PDF(Pubmed)
Abstract：
FOXC1 is a ubiquitously expressed forkhead transcription factor that plays a critical role during early development. Germline pathogenic variants in FOXC1 are associated with anterior segment dysgenesis and Axenfeld-Rieger syndrome (ARS, #602482), an autosomal dominant condition with ophthalmologic anterior segment abnormalities, high risk for glaucoma and extraocular findings including distinctive facial features, as well as dental, skeletal, audiologic, and cardiac anomalies. De Hauwere syndrome is an ultrarare condition previously associated with 6p microdeletions and characterized by anterior segment dysgenesis, joint instability, short stature, hydrocephalus, and skeletal abnormalities. Here, we report clinical findings of two unrelated adult females with FOXC1 haploinsufficiency who have ARS and skeletal abnormalities. Final molecular diagnoses of both patients were achieved using genome sequencing. Patient 1 had a complex rearrangement involving a 4.9 kB deletion including FOXC1 coding region (Hg19; chr6:1,609,721-1,614,709), as well as a 7 MB inversion (Hg19; chr6:1,614,710-8,676,899) and a second deletion of 7.1 kb (Hg19; chr6:8,676,900-8,684,071). Patient 2 had a heterozygous single nucleotide deletion, resulting in a frameshift and a premature stop codon in FOXC1 (NM_001453.3): c.467del, p.(Pro156Argfs*25). Both individuals had moderate short stature, skeletal abnormalities, anterior segment dysgenesis, glaucoma, joint laxity, pes planovalgus, dental anomalies, hydrocephalus, distinctive facial features, and normal intelligence. Skeletal surveys revealed dolichospondyly, epiphyseal hypoplasia of femoral and humeral heads, dolichocephaly with frontal bossin gand gracile long bones. We conclude that haploinsufficiency of FOXC1 causes ARS and a broad spectrum of symptoms with variable expressivity that at its most severe end also includes a phenotype overlapping with De Hauwere syndrome.
摘要：
FOXC1是一种广泛表达的叉头转录因子，在早期发育中起着关键作用。FOXC1的种系致病变异与前节发育不全和Axenfeld-Rieger综合征（ARS，#602482),常染色体显性疾病与眼科眼前节异常，青光眼和眼外表现的高风险，包括独特的面部特征，以及牙科,骨骼，听力学,和心脏异常.DeHauwere综合征是一种先前与6p微缺失相关的超常病症，其特征是眼前节发育不全。关节不稳定性，身材矮小,脑积水,和骨骼异常。这里,我们报告了2例FOXC1单倍性功能不全的非相关成年女性的临床表现,这些女性有ARS和骨骼异常.使用基因组测序实现了两名患者的最终分子诊断。患者1具有复杂的重排，涉及4.9kB缺失，包括FOXC1编码区（Hg19;chr6：1,609,721-1,614,709），以及7MB反转（Hg19;chr6：1,614,710-8,676,899）和7.1kb的第二个缺失（Hg19;chr6：8,676,900-8,684,071）。患者2具有杂合单核苷酸缺失，导致FOXC1（NM_001453.3）中的移码和过早终止密码子：c.467del，p.（Pro156Argfs*25）。两个人都有中等矮个子，骨骼异常,眼前节发育不全，青光眼,关节松弛,pes平面外翻，牙齿异常,脑积水,独特的面部特征，和正常的智力。骨骼调查显示，股骨和肱骨头骨发育不全，头颅畸形，额叶bossingandgacile长骨。我们得出的结论是，FOXC1的单倍体功能不全导致ARS和具有可变表达度的广泛症状，在其最严重的末端还包括与DeHauwere综合征重叠的表型。
