Original ArticlesHeterozygous intragenic deletions of FREM1 are not associated with trigonocephalyDawson, Angelika J.a,,b; Hovanes, Karinec; Liu, Jinga,,b; Marles, Sandrab; Greenberg, Cherylb; Mhanni, Azizb; Chudley, Albertb; Frosk, Patrickb; Sahoo, Trilochanc; Schanze, Dennyd; Zenker, MartindAuthor Information aGenomics, Shared Health Manitoba, Winnipeg bDepartment of Biochemistry and Medical Genetics, Program of Genetics and Metabolism, University of Manitoba, Winnipeg, Manitoba, Canada cInvitae, Irvine, California, USA dInstitute of Human Genetics, University Hospital Magdeburg Leipziger Str. 44 39120 Magdeburg Germany Received 6 May 2020 Accepted 27 August 2020 Correspondence to Angelika J. Dawson, PhD, Genomics, Shared Health Manitoba, 820 Sherbrook St. MS543H, Winnipeg, Manitoba, Canada, Tel: +204 787 2491; fax: +204 787 3846; e-mail: [email protected] Clinical Dysmorphology: April 2021 - Volume 30 - Issue 2 - p 83-88 doi: 10.1097/MCD.0000000000000351 Buy Metrics Abstract 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 (BNAR). 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. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.