The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.

中文翻译：

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KAT6B 疾病谱的新变异扩展了我们对临床表现和分子机制的了解

与赖氨酸乙酰转移酶 6B（KAT6B，又名MORF，MYST4 ）中的致病变异相关的表型变异性导致几种相互关联的综合征，包括 Say-Barber-Biesecker-Young-Simpson 综合征和生殖髌骨综合征。在这里，我们展示了代表 10 种新型KAT6B变体的 20 个新案例。这些患者表现出一系列临床表型，包括智力残疾、行动不便和语言困难、颅面畸形和骨骼异常。鉴于先前为KAT6B描述的功能范围相关综合征，我们已经确定了其他表型，包括对圆锥角膜的担忧、对光或噪音的敏感性、反复感染以及比以前报道的骨折数量更多。我们对临床医生进行了调查，以定性评估家庭在诊断后与遗传咨询师接触的方式。我们发现 56% (10/18) 的个体在 2 岁（中位年龄 = 1.96 岁）之前接受诊断，这使得解决未来并发症的难度很大，因为可获得的信息有限且表型严重程度很高。我们使用 CRISPR 将截短变体引入KAT6B模型细胞系中的基因，并进行染色质可及性和转录组测序，以确定关键的失调通路。这项研究扩大了临床范围，并解决了KAT6B相关疾病患者管理和遗传咨询方面的挑战。