Holt–Oram syndrome (HOS) is a rare, autosomal dominant disorder caused by heterozygous pathogenic variants in cardiac T‐box transcription factor, TBX5. Classically, it is associated with upper limb malformations and variable cardiac abnormalities. Limb manifestations are considered to be invariably present, ranging in severity from limitation in movement, to triphalangeal thumbs, absent thumbs, shortened forearms, or phocomelia. Cardiac involvement is characterized by congenital heart defects, most commonly septal structural malformations, and conduction system disease. Recently, novel TBX5 variants have also been reported in association with dilated cardiomyopathy (DCM). In this context, we report eight individuals from four unrelated families, in whom pathogenic variants in TBX5 segregated with an atypical HOS phenotype. Affected individuals exhibit relatively mild skeletal features of HOS, with a predominant cardiac phenotype, which includes several individuals affected by non‐ischaemic DCM. To our knowledge, these represent the first reported cases of DCM in families with skeletal features of HOS, some of whom also harbored variants previously linked to a classical HOS phenotype (p. Arg279* and p.Arg237Gln). This finding supports diverse roles of TBX5 in cardiovascular development and function, and confirms the importance of long‐term cardiac surveillance for individuals affected by HOS. Furthermore, these families highlight the wide phenotypic variability of HOS, which may include comparatively mild upper limb findings in respect to cardiac manifestations.

中文翻译：

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与致病性TBX5变体相关的家族性扩张性心肌病：扩大与Holt-Oram综合征相关的心脏表型。

Holt-Oram综合征（HOS）是一种罕见的常染色体显性遗传疾病，由心脏T-box转录因子TBX5的杂合病原体变异引起。传统上，它与上肢畸形和可变的心脏异常有关。肢体表现被认为是一成不变的，其严重程度从运动受限到三脚趾拇指，拇指缺失，前臂缩短或腓肠肌。心脏受累的特征是先天性心脏缺陷，最常见的是间隔结构畸形和传导系统疾病。最近，还报道了新的TBX5变异体与扩张型心肌病（DCM）相关联。在这种情况下，我们报告了来自四个不相关家庭的八个人，其中的致病变异TBX5与非典型HOS表型隔离。受影响的个体表现出相对较轻的HOS骨骼特征，并具有主要的心脏表型，其中包括几位受非缺血性DCM影响的个体。据我们所知，这些代表了具有HOS骨骼特征的家族中第一个报道的DCM病例，其中一些还具有以前与经典HOS表型相关的变体（p。Arg279 *和p.Arg237Gln）。这一发现支持了TBX5在心血管发育和功能中的多种作用，并证实了长期心监护对受HOS影响的个体的重要性。此外，这些家族突出了HOS的广泛表型变异性，其中可能包括相对于心脏表现而言相对较轻的上肢发现。