NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

X-Linked Opitz G/BBB Syndrome

Synonyms: Opitz Syndrome, X-Linked; XLOS
, PhD
Cluster in Biomedicine (CBM)
Trieste, Italy

Initial Posting: ; Last Update: July 28, 2011.


Clinical characteristics.

X-linked Opitz G/BBB syndrome (XLOS) is a multiple congenital anomaly disorder characterized by facial anomalies (ocular hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), laryngotracheoesophageal defects, and genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum). Developmental delay and intellectual disability are observed in about 50% of affected males. Cleft lip and/or palate are present in approximately 50% of affected individuals. Other malformations present in fewer than 50% of individuals include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female carriers usually manifest only ocular hypertelorism.


The diagnosis of X-linked Opitz G/BBB syndrome is established most often by clinical findings. MID1 is the only gene in which pathogenic variants are currently known to cause X-linked Opitz G/BBB syndrome. Sequence analysis of the coding exons and intron-exon boundaries or scanning for pathogenic variants using various techniques detects deletions, insertions, and missense, nonsense, and splice site variants in 15%-45% of males with clinically diagnosed Opitz G/BBB syndrome. The cohorts tested for MID1 pathogenic variants often include simplex cases (i.e., individuals with no family history of Opitz G/BBB syndrome), who therefore cannot be determined to have either the X-linked form or the autosomal dominant form. The detection rate is higher in individuals with clear X-linked inheritance.


Treatment of manifestations: Management of anomalies by a multidisciplinary team; surgical treatment of medically significant laryngotracheoesophageal malformations; tracheostomy as needed; standard surgical management of hypospadias, cleft lip/palate, imperforate anus, heart defects; speech therapy; neuropsychological and educational support.

Prevention of secondary complications: Antireflux measurements to minimize risk of aspiration.

Surveillance: Based on the type of malformations present; regular monitoring of hearing for those with cleft lip/palate.

Genetic counseling.

X-linked Opitz G/BBB syndrome is inherited in an X-linked manner. In a family with more than one affected individual, the mother of an affected male is an obligate carrier. If the mother of an affected male is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Sons who inherit the pathogenic variant will be affected; daughters who inherit the pathogenic variant will be carriers and will usually manifest hypertelorism. Mildly affected males who have children will pass the pathogenic variant to all of their daughters and none of their sons. Prenatal testing is possible for pregnancies at risk if the pathogenic variant in the family has been identified.


Clinical Diagnosis

X-linked Opitz G/BBB syndrome (XLOS) is diagnosed on the basis of clinical findings. The multiple clinical signs show variable expressivity in affected individuals, even within the same family.

The manifestations of XLOS are classified into major and minor findings based on frequency of occurrence. The clinical diagnosis of XLOS is suspected in males with ocular hypertelorism and at least one other major finding. A family history consistent with X-linked inheritance further supports the diagnosis of XLOS [Robin et al 1996, De Falco et al 2003, Fontanella et al 2008].

Major (more frequent) findings

  • Ocular hypertelorism and/or telecanthus (found in virtually all affected individuals)
  • All degrees of hypospadias that, in the most severe form, can be associated with renal malformations (85%-90%)
  • Laryngotracheoesophageal abnormalities, primarily laryngeal cleft, resulting in swallowing difficulties and respiratory dysfunction (60%-70%)

Minor findings (found in <50% of individuals)

  • Intellectual disability and developmental delay
  • Cleft lip and/or palate
  • Congenital heart defects including ventricular septal defect (VSD) or atrial septal defect (ASD), persistent left superior vena cava, patent ductus arteriosus
  • Imperforate or ectopic anus
  • Midline defects of the brain including agenesis of the corpus callosum and cerebellar vermis agenesis or hypoplasia

Molecular Genetic Testing

Gene. MID1 is the only gene in which pathogenic variants are currently known to cause X-linked Opitz G/BBB syndrome (XLOS) [Quaderi et al 1997].

Possible evidence for locus heterogeneity. A percentage of individuals with clinically diagnosed XLOS do not have identifiable pathogenic variants in MID1. The low variant detection rate may reflect either genetic heterogeneity (i.e., the presence of other, as-yet unidentified loci associated with XLOS on the X chromosome) or the presence of pathogenic variants in regions of MID1 (e.g., promoter, introns, 5’ and 3' UTR) not routinely evaluated.

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in X-Linked Opitz G/BBB Syndrome

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
MID1Sequence analysis 4Sequence variants15%-50% 5, 6, 7
Deletion/duplication analysis 8(Multi)exon or whole-gene deletion/duplicationUnknown 9

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis.


Includes the variant detection frequency using deletion/duplication analysis


Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.


Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Three whole-gene deletions have been reported [Winter et al 2003, Ferrentino et al 2007, Fontanella et al 2008].

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of XLOS is suspected based on clinical features; however, the variable expressivity of the manifestations requires identification of an MID1 pathogenic variant for confirmation.

Carrier testing for at-risk female relatives requires prior identification of the pathogenic variant in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may demonstrate hypertelorism or more rarely other clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no pathogenic variant is identified, by methods to detect gross structural abnormalities.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

Affected males. X-linked Opitz G/BBB syndrome (XLOS) is characterized by clinical abnormalities of primarily midline structures [Opitz et al 1969a, Opitz et al 1969b]. These defects include facial anomalies, laryngotracheoesophageal (LTE) defects, genitourinary abnormalities, and heart defects. Developmental delay and intellectual disability are common. Wide clinical variability has been described; individuals with a mutated MID1 allele may manifest only some of the typical clinical signs with different degrees of severity, even among members of the same family.

Table 2.

Incidence of Main Clinical Features Seen in Males with XLOS with MID1 Pathogenic Variants

FindingNumber of Males with Finding / Total Number of Males
Hypertelorism68 / 69
CL/P38 / 73
LTE defects46 / 73
Heart defects16 / 73
Anal defects16 / 73
Hypospadias63 / 73
ID 1/developmental delay25 / 73
Brain abnormalities10 / 25 2

Intellectual disability


Males with XLOS undergoing MRI examination

Facial appearance and head anomalies. The facial appearance of affected males is characterized by ocular hypertelorism, which can also be accompanied by telecanthus, a prominent forehead, widow's peak, broad nasal bridge, anteverted nares, low-set and malformed ears, microcephaly, large fontanelle, and/or prominent metopic suture. Unilateral or bilateral cleft lip and/or palate is present in approximately 50% of affected individuals. Other oral manifestations include high-arched palate, ankyloglossia, micrognathia, hypodontia, and neonatal teeth [Robin et al 1996, Shaw et al 2006, Fontanella et al 2008].

Urogenital abnormalities. Hypospadias of varying severity is present in approximately 90% of males with X-linked Opitz G/BBB syndrome and is often associated with other genital anomalies such as cryptorchidism and hypoplastic/bifid scrotum. Severe hypospadias can be associated with urinary tract dysfunction, e.g. vesicoureteric reflux and hydronephrosis [Robin et al 1996, Pinson et al 2004, Fontanella et al 2008, Zhang et al 2011].

Laryngotracheoesophageal (LTE) defects. LTE abnormalities may result in coughing and choking with feeding, recurrent pneumonia, and life-threatening aspiration. In their most severe form, LTE defects are manifest as laryngeal and tracheoesophageal clefts and in more mild form as tracheoesophageal fistulae or LTE dysmotility. The incidence of respiratory and/or gastroesophageal symptoms is probably underestimated, because mildly affected individuals may only manifest functional swallowing difficulties that improve with age and eventually disappear during infancy [Robin et al 1996, De Falco et al 2003, Pinson et al 2004].

Neurologic findings. More than one third of individuals with XLOS show developmental delay and intellectual disability; they frequently manifest delay in onset of walking, short attention span, learning difficulties, and speech problems. In some cases, these delays are secondary to surgical interventions. Midline brain anatomic defects including agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis and Dandy-Walker malformations were identified in 40% of individuals with an MID1 pathogenic variant who underwent MRI examination [Gaudenz et al 1998, Cox et al 2000, De Falco et al 2003, Winter et al 2003, Pinson et al 2004, So et al 2005, Fontanella et al 2008].

Other malformations present in approximately one fifth of individuals with XLOS are congenital heart anomalies (ventricular septal defects, atrial septal defects, coarctation of the aorta, persistent left superior vena cava, patent ductus arteriosus, patent foramen ovale) and anal abnormalities (imperforate or ectopic anus) [Robin et al 1996, De Falco et al 2003, Pinson et al 2004, Fontanella et al 2008].

Carrier females. Female carriers usually show only ocular hypertelorism and rarely other manifestations [Robin et al 1996, De Falco et al 2003, So et al 2005].

Genotype-Phenotype Correlations

In general no genotype-phenotype correlations have been observed. Pathogenic missense, nonsense, splice site, and frameshift variants, insertions, and deletions all result in highly variable phenotypes even within the same family [Gaudenz et al 1998, Cox et al 2000, De Falco et al 2003, Winter et al 2003, Pinson et al 2004].

Two possible exceptions are:

  • An association between truncating variants and the presence of anatomic brain abnormalities, in particular cerebellar defects [Fontanella et al 2008];
  • Possible correlation of a mild phenotype with pathogenic variants in the fibronectin type III domain of the protein [Mnayer et al 2006].


Usually the presence of an MID1 pathogenic variant is associated with clinical findings of XLOS; however, recently an instance of reduced penetrance has been reported [Ruiter et al 2010].


Opitz G/BBB syndrome was first reported as two separate entities, BBB syndrome [Opitz et al 1969b] and G syndrome [Opitz et al 1969a]. Subsequently, it has become apparent that the two syndromes identified in 1969 are in fact a single entity, now named Opitz G/BBB syndrome.

Other names, no longer used, include hypospadias-dysphagia syndrome, Opitz-Frias syndrome, telecanthus with associated abnormalities, and hypertelorism-hypospadias syndrome.

Of note, X-linked Opitz G/BBB syndrome (XLOS; OSX; type I) is distinct from autosomal dominant Opitz G/BBB syndrome (ADOS; type II).


The prevalence of X-linked Opitz G/BBB syndrome ranges from one in 50,000 to one in 100,000 males.

Differential Diagnosis

X-linked Opitz G/BBB syndrome (XLOS; Opitz G/BBB syndrome, type I) and autosomal dominant Opitz G/BBB syndrome (ADOS; Opitz G/BBB syndrome, type II) (OMIM) share the same clinical picture. ADOS maps to 22q11.2; the gene(s) implicated have not been identified [Robin et al 1995]. Robin et al [1996] compared the phenotypic features of the X-linked and autosomal forms of the Opitz syndrome. They found that anteverted nares and posterior pharyngeal cleft were seen only in the X-linked form, but this distinction was questioned by Cox et al [2000]. All other manifestations of the syndrome, such as hypertelorism, swallowing difficulties, hypospadias, and developmental delay can be seen in both forms. XLOS and ADOS can be distinguished by the mode of inheritance and by the fact that female carriers of XLOS are asymptomatic or show only ocular hypertelorism, whereas females with ADOS manifest a more complex phenotype [Robin et al 1995, Robin et al 1996].

Frequently, FG syndrome has been misdiagnosed as Opitz syndrome. FG syndrome is also characterized by facial dysmorphism, congenital heart defects, hypospadias, gastroesophageal reflux, and developmental delay/intellectual disability; however, features that distinguish the two conditions include the following findings not observed in Opitz G/BBB syndrome:

  • Congenital hypotonia with joint hyperlaxity that evolves into spasticity
  • Chronic constipation
  • Characteristic personality

FG syndrome is genetically heterogeneous and includes several X-linked forms:

Other malformation syndromes that share overlapping features with X-linked Opitz G/BBB syndrome:

  • Craniofrontonasal dysplasia (OMIM). In addition to some midline defects in common with Opitz G/BBB syndrome, craniofrontonasal dysplasia has skeletal, skin, nail, and hair defects. A significant proportion of individuals with craniofrontonasal dysplasia have a pathogenic variant in EFNB1.

Mowat-Wilson syndrome. Mowat-Wilson syndrome has ocular and gastrointestinal abnormalities that are not usually observed in X-linked Opitz G/BBB syndrome. It is characterized by intellectual disability, microcephaly, distinct facial features, and often Hirschshprung disease. It is caused by a pathogenic variant in ZEB2. See also Hirschshprung Disease Overview.


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked Opitz G/BBB syndrome, the following evaluations by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech pathologist, and clinical geneticist) are recommended:

  • Past medical history and physical examination with attention to head and facial measurements, palate, heart, genitourinary system, and lower respiratory system
  • Complete eye evaluation including assessment of visual acuity, refractive error, and ocular alignment for possible strabismus
  • Assessment of hypospadias by a urologist, including ultrasound examination to evaluate for renal/urinary tract abnormalities in males with severe hypospadias
  • Laryngoscopy and chest x-ray in individuals who have choking with feeding, recurrent pneumonia, and/or aspiration
  • Assessment of cleft lip/palate (CLP) by a craniofacial surgeon
  • Age-appropriate assessment of development and intellectual abilities
  • Assessment of anal position and patency
  • Echocardiogram
  • Cranial imaging

Treatment of Manifestations

Management of anomalies by a multidisciplinary team (including craniofacial surgeon, ophthalmologist, pediatrician, pediatric urologist, cardiologist, pulmonologist, speech pathologist, and clinical geneticist) to help assure coordination of care is indicated.

  • Treatment as needed by an ophthalmologist
  • Surgical intervention as needed for hypospadias
  • Surgical treatment of medically significant laryngotracheoesophageal (LTE) abnormalities; often tracheostomy is necessary initially to assure an adequate airway.
  • Surgical management for cleft lip/palate and other craniofacial anomalies; therapy for speech problems secondary to the cleft lip and palate
  • Neuropsychological support; many males with X-linked Opitz G/BBB syndrome require special educational programs.
  • Surgical intervention for imperforate anus
  • Surgical repair as needed for heart defects

Prevention of Primary Manifestations

All primary manifestations are present at birth. To date no factors that can influence their expression have been identified.

Prevention of Secondary Complications

Antireflux pharmacologic therapy minimizes the risk for aspiration until laryngeal competence is assured.


Regular follow-up depending on the type of malformations present:

  • Craniofacial team follow-up for those with cleft lip/palate, including regular monitoring of hearing
  • Urology follow-up for those with significant hypospadias and/or renal defects
  • Cardiac follow-up for those with cardiac defects
  • Gastroenterology, pulmonary, and/or surgical follow-up for those with LTE defects
  • Gastroenterology and/or surgical follow-up for those with anal defects

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

X-linked Opitz G/BBB syndrome (XLOS) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to sibs depends on the carrier status of the mother:

  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers and will usually only manifest hypertelorism.
  • If the pathogenic variant cannot be detected in DNA extracted from the leukocytes of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Mildly affected males will pass the pathogenic variant to all of their daughters and none of their sons.

Other family members of a proband. The proband's maternal aunts may be at risk of being carriers and the aunt's offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the pathogenic variant has been identified in the proband.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the MID1 pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for XLOS are possible options. Knowing before delivery that a child has XLOS may help families to prepare emotionally and physicians to prepare for the medical needs of a child with birth defects.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
  • Cleft Palate Foundation (CPF)
    1504 East Franklin Street
    Suite 102
    Chapel Hill NC 27514-2820
    Phone: 800-242-5338 (toll-free); 919-933-9044
    Fax: 919-933-9604
  • Medline Plus

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

X-Linked Opitz G/BBB Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
MID1Xp22​.2E3 ubiquitin-protein ligase Midline-1MID1 @ LOVDMID1

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for X-Linked Opitz G/BBB Syndrome (View All in OMIM)

300552MIDLINE 1; MID1

Gene structure. MID1 is composed of nine coding exons and variable and alternative 5' untranslated regions [Quaderi et al 1997, Gaudenz et al 1998, Perry et al 1998, Van den Veyver et al 1998, Cox et al 2000, Landry & Mager 2002]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign allelic variants. Polymorphic variants are not common.

Pathogenic allelic variants. To date, pathogenic variants in MID1 have been found in approximately 80 individuals with X-linked Opitz G/BBB syndrome (XLOS) [Gaudenz et al 1998, Cox et al 2000, De Falco et al 2003, Winter et al 2003, Pinson et al 2004, So et al 2005, Mnayer et al 2006; Ferrentino et al 2007; Fontanella et al 2008]. No pathogenic variants are recurrent with the exception of p.Arg495Ter, which was identified in five unrelated individuals and p.Arg277Ter, identified in three unrelated individuals. The other pathogenic variants are missense and nonsense variants, small deletions, or insertions located along the entire length of the gene, the majority in the most 3' portion of the gene.

A duplication of the first coding exon leading to a premature stop codon has been detected in one individual with XLOS [Winter et al 2003].

Three whole-gene deletions have been reported [Winter et al 2003, Ferrentino et al 2007, Fontanella et al 2008].

Normal gene product. The normal gene product is E3 ubiquitin-protein ligase Midline-1, which is anchored to the microtubules [Cainarca et al 1999, Schweiger et al 1999, Cox et al 2000] and acts as an E3 ubiquitin ligase that regulates the degradation of phosphatase 2A [Liu et al 2001, Trockenbacher et al 2001, Short et al 2002]. The role of this protein function within the cell and during development is yet to be clarified.

Abnormal gene product. The missense and truncated forms lower their affinity for the microtubular apparatus. The pathogenic mechanism is likely to be caused by the loss of E3 ubiquitin-protein ligase Midline-1 function on the microtubules.


Literature Cited

  • Briault S, Hill R, Shrimpton A, Zhu D, Till M, Ronce N, Margaritte-Jeannin P, Baraitser M, Middleton-Price H, Malcolm S, Thompson E, Hoo J, Wilson G, Romano C, Guichet A, Pembrey M, Fontes M, Poustka A, Moraine C. A gene for FG syndrome maps in the Xq12-q21.31 region. Am J Med Genet. 1997;73:87–90. [PubMed: 9375929]
  • Briault S, Odent S, Lucas J, Le Merrer M, Turleau C, Munnich A, Moraine C. Paracentric inversion of the X chromosome [inv(X)(q12q28)] in familial FG syndrome. Am J Med Genet. 1999;86:112–4. [PubMed: 10449643]
  • Briault S, Villard L, Rogner U, Coy J, Odent S, Lucas J, Passage E, Zhu D, Shrimpton A, Pembrey M, Till M, Guichet A, Dessay S, Fontes M, Poustka A, Moraine C. Mapping of X chromosome inversion breakpoints [inv(X)(q11q28)] associated with FG syndrome: a second FG locus. Am J Med Genet. 2000;95:178–81. [FGS2] [PubMed: 11078572]
  • Cainarca S, Messali S, Ballabio A, Meroni G. Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle. Hum Mol Genet. 1999;8:1387–96. [PubMed: 10400985]
  • Cox TC, Allen LR, Cox LL, Hopwood B, Goodwin B, Haan E, Suthers GK. New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome. Hum Mol Genet. 2000;9:2553–62. [PubMed: 11030761]
  • De Falco F, Cainarca S, Andolfi G, Ferrentino R, Berti C, Rodriguez Criado G, Rittinger O, Dennis N, Odent S, Rastogi A, Liebelt J, Chitayat D, Winter R, Jawanda H, Ballabio A, Franco B, Meroni G. X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet. 2003;120A:222–8. [PubMed: 12833403]
  • Dessay S, Moizard MP, Gilardi JL, Opitz JM, Middleton-Price H, Pembrey M, Moraine C, Briault S. FG syndrome: linkage analysis in two families supporting a new gene localization at Xp22.3. Am J Med Genet. 2002;112:6–11. [FGS3] [PubMed: 12239712]
  • Ferrentino R, Bassi MT, Chitayat D, Tabolacci E, Meroni G. MID1 mutation screening in a large cohort of Opitz G/BBB syndrome patients: twenty-nine novel mutations identified. Hum Mutat. 2007;28:206–7. [PubMed: 17221865]
  • Fontanella B, Russolillo G, Meroni G. MID1 mutations in patients with X-linked Opitz G/BBB syndrome. Hum Mutat. 2008;29:584–94. [PubMed: 18360914]
  • Gaudenz K, Roessler E, Quaderi N, Franco B, Feldman G, Gasser DL, Wittwer B, Horst J, Montini E, Opitz JM, Ballabio A, Muenke M. Opitz G/BBB syndrome in Xp22: mutations in the MID1 gene cluster in the carboxy-terminal domain. Am J Hum Genet. 1998;63:703–10. [PMC free article: PMC1377398] [PubMed: 9718340]
  • Graham JM Jr, Tackels D, Dibbern K, Superneau D, Rogers C, Corning K, Schwartz CE. FG syndrome: report of three new families with linkage to Xq12-q22.1. Am J Med Genet. 1998;80:145–56. [PubMed: 9805132]
  • Jehee FS, Rosenberg C, Krepischi-Santos AC, Kok F, Knijnenburg J, Froyen G, Vianna-Morgante AM, Opitz JM, Passos-Bueno MR. An Xq22.3 duplication detected by comparative genomic hybridization microarray (Array-CGH) defines a new locus (FGS5) for FG syndrome. Am J Med Genet A. 2005;139:221–6. [PubMed: 16283679]
  • Landry JR, Mager DL. Widely spaced alternative promoters, conserved between human and rodent, control expression of the Opitz syndrome gene MID1. Genomics. 2002;80:499–508. [PubMed: 12408967]
  • Liu J, Prickett TD, Elliott E, Meroni G, Brautigan DL. Phosphorylation and microtubule association of the Opitz syndrome protein mid-1 is regulated by protein phosphatase 2A via binding to the regulatory subunit alpha 4. Proc Natl Acad Sci U S A. 2001;98:6650–5. [PMC free article: PMC34408] [PubMed: 11371618]
  • Mnayer L, Khuri S, Merheby HA, Meroni G, Elsas LJ. A structure-function study of MID1 mutations associated with a mild Opitz phenotype. Mol Genet Metab. 2006;87:198–203. [PubMed: 16378742]
  • Opitz JM, Frias JL, Gutenberger JE, Pellet JR. The G syndrome of multiple congenital anomalies. Birth defects: Original Article Series. 1969a;2(V):95–102.
  • Opitz JM, Summitt RL, Smith DW. The BBB syndrome familial telecanthus with associated congenital anomalies. Birth Defects: Original Article Series. 1969b;2(V):86–94.
  • Perry J, Feather S, Smith A, Palmer S, Ashworth A. The human FXY gene is located within Xp22.3: implications for evolution of the mammalian X chromosome. Hum Mol Genet. 1998;7:299–305. [PubMed: 9425238]
  • Piluso G, Carella M, D'Avanzo M, Santinelli R, Carrano EM, D'Avanzo A, D'Adamo AP, Gasparini P, Nigro V. Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family. Hum Genet. 2003;112:124–30. [PubMed: 12522552]
  • Piluso G, D'Amico F, Saccone V, Bismuto E, Rotundo IL, Di Domenico M, Aurino S, Schwartz CE, Neri G, Nigro V. A missense mutation in CASK causes FG syndrome in an Italian family. Am J Hum Genet. 2009;84:162–77. [PMC free article: PMC2668001] [PubMed: 19200522]
  • Pinson L, Auge J, Audollent S, Mattei G, Etchevers H, Gigarel N, Razavi F, Lacombe D, Odent S, Le Merrer M, Amiel J, Munnich A, Meroni G, Lyonnet S, Vekemans M, Attie-Bitach T. Embryonic expression of the human MID1 gene and its mutations in Opitz syndrome. J Med Genet. 2004;41:381–6. [PMC free article: PMC1735763] [PubMed: 15121778]
  • Quaderi NA, Schweiger S, Gaudenz K, Franco B, Rugarli EI, Berger W, Feldman GJ, Volta M, Andolfi G, Gilgenkrantz S, Marion RW, Hennekam RC, Opitz JM, Muenke M, Ropers HH, Ballabio A. Opitz G/BBB syndrome, a defect of midline development, is due to mutations in a new RING finger gene on Xp22. Nat Genet. 1997;17:285–91. [PubMed: 9354791]
  • Risheg H, Graham JM Jr, Clark RD, Rogers RC, Opitz JM, Moeschler JB, Peiffer AP, May M, Joseph SM, Jones JR, Stevenson RE, Schwartz CE, Friez MJ. A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome. Nat Genet. 2007;39:451–3. [PubMed: 17334363]
  • Robin NH, Feldman GJ, Aronson AL, Mitchell HF, Weksberg R, Leonard CO, Burton BK, Josephson KD, Laxová R, Aleck KA, Allanson JE, Guion-Almeida ML, Martin RA, Leichtman LG, Price RA, Opitz JM, Muenke M. Opitz syndrome is genetically heterogeneous, with one locus on Xp22, and a second locus on 22q11.2. Nat Genet. 1995;11:459–61. [PubMed: 7493033]
  • Robin NH, Opitz JM, Muenke M. Opitz G/BBB syndrome: clinical comparisons of families linked to Xp22 and 22q, and a review of the literature. Am J Med Genet. 1996;62:305–17. [PubMed: 8882794]
  • Ruiter M, Kamsteeg EJ, Meroni G, de Vries BB. A MID1 mutation associated with reduced penetrance of X-linked Opitz G/BBB syndrome. Clin Dysmorphol. 2010;19:195–7. [PubMed: 20671548]
  • Schweiger S, Foerster J, Lehmann T, Suckow V, Muller YA, Walter G, Davies T, Porter H, van Bokhoven H, Lunt PW, Traub P, Ropers HH. The Opitz syndrome gene product, MID1, associates with microtubules. Proc Natl Acad Sci U S A. 1999;96:2794–9. [PMC free article: PMC15848] [PubMed: 10077590]
  • Shaw A, Longman C, Irving M, Splitt M. Neonatal teeth in X-linked Opitz (G/BBB) syndrome. Clin Dysmorphol. 2006;15:185–6. [PubMed: 16760742]
  • Short KM, Hopwood B, Yi Z, Cox TC. MID1 and MID2 homo- and heterodimerise to tether the rapamycin-sensitive PP2A regulatory subunit, Alpha 4, to microtubules: implications for the clinical variability of X-linked Opitz GBBB syndrome and other developmental disorders. BMC Cell Biol. 2002;3:1. [PMC free article: PMC64779] [PubMed: 11806752]
  • So J, Suckow V, Kijas Z, Kalscheuer V, Moser B, Winter J, Baars M, Firth H, Lunt P, Hamel B, Meinecke P, Moraine C, Odent S, Schinzel A, van der Smagt JJ, Devriendt K, Albrecht B, Gillessen-Kaesbach G, van der Burgt I, Petrij F, Faivre L, McGaughran J, McKenzie F, Opitz JM, Cox T, Schweiger S. Mild phenotypes in a series of patients with Opitz GBBB syndrome with MID1 mutations. Am J Med Genet A. 2005;132A:1–7. [PubMed: 15558842]
  • Trockenbacher A, Suckow V, Foerster J, Winter J, Krauss S, Ropers HH, Schneider R, Schweiger S. MID1, mutated in Opitz syndrome, encodes an ubiquitin ligase that targets phosphatase 2A for degradation. Nat Genet. 2001;29:287–94. [PubMed: 11685209]
  • Unger S, Mainberger A, Spitz C, Bähr A, Zeschnigk C, Zabel B, Superti-Furga A, Morris-Rosendahl DJ. Filamin A mutation is one cause of FG syndrome. Am J Med Genet A. 2007;143A:1876–9. [PubMed: 17632775]
  • Van den Veyver IB, Cormier TA, Jurecic V, Baldini A, Zoghbi HY. Characterization and physical mapping in human and mouse of a novel RING finger gene in Xp22. Genomics. 1998;51:251–61. [PubMed: 9722948]
  • Winter J, Lehmann T, Suckow V, Kijas Z, Kulozik A, Kalscheuer V, Hamel B, Devriendt K, Opitz J, Lenzner S, Ropers HH, Schweiger S. Duplication of the MID1 first exon in a patient with Opitz G/BBB syndrome. Hum Genet. 2003;112:249–54. [PubMed: 12545276]
  • Zhang X, Chen Y, Zhao S, Markljung E, Nordenskjöld A. Hypospadias associated with hypertelorism, the mildest phenotype of Opitz syndrome. J Hum Genet. 2011;56:348–51. [PubMed: 21326312]

Chapter Notes

Author Notes

Basic research on the molecular basis of X-linked Opitz syndrome, functional study of MID1 and proteins belonging to the TRIM/RBCC family.

Revision History

  • 28 July 2011 (me) Comprehensive update posted live
  • 20 June 2007 (cd) Revision: deletion/duplication analysis available clinically
  • 18 January 2007 (me) Comprehensive update posted to live Web site
  • 17 December 2004 (me) Review posted to live Web site
  • 30 June 2004 (gm) Original submission
Copyright © 1993-2017, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source ( and copyright (© 1993-2017 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1327PMID: 20301502


Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...