BACKGROUND Amelogenesis imperfecta (AI) is a highly heterogeneous group of hereditary developmental abnormalities which mainly affects the dental enamel during tooth development in terms of its thickness, structure, and composition. It appears both in syndromic as well as non-syndromic forms. In the affected individuals, the enamel is usually thin, soft, rough, brittle, pitted, chipped, and abraded, having reduced functional ability and aesthetics. It leads to severe complications in the patient, like early tooth loss, severe discomfort, pain, dental caries, chewing difficulties, and discoloration of teeth from yellow to yellowish-brown or creamy type. The study aimed to identify the disease-causing variant in a consanguineous family. METHODS We recruited a consanguineous Pashtun family of Pakistani origin. Exome sequencing analysis was followed by Sanger sequencing to identify the pathogenic variant in this family. RESULTS Clinical analysis revealed hypomaturation AI having generalized yellow-brown or creamy type of discoloration in affected members. We identified a novel nonsense sequence variant c.1192C > T (p.Gln398*) in exon-12 of SLC24A4 by using exome sequencing. Later, its co-segregation within the family was confirmed by Sanger sequencing. The human gene mutation database (HGMD, 2019) has a record of five pathogenic variants in SLC24A4, causing AI phenotype. CONCLUSION This nonsense sequence variant c.1192C > T (p.Gln398*) is the sixth disease-causing variant in SLC24A4, which extends its mutation spectrum and confirms the role of this gene in the morphogenesis of human tooth enamel. The identified variant highlights the critical role of SLC24A4 in causing a rare AI type in humans.

中文翻译：

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SLC24A4中的一种新的无意义变异，在巴基斯坦家庭中引起罕见形式的牙釉质发育不全。

背景技术成牙不全症（AI）是遗传发育异常的高度异质性组，其在牙齿发育期间就其厚度，结构和组成而言主要影响牙釉质。它以症状形式和非症状形式出现。在受影响的个体中，牙釉质通常较薄，柔软，粗糙，易碎，有凹痕，碎裂和磨蚀，具有降低的功能能力和美观性。它会导致患者出现严重的并发症，例如早期掉牙，严重的不适，疼痛，龋齿，咀嚼困难以及牙齿从黄色变黄棕色或乳白色。这项研究旨在确定近亲家庭的致病变异。方法我们招募了来自巴基斯坦的近亲普什图人家庭。外显子组测序分析之后是Sanger测序，以鉴定该家族中的致病变异。结果临床分析表明，过早成熟的AI在患病的成员中普遍出现黄褐色或乳白色的变色。我们通过外显子组测序在SLC24A4的第12外显子中鉴定了一个新的无意义序列变体c.1192C> T（p.Gln398 *）。后来，通过Sanger测序证实了其在家庭中的共隔离。人类基因突变数据库（HGMD，2019）记录了SLC24A4中五种致病变体，导致AI表型。结论该无意义序列变体c.1192C> T（p.Gln398 *）是SLC24A4中的第六种致病变体，它扩展了其突变谱，并证实了该基因在人牙釉质形态发生中的作用。