Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a “Dubowitz‐like” condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome‐wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy‐number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next‐generation sequencing. Overall, the DubS‐like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

中文翻译：

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针对杜博维茨综合征临床诊断个体的替代基因组诊断


杜博维茨综合征 (DubS) 被认为是一种可识别的综合征，其特征是独特的面部外观以及生长发育缺陷。据报道，已有超过 200 人患有杜博维茨病或“杜博维茨样”病症，但没有任何一个基因被认为是其病因。我们对 31 名临床诊断患有 DubS 的个体进行了外显子组 (ES) 或基因组测序 (GS)。经过全基因组测序、罕见变异过滤以及计算和孟德尔基因组分析后，对 13/27 (48%) 个家庭进行了推定分子诊断。分子诊断包括SKIV2L 、 SLC35C1 、 BRCA1 、 NSUN2的双等位基因变异； ARID1B 、 ARID1A 、 CREBBP 、 POGZ 、 TAF1 、 HDAC8中的从头变异以及 1p36.11( ARID1A )、8q22.2( VPS13B )、Xp22 和 Xq13( HDAC8 ) 的拷贝数变异。在 7/27 (26%) 的其他家族中观察到已知疾病基因以及意义不确定的基因中未知意义的变异。只有一种基因HDAC8可以解释多个家族的表型 ( N = 2)。自新一代测序引入以来，除了两项基因组诊断外，所有基因组诊断都是针对发现的基因或识别的条件。总体而言，DubS 样临床表型与广泛的位点异质性相关，并且所做的分子诊断是针对具有与 DubS 表型重叠的特征的新出现的临床病症。