Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, large protuberant ears, and fetal finger pads. Most disease-causing variants identified to date are putative loss-of-function alleles, although 15-20% of cases are attributed to missense variants. We describe here four patients (including one previously published patient) with de novo KMT2D missense variants and with shared but unusual clinical findings not typically seen in Kabuki syndrome, including athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. These individuals also lack the typical dysmorphic facial features found in Kabuki syndrome. Two of the four patients had severe interstitial lung disease. All of these variants cluster within a 40-amino-acid region of the protein that is located just N-terminal of an annotated coiled coil domain. These findings significantly expand the phenotypic spectrum of features associated with variants in KMT2D beyond those seen in Kabuki syndrome and suggest a possible new underlying disease mechanism for these patients.

中文翻译：

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KMT2D相关疾病的表型扩展：超越歌舞uki综合征。

KMT2D中的致病变异体编码2D赖氨酸特异性甲基转移酶，引起常染色体显性遗传Kabuki综合征，伴有明显的畸形特征，包括眉毛拱形，长睑裂，下睑外翻，大突起耳朵和胎儿手指垫。迄今为止确定的大多数致病变异是推定的功能丧失等位基因，尽管有15-20％的病例归因于错义变异。我们在此描述了4例患有de novo KMT2D错义变异并具有共同但不寻常的临床发现的患者（包括一名先前发表的患者），这些发现通常不见于歌舞uki综合征，包括无侧突（乳头缺失），胸膜闭锁，甲状旁腺功能低下，青春期发育迟缓或缺乏，和极短的身材。这些人还缺乏在歌舞uki综合征中发现的典型的畸形面部特征。四名患者中有两名患有严重的间质性肺疾病。所有这些变体都聚集在蛋白质的40个氨基酸区域内，该区域仅位于带注释的卷曲螺旋结构域的N端。这些发现大大扩展了与KMT2D变异相关的特征的表型谱，超出了歌舞uki综合症所见的特征，并为这些患者提出了可能的新的潜在疾病机制。