In medical genetics even defined clinical syndromes with clear etiology and uniform underlying genetic cause can show large variance in signs and symptoms. This and other factors, like clinician's experience, onsite testing availability or country's reimbursement system influence speed and possibilities to provide diagnoses to patients and their families (Nguyen et al., 2012). Such hurdles are especially true for patients with small supernumerary marker chromosomes (sSMCs). sSMCs are detected by banding cytogenetics in correspondingly specialized laboratories, most often in infertile patients or such with clear clinical abnormalities (Liehr, 2021). Even though several sSMC-related syndromes are defined, between 1% and 30% of such sSMC carriers show no (or only mild) symptoms, most likely due to mosaicism (Iourov et al., 2019; Liehr, 2021; Liehr & Al-Rikabi, 2019). This kind of variance is also known for cat-eye syndrome (CES) patients, presenting an sSMC derived from chromosome 22, first reported in 1965 (OMIM; #115470). Usually CES patients have a karyotype 47,XN,+inv dup(22)(q11.2), leading to a partial tetrasomy of 22pter to 22q11.2. According to literature CES patients have a typical face with coloboma, preauricular pits, and anal atresia. However, the latter three conduction symptoms can be even completely absent (Liehr, 2021; Liehr & Al-Rikabi, 2019).

CES patients may not have a diagnosis either due to (i) lack of diagnostic capabilities or (ii) as the local diagnostic capabilities are even too advanced. (i) Most of mankind lives in countries with underdeveloped medical systems, where CES patients may in best case get a karyotype, an sSMC is detected, but there are no financial means to further characterize its origin and content (Liehr et al., 2018). (ii) In countries with better medical systems sSMC cases can be solved and CES patients with symptoms will get their diagnoses. In case of mild symptoms due to sSMC mosaicism or in sSMC causing infertility, standard clinical practice tests such cases by molecular karyotyping and/or next-generation sequencing; here the chance to miss (euchromatic parts of) sSMC is ~80% (Liehr & Hamid Al-Rikabi, 2018). If in such a case banding cytogenetics as bases test has been skipped, (mosaic) sSMCs are missed and/or results misinterpreted: the centromere-near tetrasomy 22 may be interpreted as less harmful partial trisomy or intrachromosomal duplication.

A way to overcome these hurdles is applying next-generation phenotyping (NGP) approaches; therefore just portrait 2D facial photos of a patient are needed, being analyzed by computer vision, and deep learning algorithms that suggest suspected clinical diagnoses (Liehr et al., 2018). Recently we applied NGP with an online tool called Face2Gene (FDNA inc. USA) for the identification of facial phenotypes of two other sSMC-associated syndromes (Emanuel and Pallister Killian syndrome) and published the results (Liehr et al., 2018). Here, we present the extension of this approach to CES.

The study (Ethical commission, Friedrich Schiller Universität Jena, Germany—#4738-03/16 approved) was based on anonymized frontal images (facial gestalt), collected from individuals having either a definite CES diagnosis or considered as clinically normal. Forty-two images from 27 CES-patients between 0 and 40 years of age, and 42 images of matched controls were applied (Figure 1). The separation quality (CES vs. controls) was evaluated by creating composite images of both groups (Figure 1a) and measuring the Area Under the Curve (AUC = 0.89) of the receiver operating characteristic (ROC) curve (Figure 1b) as previously described(Liehr et al., 2018). A significant separation between both groups (p < 0.0001) leading us to the conclusion that the algorithms can identify the facial phenotype of CES patients, and thus help guide clinicians to the correct type of further laboratory testing needed.

Even though today next-generation sequencing technologies with DNA-variant interpretations are clearly “en vogue,” these are not able to solve all problems of medical genetics. sSMCs are evidence proving that cytogenetics still has its place in the concert of cytogenomic approaches. Moreover, NGP technologies, such as the one described here is another, new player in cytogenomics, which needs more attention—more such syndromes need to be included.

在医学遗传学中，即使是具有明确病因和统一潜在遗传原因的临床综合征也可能在体征和症状上表现出很大差异。这个和其他因素，如临床医生的经验、现场测试的可用性或国家的报销系统会影响向患者及其家人提供诊断的速度和可能性（Nguyen 等人，2012 年）。对于具有小的多生标记染色体 (sSMCs) 的患者而言，此类障碍尤其如此。sSMC 通过在相应专业实验室进行细胞遗传学条带检测，最常见于不育患者或具有明显临床异常的患者 (Liehr, 2021）。尽管定义了几种 sSMC 相关综合征，但 1% 到 30% 的此类 sSMC 携带者没有（或仅有轻微）症状，很可能是由于嵌合现象（Iourov 等人，2019 年；Liehr，2021 年；Liehr & Al-里卡比，2019 年）。这种变异在猫眼综合征 (CES) 患者中也很常见，表现为 22 号染色体衍生的 sSMC，于 1965 年首次报道 (OMIM;#115470)。通常 CES 患者的核型为 47,XN,+inv dup(22)(q11.2)，导致 22pter 到 22q11.2 的部分四体。据文献报道，CES 患者有典型的面部缺损、耳前凹陷和肛门闭锁。然而，后三种传导症状甚至可以完全不存在 (Liehr, 2021 ; Liehr & Al-Rikabi, 2019）。

CES 患者可能由于 (i) 缺乏诊断能力或 (ii) 由于本地诊断能力过于先进而无法得到诊断。(i) 大多数人类生活在医疗系统不发达的国家，CES 患者在最好的情况下可能会获得核型，检测到 sSMC，但没有财务手段来进一步表征其来源和内容（Liehr 等，2018）。(ii) 在医疗系统较好的国家，sSMC 病例可以得到解决，有症状的 CES 患者将得到诊断。如果由于 sSMC 嵌合或 sSMC 导致不育而出现轻微症状，标准临床实践会通过分子核型分析和/或下一代测序对此类病例进行测试；这里错过（常色部分）sSMC 的机会约为 80% (Liehr & Hamid Al-Rikabi,2018 年）。如果在这种情况下，将带状细胞遗传学作为碱基测试被跳过，（马赛克）sSMC 被遗漏和/或结果被误解：着丝粒附近的 22 号四体可能被解释为危害较小的部分三体或染色体内重复。

克服这些障碍的一种方法是应用下一代表型 (NGP) 方法；因此，只需要患者的肖像 2D 面部照片，通过计算机视觉和深度学习算法进行分析，从而提出可疑的临床诊断（Liehr 等人，2018 年）。最近，我们将 NGP 与名为 Face2Gene (FDNA inc. USA) 的在线工具应用于识别其他两种 sSMC 相关综合征（Emanuel 和 Pallister Killian 综合征）的面部表型并公布了结果（Liehr 等人，2018 年）。在这里，我们将这种方法扩展到 CES。

该研究（伦理委员会，Friedrich Schiller Universität Jena，Germany—#4738-03/16 批准）基于匿名正面图像（面部格式塔），收集自具有明确 CES 诊断或被认为临床正常的个体。应用了来自 27 名 0 至 40 岁的 CES 患者的 42 张图像，以及 42 张匹配对照的图像（图 1）。如前所述，通过创建两组的合成图像（图 1a）和测量接收器操作特性（ROC）曲线（图 1b）的曲线下面积（AUC = 0.89）来评估分离质量（CES 与对照） （Liehr 等人，2018 年）。两组之间的显着分离（p < 0.0001）使我们得出结论，该算法可以识别 CES 患者的面部表型，从而帮助指导临床医生进行所需的进一步实验室测试的正确类型。

尽管今天具有 DNA 变异解释的下一代测序技术显然是“流行的”，但这些技术并不能解决医学遗传学的所有问题。sSMC 是证明细胞遗传学仍然在细胞基因组学方法中占有一席之地的证据。此外，NGP 技术，例如此处描述的技术，是细胞基因组学中的另一种新参与者，需要更多关注——需要包括更多此类综合征。