Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations.
Opitz syndrome (OS; MIM 145410 and MIM 300000) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal (LTE) abnormalities, imperforate anus, developmental delay, and cardiac defects. The X-linked form (XLOS) is caused by mutations in the MID1 gene, which encodes a microtubule-associated RBCC protein. In this study, phenotypic manifestations of patients with and without MID1 mutations were compared to determine genotype-phenotype correlations. We detected 10 novel mutations, 5 in familial cases, 2 in sporadic cases, and 3 in families for whom it was not clear if they were familial or sporadic. The genotype and phenotype was compared for these 10 families, clinically diagnosed OS patients found not to have MID1 mutations, and 4 families in whom we have previously reported MID1 mutations. This combined data set includes clinical and mutation data on 70 patients. The XLOS patients with MID1 mutations were less severely affected than patients with MID1 mutations reported in previous studies, particularly in functionally significant neurologic, LTE, anal, and cardiac abnormalities. Minor anomalies were more prevalent in patients with MID1 mutations compared to those without mutations in this study. Female MID1 mutation carriers had milder phenotypes compared to male MID1 mutation carriers, with the most common manifestation being hypertelorism in both sexes. Most of the anomalies found in the patients of the present study do not correlate with the MID1 mutation type, with the possible exception of LTE malformations. This study demonstrates the wide spectrum of severity and manifestations of OS. It also shows that XLOS patients with MID1 mutations may be less severely affected than indicated in prior reports.
So
Joyce
J
Max Planck Institute for Molecular Genetics, Berlin, Germany.
Suckow
Vanessa
V
Kijas
Zofia
Z
Kalscheuer
Vera
V
Moser
Bettina
B
Winter
Jennifer
J
Baars
Marieke
M
Firth
Helen
H
Lunt
Peter
P
Hamel
Ben
B
Meinecke
Peter
P
Moraine
Claude
C
Odent
Sylvie
S
Schinzel
Albert
A
van der Smagt
J J
JJ
Devriendt
Koen
K
Albrecht
Beate
B
Gillessen-Kaesbach
Gabriele
G
van der Burgt
Ineke
I
Petrij
Fred
F
Faivre
Laurence
L
McGaughran
Julie
J
McKenzie
Fiona
F
Opitz
John M
JM
Cox
Timothy
T
Schweiger
Susann
S
D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics; D006801:Humans; D008297:Male; D008868:Microtubule Proteins / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases
D008868:Microtubule Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C109052:MID1 protein, human; D044767:Ubiquitin-Protein Ligases