X‐linked Opitz syndrome: Novel mutations in the MID1 gene and redefinition of the clinical spectrum

Abstract

Opitz (or G/BBB) syndrome is a pleiotropic genetic disorder characterized by hypertelorism, hypospadias, and additional midline defects. This syndrome is heterogeneous with an X-linked (XLOS) and an autosomal dominant (ADOS) form. The gene implicated in the XLOS form, MID1, encodes a protein containing a RING-Bbox-Coiled-coil motif belonging to the tripartite motif (TRIM) family. To further clarify the molecular basis of XLOS, we have undertaken mutation analysis of the MID1 gene in patients with Opitz syndrome (OS). We found novel mutations in 11 of 63 male individuals referred to us as sporadic or familial X-linked OS cases. The mutations are scattered throughout the gene, although more are represented in the 3' region. By reviewing all the MID1-mutated OS patients so far described, we confirmed that hypertelorism and hypospadias are the most frequent manifestations, being present in almost every XLOS individual. However, it is clear that laryngo-tracheo-esophageal (LTE) defects are also common anomalies, being manifested by all MID1-mutated male patients. Congenital heart and anal abnormalities are less frequent than reported in literature. In addition, we can include limb defects in the OS clinical synopsis as we found a MID1-mutated patient showing syndactyly. The low frequency of mutations in MID1 and the high variability of the phenotype suggest the involvement of other genes in the OS phenotype.

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

“…1) and represent private mutations with only one case of recurrent mutation (p.Arg495X) found in three unrelated patients (Cox, et al, 2000;De Falco, et al, 2003;Pinson, et al, 2004). The majority of the mutations are concentrated in the 3' portion of the gene where many insertions and deletions are found, possibly mediated by the presence of short repeated sequences.…”

“…Schematic representation of the MID1 protein product with the mutations found in our cohort of OS patients; red, missense mutations; green, nonsense mutations; blue, frame shift mutations; orange, in frame deletions; grey, splice site mutations; lines, deletions. In the bottom part of the figure with arrowheads (color code as above) and lines are indicated the mutations previously reported (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;.…”

“…OS patients often show mental retardation and brain anatomical midline defects (De Falco, et al, 2003;Pinson, et al, 2004). OS is genetically heterogeneous with an autosomal dominant and an X-linked form (Robin, et al, 1995).…”

“…The phenotype presents with variable expressivity and may include a typical faces characterized by hypertelorism, frontal bossing, broad nasal bridge, cleft lip and/or palate; DOI: 10.1002/humu.9480 laryngo-tracheo-esophageal (LTE) abnormalities; cardiac and anal defects and hypospadias (De Falco, et al, 2003;Robin, et al, 1996). OS patients often show mental retardation and brain anatomical midline defects (De Falco, et al, 2003;Pinson, et al, 2004). OS is genetically heterogeneous with an autosomal dominant and an X-linked form (Robin, et al, 1995).…”

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

“…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].…”