功能研究进行了对比。虽然最近杂合SPTBN1变异与以全球发育迟缓、智力障碍和行为异常为特征的神经发育障碍有关，但本研究中的两名患者将表型谱扩展到包括在没有更严重神经发育障碍（如ASD和中度至重度ID）的情况下的ADHD。此外，这些数据与现有报道病例的汇总表明，包括功能丧失和错义事件在内的变异是比以前所理解的更广泛临床谱的基础。
