Recessive mutations in FRAS1-related extracellular matrix 1 (FREM1) are associated with two rare genetic disorders, Manitoba-oculo-tricho-anal (MOTA) and bifid nose with or without anorectal and renal anomalies. Fraser syndrome is a more severe disorder that shows phenotypic overlap with both MOTA and anorectal and renal anomalies and results from mutations in FRAS1, FREM2 and GRIP1. Heterozygous missense mutations in FREM1 were reported in association with isolated trigonocephaly with dominant inheritance and incomplete penetrance. Moreover, large deletions encompassing FREM1 have been reported in association with a syndromic form of trigonocephaly and were designated as trigonocephaly type 2. Trigonocephaly results from premature closure of the metopic suture and typically manifests as a form of nonsyndromic craniosynostosis. We report on 20 patients evaluated for developmental delay and without abnormal metopic suture. Chromosomal microarray analysis revealed heterozygous FREM1 deletions in 18 patients and in 4 phenotypically normal parents. Two patients were diagnosed with MOTA and had homozygous FREM1 deletions. Therefore, although our results are consistent with the previous reports of homozygous deletions causing MOTA, we report no association between heterozygous FREM1 deletions and trigonocephaly in this cohort.

中文翻译：

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FREM1 杂合基因内缺失与三角头畸形无关。

FRAS1 相关细胞外基质 1 (FREM1) 的隐性突变与两种罕见的遗传性疾病相关，即马尼托巴眼毛肛 (MOTA) 和分鼻，伴有或不伴有肛门直肠和肾脏异常。弗雷泽综合征是一种更严重的疾病，与 MOTA 以及肛门直肠和肾脏异常表现出表型重叠，是由 FRAS1、FREM2 和 GRIP1 突变引起的。据报道，FREM1 杂合错义突变与显性遗传和不完全外显的孤立性三角头畸形有关。此外，据报道，包含 FREM1 的大缺失与综合症形式的三角头畸形有关，并被指定为三角头畸形 2 型。三角头畸形是由同位缝过早闭合引起的，通常表现为一种非综合症性颅缝早闭。我们报告了 20 名患有发育迟缓且没有异位缝异常的患者。染色体微阵列分析显示，18 名患者和 4 名表型正常的父母存在杂合 FREM1 缺失。两名患者被诊断患有 MOTA 并具有纯合 FREM1 缺失。因此，尽管我们的结果与之前关于导致 MOTA 的纯合缺失的报告一致，但我们报告该队列中杂合 FREM1 缺失与三角头畸形之间没有关联。