Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations

Abstract

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.

MID1 mutations in patients with X-linked Opitz G/BBB syndrome

“…To date, 79 OS male index cases have been published that carry mutations in the MID1 gene [Cho et al, 2006;Cox et al, 2000;De Falco et al, 2003;Ferrentino et al, 2007;Gaudenz et al, 1998;Mnayer et al, 2006;Pinson et al, 2004;Quaderi et al, 1997;Schweiger et al, 1999;Shaw et al, 2006;So et al, 2005;Winter et al, 2003] and three additional OS patients are reported here [Tania Attié-Bitach, personal communication; and our unpublished results] for a total of 82 OS index cases who carry mutations in the MID1 gene. Table 1 lists all the mutations found in the MID1 gene, their position and their putative effect on the protein product or on the transcript.…”

“…The expressivity of OS clinical manifestations is highly variable [Cordero and Holmes, 1978;Cox et al, 2000;De Falco et al, 2003;Opitz et al, 1969aOpitz et al, , 1969bPinson et al, 2004;Robin et al, 1996;So et al, 2005]. The clinical signs in this disorder are due to anomalies during the formation, definition, and closure of embryonic ventral midline structures leading to hypertelorism, LTE defects, and hypospadias, present in most of the patients, as well as to other less frequent signs, such as cleft lip and/or palate, cardiac and anal abnormalities and neurological defects [De Falco et al, 2003;Pinson et al, 2004;Robin et al, 1996].…”

“…OS patients usually present with characteristic facial anomalies, including hypertelorism/telecanthus and clefts of lip and/or palate (CL/P), laryngo-tracheo-esophageal (LTE) abnormalities, congenital heart and anal defects, and hypospadias [Cox et al, 2000;De Falco et al, 2003;Ferrentino et al, 2007;Gaudenz et al, 1998;Mnayer et al, 2006;Pinson et al, 2004;Robin et al, 1996;So et al, 2005;Winter et al, 2003]. Developmental delay and mental retardation (MR) have also been documented [De Falco et al, 2003;Pinson et al, 2004].…”

“…Developmental delay and mental retardation (MR) have also been documented [De Falco et al, 2003;Pinson et al, 2004]. The OS symptoms show a wide spectrum of severity and a highly variable expressivity, even within the same family [De Falco et al, 2003;So et al, 2005]. OS is genetically heterogeneous presenting with an autosomal dominant and an X-linked form [Robin et al, 1995]; the two forms cannot be differentiated on the basis of the clinical phenotype and in both the phenotype is more complex and more severe in male than in female patients [Robin et al, 1996].…”

MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified

“…MID1 acts as an E3 ubiquitin ligase associated to the microtubules and is implicated in the control of Phosphatase 2A protein levels Schweiger, et al, 1999;Short, et al, 2002;Trockenbacher, et al, 2001). Approximately 40 mutations have been found along the entire length of the MID1 gene in both sporadic and familial cases of OS (Cox, et al, 2000;De Falco, et al, 2003;Gaudenz, et al, 1998;Mnayer, et al, 2006;Pinson, et al, 2004;So, et al, 2005;. The expressivity of the OS symptoms is highly variable and analysis of MID1-mutated patients highlighted the presence of clinical manifestations present in almost all patients (hypertelorism, LTE defects and hypospadias) and other less frequent signs such as cleft lip and/or palate, cardiac and anal defects (De Falco, et al, 2003).…”