Variable Anterior Segment Dysgenesis and Cardiac Anomalies Caused by a Novel Truncating Variant of FOXC1.
Variable Anterior Segment Dysgenesis and Cardiac Anomalies Caused by a Novel Truncating Variant of FOXC1.
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DOI：
10.3390/genes13030411
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发表时间：
2022-02-24
期刊：
影响因子：
3.5
通讯作者：
Hufnagel RB
中科院分区：
文献类型：
--
作者：
Ahmed MR;Sethna S;Krueger LA;Yang MB;Hufnagel RB
前段发育不良（ASD）包括广泛的眼前段发育异常，包括先天性白内障、虹膜发育不全、无虹膜、虹膜角膜粘连，以及Peters、Axenfeld和Rieger异常。在这里，我们报告了一个大的五代高加索家族表现出非典型综合征ASD分离与FOXC1的一个新的截断变体。家族史与高度可变的常染色体显性症状一致，包括孤立性青光眼、虹膜发育不全、无虹膜、白内障、甲状腺功能减退和先天性心脏异常。全外显子组测序揭示了一种新的变异[c.313_314insA；p.(Tyr105*)]在FOXC1中破坏dna结合叉头盒结构域的α-螺旋区。利用异种细胞系统进行的体外研究显示，携带Tyr105*变异的FOXC1细胞质定位异常，可能妨碍了下游转录功能。文献荟萃分析强调了与FOXC1截断等位基因相关的家族内变异。本研究突出了ASD的临床变异性，表明了临床和分子分析方法相结合以建立完整诊断的重要性。
Anterior segment dysgenesis (ASD) encompasses a wide spectrum of developmental abnormalities of the anterior ocular segment, including congenital cataract, iris hypoplasia, aniridia, iridocorneal synechiae, as well as Peters, Axenfeld, and Rieger anomalies. Here, we report a large five-generation Caucasian family exhibiting atypical syndromic ASD segregating with a novel truncating variant of FOXC1. The family history is consistent with highly variable autosomal dominant symptoms including isolated glaucoma, iris hypoplasia, aniridia, cataract, hypothyroidism, and congenital heart anomalies. Whole-exome sequencing revealed a novel variant [c.313_314insA; p.(Tyr105*)] in FOXC1 that disrupts the α-helical region of the DNA-binding forkhead box domain. In vitro studies using a heterologous cell system revealed aberrant cytoplasmic localization of FOXC1 harboring the Tyr105* variant, likely precluding downstream transcription function. Meta-analysis of the literature highlighted the intrafamilial variability related to FOXC1 truncating alleles. This study highlights the clinical variability in ASD and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis.
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影响因子：
16.6
作者：
Sethna S;Scott PA;Giese APJ;Duncan T;Jian X;Riazuddin S;Randazzo PA;Redmond TM;Bernstein SL;Riazuddin S;Ahmed ZM
通讯作者：
Ahmed ZM
影响因子：
30.8
作者：
Aldinger, Kimberly A.;Lehmann, Ordan J.;Hudgins, Louanne;Chizhikov, Victor V.;Bassuk, Alexander G.;Ades, Lesley C.;Krantz, Ian D.;Dobyns, William B.;Millen, Kathleen J.
通讯作者：
Millen, Kathleen J.
影响因子：
2
作者：
Chavarria-Soley, Gabriela;Michels-Rautenstrauss, Karin;Rautenstrauss, Bernd
通讯作者：
Rautenstrauss, Bernd
影响因子：
3.9
作者：
Kelberman, Daniel;Islam, Lily;Sowden, Jane C.
通讯作者：
Sowden, Jane C.
影响因子：
5.2
作者：
Mirzayans, F;Gould, DB;Walter, MA
通讯作者：
Walter, MA