TY - JOUR
T1 - Novel FREM1 mutations expand the phenotypic spectrum associated with manitoba-oculo-tricho-anal (MOTA) syndrome and bifid nose renal agenesis anorectal malformations (BNAR) syndrome
AU - Nathanson, Jared
AU - Swarr, Daniel T.
AU - Singer, Amihood
AU - Liu, Mochi
AU - Chinn, Amy
AU - Jones, Wendy
AU - Hurst, Jane
AU - Khalek, Nahla
AU - Zackai, Elaine
AU - Slavotinek, Anne
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - Bifid nose renal agenesis anorectal malformations (BNAR) syndrome
KW - FREM1
KW - Manitoba-oculo-tricho-anal (MOTA) syndrome
KW - Vaginal atresia
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U2 - 10.1002/ajmg.a.35736
DO - 10.1002/ajmg.a.35736
M3 - Article
C2 - 23401257
AN - SCOPUS:84874215868
SN - 1552-4825
VL - 161
SP - 473
EP - 478
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 3
ER -