title: Novel FREM1 mutations expand the phenotypic spectrum associated with Manitoba-oculo-tricho-anal (MOTA) syndrome and bifid nose renal agenesis anorectal malformations (BNAR) syndrome.
abstract: Loss of function mutations in FREM1 have been demonstrated in Manitoba-oculo-tricho-anal (MOTA) syndrome and Bifid Nose Renal Agenesis and Anorectal malformations (BNAR) syndrome, but the wider phenotypic spectrum that is associated with FREM1 mutations remains to be defined. We screened three probands with phenotypic features of MOTA syndrome. In one severely affected infant who was diagnosed with MOTA syndrome because of bilateral eyelid colobomas, a bifid nasal tip, hydrometrocolpos and vaginal atresia, we found two nonsense mutations that likely result in complete loss of FREM1 function. This infant also had renal dysplasia, a finding more consistent with BNAR syndrome. Another male who was homozygous for a novel stop mutation had an extensive eyelid colobomas, corneopalpebral synechiae, and unilateral renal agenesis. A third male child diagnosed with MOTA syndrome because of corneopalpebral synechiae and eyelid colobomas had a homozygous splice site mutation in FREM1. These cases illustrate that disruption of the FREM1 gene can produce a spectrum of clinical manifestations encompassing the previously described MOTA and BNAR syndromes, and that features of both syndromes may be seen in the same individual. The phenotype of FREM1-related disorders is thus more pleiotropic than for MOTA and BNAR syndrome alone and more closely resembles the widespread clinical involvement seen with Fraser syndrome. Moreover, our first case demonstrates that vaginal atresia may be a feature of FREM1-related disorders.
authors: Division of Genetics, Department of Pediatrics, University of California, San Francisco, California 94143-0748, USA.
authors: Jared
authors: J
authors: Nathanson
authors: Daniel T
authors: DT
authors: Swarr
authors: Amihood
authors: A
authors: Singer
authors: Mochi
authors: M
authors: Liu
authors: Amy
authors: A
authors: Chinn
authors: Wendy
authors: W
authors: Jones
authors: Jane
authors: J
authors: Hurst
authors: Nahla
authors: N
authors: Khalek
authors: Elaine
authors: E
authors: Zackai
authors: Anne
authors: A
authors: Slavotinek
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics; D001003:Anal Canal / Q000002:abnormalities; D003103:Coloboma / Q000175:diagnosis* / Q000235:genetics; D003241:Consanguinity; D017809:Fatal Outcome; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D006972:Hypertelorism / Q000175:diagnosis* / Q000235:genetics; D007223:Infant; D007231:Infant, Newborn; D007674:Kidney Diseases / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D025202:Molecular Diagnostic Techniques; D009154:Mutation; D009666:Nose / Q000002:abnormalities; D010641:Phenotype; D018123:Receptors, Interleukin / Q000235:genetics*; D012002:Rectal Diseases / Q000175:diagnosis* / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: C548979:Frem1 protein, human; D018123:Receptors, Interleukin
references: Cell Tissue Res. 2010 Jan;339(1):167-88
references: 19756754
references: Am J Med Genet A. 2007 Dec 15;143A(24):3194-203
references: 18000968
references: Curr Pharm Des. 2009;15(12):1277-94
references: 19355968
references: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):11981-6
references: 16880404
references: Nat Methods. 2010 Aug;7(8):575-6
references: 20676075
references: Genet Couns. 2001;12(1):101-2
references: 11332973
references: Am J Med Genet A. 2008 Sep 1;146A(17):2252-7
references: 18671281
references: J Med Genet. 2002 Sep;39(9):623-33
references: 12205104
references: PLoS Genet. 2011 Sep;7(9):e1002278
references: 21931569
references: Clin Dysmorphol. 2002 Jan;11(1):33-8
references: 11822703
references: Am J Med Genet A. 2009 Feb 15;149A(4):767-9
references: 19291776
references: Int J Biochem Cell Biol. 2011 Apr;43(4):487-95
references: 21182980
references: Ophthalmic Plast Reconstr Surg. 2002 Sep;18(5):373-7
references: 12352825
references: Matrix Biol. 2007 Jul;26(6):456-62
references: 17462874
references: Birth Defects Res C Embryo Today. 2010 Mar;90(1):8-31
references: 20301220
references: Am J Med Genet. 1992 Apr 1;42(6):793-9
references: 1554017
references: J Med Genet. 2011 Jun;48(6):375-82
references: 21507892
references: J Med Genet. 2012 May;49(5):303-6
references: 22510445
references: Pediatr Pulmonol. 2005 Nov;40(5):445-8
references: 16161157
references: Mol Vis. 2012;18:1301-11
references: 22690109
references: IUBMB Life. 2007 Jul;59(7):427-35
references: 17654118
references: Am J Hum Genet. 2009 Sep;85(3):414-8
references: 19732862