Opitz G/BBB syndrome

Mendelian MONDO:0017138 Pathograph 13 hereditary disease

Opitz G/BBB syndrome is a rare congenital midline malformation syndrome. The core phenotype includes hypertelorism, hypospadias in affected males, laryngo-tracheo-esophageal malformations, clefting, cardiac defects, and variable anorectal and neurodevelopmental involvement. The best-established molecular cause is X-linked MID1 loss of function, while historical autosomal-dominant Opitz-like presentations overlap with, but should be distinguished from, SPECC1L-related syndrome.

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2
Inheritance
2
Pathophys.
11
Phenotypes
13
Pathograph
1
Genes
3
Treatments
3
Differentials
7
References
1
Deep Research
👪

Inheritance

2
X-linked inheritance HP:0001417
MID1-related Opitz G/BBB syndrome is inherited in an X-linked pattern, with affected males typically carrying hemizygous pathogenic MID1 variants.
X-linked inheritance
Show evidence (1 reference)
PMID:31630581 SUPPORT Human Clinical
"X-linked Opitz G/BBB syndrome (XLOS) is a multiple congenital disorder inherited in an X-linked manner."
This directly supports the X-linked inheritance pattern for the MID1-related form.
Autosomal dominant Opitz-like spectrum HP:0000006
Autosomal-dominant Opitz-like families have been reported, especially in relation to 22q11 and SPECC1L, but recent nosology literature separates many SPECC1L presentations from canonical MID1-related Opitz G/BBB.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:35205294 PARTIAL Human Clinical
"mutations in the SPECC1L gene in 22q11 have been linked to few cases of the autosomal dominant form of this disorder, as well as to other genetic syndromes."
This supports an autosomal-dominant Opitz-like historical locus while also signaling genetic and nosologic heterogeneity.
⚙

Pathophysiology

2
MID1 loss of function disrupts midline developmental patterning
Pathogenic MID1 variation alters an X-linked microtubule-associated ubiquitin-ligase pathway. The resulting defects in cytoskeletal signaling, protein ubiquitination, and embryonic patterning help explain the congenital midline malformations in craniofacial, foregut-airway, urogenital, anorectal, cardiac, and nervous-system structures.
MID1 link
protein ubiquitination link ⚠ ABNORMAL ubiquitin-dependent protein catabolic process link ⚠ ABNORMAL microtubule cytoskeleton organization link ⚠ ABNORMAL positive regulation of TOR signaling link ⚠ ABNORMAL embryonic morphogenesis link ⚠ ABNORMAL
Downstream
Hypertelorism Abnormal craniofacial midline development contributes to widely spaced eyes.
Laryngeal cleft Abnormal foregut and airway development contributes to laryngo-tracheo-esophageal malformations.
Hypospadias Abnormal urogenital development contributes to hypospadias in affected males.
Anal atresia Abnormal caudal midline development contributes to anorectal malformations.
Ventricular septal defect Disrupted developmental patterning can include congenital cardiac malformations.
Show evidence (2 references)
PMID:35953512 SUPPORT Human Clinical
"Loss-of-function variants in MID1 are the most common cause of Opitz G/BBB syndrome (OS)."
This directly links MID1 loss of function to Opitz G/BBB syndrome.
PMID:30472488 SUPPORT Other
"MID1 is an RBCC (RING-finger, B-boxes and Coiled-coil) scaffold protein. It forms a large microtubule-associated protein complex that stabilizes microtubules."
This supports the microtubule-associated MID1 mechanism used to connect MID1 dysfunction to malformation biology.
MID1 RING-domain isoform loss causes brain-patterning defects
Human iPSC-derived organoid modeling shows that loss of RING-domain containing MID1 isoforms causes early patterning defects, a neurogenic deficit, reduced neural tissue, and increased choroid plexus-like tissue, supporting a developmental mechanism for CNS and neurodevelopmental involvement.
neural cell link neuron link
MID1 link
central nervous system development link ⚠ ABNORMAL
Downstream
Global developmental delay Abnormal early neural patterning can contribute to neurodevelopmental impairment.
Congenital brain malformation Abnormal early neural patterning can contribute to CNS structural anomalies in the Opitz G/BBB spectrum.
Show evidence (2 references)
PMID:38238086 SUPPORT In Vitro
"By using genome-edited human induced pluripotent stem cell lines, we here show that absence of isoforms containing the RING domain of MID1 causes severe patterning defects in human brain organoids."
This in vitro human organoid study directly supports a MID1-dependent brain-patterning mechanism.
PMID:38238086 SUPPORT In Vitro
"We observed a prominent neurogenic deficit with a reduction in neural tissue and a concomitant increase in choroid plexus-like structures."
This supports the neurodevelopmental downstream consequences of MID1 RING-domain isoform loss.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Referential integrity issues (2):
  • Target 'Global developmental delay' (from 'MID1 RING-domain isoform loss causes brain-patterning defects') not found in named elements
  • Target 'Congenital brain malformation' (from 'MID1 RING-domain isoform loss causes brain-patterning defects') not found in named elements
Pathograph: causal mechanism network for Opitz G/BBB syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

11
Cardiovascular 1
Ventricular septal defect Ventricular septal defect (HP:0001629)
Show evidence (1 reference)
PMID:37181966 SUPPORT Human Clinical
"He had hypertelorism, hypospadias, a ventricular septal defect, and a history of cryptorchidism."
This case provides direct clinical evidence for ventricular septal defect in an affected individual.
Digestive 2
Tracheoesophageal fistula Tracheoesophageal fistula (HP:0002575)
Show evidence (1 reference)
PMID:37181966 PARTIAL Human Clinical
"it can also include other midline structural anomalies, such as cleft lip and palate, cryptorchidism, congenital heart problem, laryngotracheal cleft, esophageal fistula, and irregular scrotum."
The abstract supports esophageal fistula within the airway-foregut malformation spectrum; the HPO term is the closest available tracheoesophageal mapping.
Anal atresia Anal atresia (HP:0002023)
Show evidence (1 reference)
PMID:30472488 SUPPORT Human Clinical
"Congenital anomalies include hypospadias, cleft lip/palate, laryngeal and tracheoesophageal abnormalities (typically: cleft larynx), imperforate anus and cardiac defects."
This review explicitly includes imperforate anus among congenital anomalies of X-linked Opitz syndrome.
Eye 1
Hypertelorism Hypertelorism (HP:0000316)
Show evidence (1 reference)
PMID:35205294 SUPPORT Human Clinical
"The main clinical signs are represented by hypertelorism, laryngo-tracheo-esophageal defects and hypospadias."
This directly names hypertelorism as a main Opitz G/BBB clinical sign.
Genitourinary 2
Hypospadias Hypospadias (HP:0000047)
Show evidence (1 reference)
PMID:37181966 SUPPORT Human Clinical
"Hypertelorism and hypospadias are the main characteristics of telecanthus-hypospadias syndrome"
This case report review identifies hypospadias as a main feature of the syndrome.
Cryptorchidism Cryptorchidism (HP:0000028)
Show evidence (1 reference)
PMID:37181966 SUPPORT Human Clinical
"He had hypertelorism, hypospadias, a ventricular septal defect, and a history of cryptorchidism."
This directly supports cryptorchidism in the reported pediatric patient.
Head and Neck 1
Orofacial cleft Orofacial cleft (HP:0000202)
Show evidence (1 reference)
PMID:37181966 SUPPORT Human Clinical
"it can also include other midline structural anomalies, such as cleft lip and palate, cryptorchidism, congenital heart problem, laryngotracheal cleft, esophageal fistula, and irregular scrotum."
The abstract directly lists cleft lip and palate among associated midline structural anomalies, supporting the broader orofacial cleft term.
Nervous System 1
Intellectual disability Intellectual disability (HP:0001249)
Show evidence (1 reference)
PMID:30472488 PARTIAL Human Clinical
"Developmental delay and intellectual disability are inconstant."
This supports variable neurodevelopmental involvement rather than a uniformly present phenotype.
Other 3
Laryngeal cleft Laryngeal cleft (HP:0008751)
Show evidence (1 reference)
PMID:37181966 SUPPORT Human Clinical
"it can also include other midline structural anomalies, such as cleft lip and palate, cryptorchidism, congenital heart problem, laryngotracheal cleft, esophageal fistula, and irregular scrotum."
This lists laryngotracheal cleft among associated midline malformations.
Fetal hydrothorax Fetal hydrothorax (HP:0025678)
Show evidence (1 reference)
PMID:32926417 PARTIAL Human Clinical
"We report two fetal cases carrying a de novo MID1 mutation and presenting with severe hydrothorax, suggesting the expansion of the phenotype of Opitz GBBB syndrome."
This supports fetal hydrothorax as a rare phenotype extension based on two fetal cases.
Telecanthus Telecanthus (HP:0000506)
Show evidence (1 reference)
PMID:37181966 PARTIAL Human Clinical
"Hypertelorism and hypospadias are the main characteristics of telecanthus-hypospadias syndrome"
The clinical case report frames the condition as telecanthus-hypospadias syndrome, supporting telecanthus as a named craniofacial feature with partial specificity.
🧬

Genetic Associations

1
MID1 (Causative)
X-linked
Show evidence (2 references)
PMID:31630581 SUPPORT Human Clinical
"Pathogenetic variants in MID1 gene have been reported in individuals with XLOS."
This directly supports MID1 as the XLOS disease gene.
PMID:35953512 SUPPORT In Vitro
"Minigene assay supports functional effects from MID1 intronic variants."
This supports splice-altering MID1 variants and minigene assays as functional evidence for pathogenicity.
💊

Treatments

3
Surgical repair of congenital anomalies
Action: surgical repair MAXO:0009072
Management is primarily anomaly-directed, including staged hypospadias repair and repair of clefting or other structural defects when present.
Target Phenotypes: Hypospadias ↗ orofacial cleft ↗
Show evidence (1 reference)
PMID:37181966 SUPPORT Human Clinical
"The patient underwent surgery for first-stage hypospadias correction and was advised to follow up for additional surgery and maintenance procedures before being discharged."
This directly supports staged surgical correction for hypospadias in an affected child.
Multidisciplinary supportive care
Action: supportive care MAXO:0000950
Affected individuals require coordinated supportive management across pediatrics, urology or pediatric surgery, cardiology, craniofacial or oral surgery, and other specialties depending on organ involvement.
Target Phenotypes: Ventricular septal defect ↗ Laryngeal cleft ↗
Show evidence (1 reference)
PMID:37181966 SUPPORT Human Clinical
"A multidisciplinary approach involved pediatricians, oral surgeons, cardiologists, and pediatric surgeons."
This supports multidisciplinary supportive management for multisystem disease.
Genetic counseling
Action: genetic counseling MAXO:0000079
Families with an identified MID1 variant should receive counseling about X-linked recurrence risk, carrier testing, and prenatal diagnostic options.
Show evidence (1 reference)
PMID:31630581 PARTIAL Human Clinical
"Prenatal genetic testing is offered for pregnancies at risk, in which the mutation in the family has been identified."
This supports the genetic-counseling context for recurrence-risk and prenatal-testing discussions.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Opitz G/BBB syndrome:

SPECC1L-related syndrome
Overlapping Features SPECC1L-related craniofacial syndromes can overlap with Opitz G/BBB through hypertelorism and clefting, but recent nosology work argues that pathogenic SPECC1L presentations should be kept distinct because canonical laryngeal malformations and male genital anomalies are generally absent.
Show evidence (2 references)
PMID:30472488 SUPPORT Human Clinical
"Although the phenotype of individuals with SPECC1L mutations shows overlap with Opitz syndrome in its craniofacial anomalies, the canonical laryngeal malformations and male genital anomalies are not observed."
This directly supports SPECC1L-related syndrome as an overlapping but distinguishable differential.
PMID:30472488 SUPPORT Human Clinical
"In conclusion, we suggest that patients with pathogenic variants in SPECC1L should not be described as "dominant (or type 2) Opitz GBBB syndrome", and instead should be referred to as "SPECC1L syndrome""
This supports keeping SPECC1L-related disease separate in the differential diagnosis section.
Teebi hypertelorism syndrome Not Yet Curated MONDO:0030639
Overlapping Features Teebi hypertelorism syndrome overlaps through craniofacial hypertelorism, but the broader pattern of malformations differs from canonical MID1-related Opitz G/BBB syndrome.
Baraitser-Winter cerebrofrontofacial syndrome Not Yet Curated MONDO:0017579
Overlapping Features Baraitser-Winter cerebrofrontofacial syndrome overlaps through craniofacial anomalies and neurodevelopmental findings, but it is an actin-related disorder with distinct neurologic and muscular features.
{ }

Source YAML

click to show 
name: Opitz G/BBB syndrome
creation_date: "2026-05-09T14:46:57Z"
updated_date: "2026-05-09T22:35:49Z"
category: Mendelian
description: >-
  Opitz G/BBB syndrome is a rare congenital midline malformation syndrome.
  The core phenotype includes hypertelorism, hypospadias in affected males,
  laryngo-tracheo-esophageal malformations, clefting, cardiac defects, and
  variable anorectal and neurodevelopmental involvement. The best-established
  molecular cause is X-linked MID1 loss of function, while historical
  autosomal-dominant Opitz-like presentations overlap with, but should be
  distinguished from, SPECC1L-related syndrome.
disease_term:
  preferred_term: Opitz G/BBB syndrome
  term:
    id: MONDO:0017138
    label: Opitz G/BBB syndrome
parents:
- hereditary disease
inheritance:
- name: X-linked inheritance
  description: >-
    MID1-related Opitz G/BBB syndrome is inherited in an X-linked pattern, with
    affected males typically carrying hemizygous pathogenic MID1 variants.
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  evidence:
  - reference: PMID:31630581
    reference_title: "First trimester ultrasound features of X-linked Opitz syndrome and early molecular diagnosis: case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      X-linked Opitz G/BBB syndrome (XLOS) is a multiple congenital disorder
      inherited in an X-linked manner.
    explanation: This directly supports the X-linked inheritance pattern for the MID1-related form.
- name: Autosomal dominant Opitz-like spectrum
  description: >-
    Autosomal-dominant Opitz-like families have been reported, especially in
    relation to 22q11 and SPECC1L, but recent nosology literature separates
    many SPECC1L presentations from canonical MID1-related Opitz G/BBB.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:35205294
    reference_title: SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mutations in the SPECC1L gene in 22q11 have been linked to few cases of
      the autosomal dominant form of this disorder, as well as to other genetic
      syndromes.
    explanation: This supports an autosomal-dominant Opitz-like historical locus while also signaling genetic and nosologic heterogeneity.
pathophysiology:
- name: MID1 loss of function disrupts midline developmental patterning
  description: >-
    Pathogenic MID1 variation alters an X-linked microtubule-associated
    ubiquitin-ligase pathway. The resulting defects in cytoskeletal signaling,
    protein ubiquitination, and embryonic patterning help explain the
    congenital midline malformations in craniofacial, foregut-airway,
    urogenital, anorectal, cardiac, and nervous-system structures.
  genes:
  - preferred_term: MID1
    modifier: DECREASED
    term:
      id: hgnc:7095
      label: MID1
  biological_processes:
  - preferred_term: protein ubiquitination
    modifier: ABNORMAL
    term:
      id: GO:0016567
      label: protein ubiquitination
  - preferred_term: ubiquitin-dependent protein catabolic process
    modifier: ABNORMAL
    term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
  - preferred_term: microtubule cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
  - preferred_term: positive regulation of TOR signaling
    modifier: ABNORMAL
    term:
      id: GO:0032008
      label: positive regulation of TOR signaling
  - preferred_term: embryonic morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0048598
      label: embryonic morphogenesis
  downstream:
  - target: Hypertelorism
    description: Abnormal craniofacial midline development contributes to widely spaced eyes.
  - target: Laryngeal cleft
    description: Abnormal foregut and airway development contributes to laryngo-tracheo-esophageal malformations.
  - target: Hypospadias
    description: Abnormal urogenital development contributes to hypospadias in affected males.
  - target: Anal atresia
    description: Abnormal caudal midline development contributes to anorectal malformations.
  - target: Ventricular septal defect
    description: Disrupted developmental patterning can include congenital cardiac malformations.
  evidence:
  - reference: PMID:35953512
    reference_title: "Opitz syndrome: improving clinical interpretation of intronic variants in MID1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loss-of-function variants in MID1 are the most common cause of Opitz
      G/BBB syndrome (OS).
    explanation: This directly links MID1 loss of function to Opitz G/BBB syndrome.
  - reference: PMID:30472488
    reference_title: "Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MID1 is an RBCC (RING-finger, B-boxes and Coiled-coil) scaffold protein.
      It forms a large microtubule-associated protein complex that stabilizes
      microtubules.
    explanation: This supports the microtubule-associated MID1 mechanism used to connect MID1 dysfunction to malformation biology.
- name: MID1 RING-domain isoform loss causes brain-patterning defects
  description: >-
    Human iPSC-derived organoid modeling shows that loss of RING-domain
    containing MID1 isoforms causes early patterning defects, a neurogenic
    deficit, reduced neural tissue, and increased choroid plexus-like tissue,
    supporting a developmental mechanism for CNS and neurodevelopmental
    involvement.
  genes:
  - preferred_term: MID1
    modifier: DECREASED
    term:
      id: hgnc:7095
      label: MID1
  cell_types:
  - preferred_term: neural cell
    term:
      id: CL:0002319
      label: neural cell
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: central nervous system development
    modifier: ABNORMAL
    term:
      id: GO:0007417
      label: central nervous system development
  downstream:
  - target: Global developmental delay
    description: Abnormal early neural patterning can contribute to neurodevelopmental impairment.
  - target: Congenital brain malformation
    description: Abnormal early neural patterning can contribute to CNS structural anomalies in the Opitz G/BBB spectrum.
  evidence:
  - reference: PMID:38238086
    reference_title: Absence of the RING domain in MID1 results in patterning defects in the developing human brain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      By using genome-edited human induced pluripotent stem cell lines, we here
      show that absence of isoforms containing the RING domain of MID1 causes
      severe patterning defects in human brain organoids.
    explanation: This in vitro human organoid study directly supports a MID1-dependent brain-patterning mechanism.
  - reference: PMID:38238086
    reference_title: Absence of the RING domain in MID1 results in patterning defects in the developing human brain.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We observed a prominent neurogenic deficit with a reduction in neural
      tissue and a concomitant increase in choroid plexus-like structures.
    explanation: This supports the neurodevelopmental downstream consequences of MID1 RING-domain isoform loss.
phenotypes:
- name: Hypertelorism
  category: Craniofacial
  description: Widely spaced eyes are one of the main clinical signs.
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:35205294
    reference_title: SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main clinical signs are represented by hypertelorism,
      laryngo-tracheo-esophageal defects and hypospadias.
    explanation: This directly names hypertelorism as a main Opitz G/BBB clinical sign.
- name: Hypospadias
  category: Genitourinary
  description: Hypospadias is a major urogenital malformation in affected males.
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  evidence:
  - reference: PMID:37181966
    reference_title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertelorism and hypospadias are the main characteristics of
      telecanthus-hypospadias syndrome
    explanation: This case report review identifies hypospadias as a main feature of the syndrome.
- name: Orofacial cleft
  category: Craniofacial
  description: Orofacial clefting is part of the midline malformation spectrum.
  phenotype_term:
    preferred_term: orofacial cleft
    term:
      id: HP:0000202
      label: Orofacial cleft
  evidence:
  - reference: PMID:37181966
    reference_title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it can also include other midline structural anomalies, such as cleft lip
      and palate, cryptorchidism, congenital heart problem, laryngotracheal
      cleft, esophageal fistula, and irregular scrotum.
    explanation: The abstract directly lists cleft lip and palate among associated midline structural anomalies, supporting the broader orofacial cleft term.
- name: Laryngeal cleft
  category: Respiratory
  description: Laryngeal cleft is a representative laryngo-tracheo-esophageal malformation.
  phenotype_term:
    preferred_term: Laryngeal cleft
    term:
      id: HP:0008751
      label: Laryngeal cleft
  evidence:
  - reference: PMID:37181966
    reference_title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it can also include other midline structural anomalies, such as cleft lip
      and palate, cryptorchidism, congenital heart problem, laryngotracheal
      cleft, esophageal fistula, and irregular scrotum.
    explanation: This lists laryngotracheal cleft among associated midline malformations.
- name: Tracheoesophageal fistula
  category: Gastrointestinal
  description: Foregut-airway malformations can include esophageal or tracheoesophageal fistula.
  phenotype_term:
    preferred_term: esophageal fistula
    term:
      id: HP:0002575
      label: Tracheoesophageal fistula
  evidence:
  - reference: PMID:37181966
    reference_title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      it can also include other midline structural anomalies, such as cleft lip
      and palate, cryptorchidism, congenital heart problem, laryngotracheal
      cleft, esophageal fistula, and irregular scrotum.
    explanation: The abstract supports esophageal fistula within the airway-foregut malformation spectrum; the HPO term is the closest available tracheoesophageal mapping.
- name: Anal atresia
  category: Gastrointestinal
  description: Imperforate anus or other anorectal anomalies can occur in the syndrome.
  phenotype_term:
    preferred_term: Anal atresia
    term:
      id: HP:0002023
      label: Anal atresia
  evidence:
  - reference: PMID:30472488
    reference_title: "Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital anomalies include hypospadias, cleft lip/palate, laryngeal and
      tracheoesophageal abnormalities (typically: cleft larynx), imperforate
      anus and cardiac defects.
    explanation: This review explicitly includes imperforate anus among congenital anomalies of X-linked Opitz syndrome.
- name: Ventricular septal defect
  category: Cardiovascular
  description: Structural cardiac anomalies can include ventricular septal defect.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:37181966
    reference_title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had hypertelorism, hypospadias, a ventricular septal defect, and a
      history of cryptorchidism.
    explanation: This case provides direct clinical evidence for ventricular septal defect in an affected individual.
- name: Cryptorchidism
  category: Genitourinary
  description: Undescended testes can occur alongside hypospadias and other genital anomalies.
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:37181966
    reference_title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      He had hypertelorism, hypospadias, a ventricular septal defect, and a
      history of cryptorchidism.
    explanation: This directly supports cryptorchidism in the reported pediatric patient.
- name: Intellectual disability
  category: Neurodevelopmental
  description: Neurodevelopmental involvement is variable and can include developmental delay or intellectual disability.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:30472488
    reference_title: "Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Developmental delay and intellectual disability are inconstant.
    explanation: This supports variable neurodevelopmental involvement rather than a uniformly present phenotype.
- name: Fetal hydrothorax
  category: Respiratory
  description: Rare fetal cases with de novo MID1 variants have expanded the prenatal phenotype to include severe hydrothorax.
  phenotype_term:
    preferred_term: Fetal hydrothorax
    term:
      id: HP:0025678
      label: Fetal hydrothorax
  evidence:
  - reference: PMID:32926417
    reference_title: "Hydrothorax in fetal cases of Opitz G/BBB diagnosis: Extending the phenotype?"
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report two fetal cases carrying a de novo MID1 mutation and presenting
      with severe hydrothorax, suggesting the expansion of the phenotype of
      Opitz GBBB syndrome.
    explanation: This supports fetal hydrothorax as a rare phenotype extension based on two fetal cases.
- name: Telecanthus
  category: Craniofacial
  description: Telecanthus is part of the historical telecanthus-hypospadias presentation.
  phenotype_term:
    preferred_term: Telecanthus
    term:
      id: HP:0000506
      label: Telecanthus
  evidence:
  - reference: PMID:37181966
    reference_title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertelorism and hypospadias are the main characteristics of
      telecanthus-hypospadias syndrome
    explanation: The clinical case report frames the condition as telecanthus-hypospadias syndrome, supporting telecanthus as a named craniofacial feature with partial specificity.
genetic:
- name: MID1
  gene_term:
    preferred_term: MID1
    term:
      id: hgnc:7095
      label: MID1
  association: Causative
  inheritance:
  - name: X-linked
  features: >-
    Hemizygous pathogenic MID1 variants cause X-linked Opitz G/BBB syndrome.
    Reported variant classes include loss-of-function and splice-altering
    variants, and intronic variants may require functional assays for
    classification.
  evidence:
  - reference: PMID:31630581
    reference_title: "First trimester ultrasound features of X-linked Opitz syndrome and early molecular diagnosis: case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenetic variants in MID1 gene have been reported in individuals with
      XLOS.
    explanation: This directly supports MID1 as the XLOS disease gene.
  - reference: PMID:35953512
    reference_title: "Opitz syndrome: improving clinical interpretation of intronic variants in MID1 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Minigene assay supports functional effects from MID1 intronic variants.
    explanation: This supports splice-altering MID1 variants and minigene assays as functional evidence for pathogenicity.
diagnosis:
- name: MID1 molecular genetic testing
  description: >-
    Sequencing and deletion/duplication analysis of MID1 are central tests when
    the X-linked form is suspected clinically.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: MID1
        term:
          id: hgnc:7095
          label: MID1
  evidence:
  - reference: PMID:35953512
    reference_title: "Opitz syndrome: improving clinical interpretation of intronic variants in MID1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exon sequencing of a 2-year-old boy with OS showed that he was a carrier
      of the de novo c.1286-10G>T variant in MID1.
    explanation: This supports MID1 sequencing in a clinically affected child.
- name: Functional splicing assay for MID1 intronic variants
  description: >-
    When MID1 intronic or splice-region variants are found, minigene assays can
    provide second-tier functional evidence because patient blood mRNA may be
    unavailable.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:35953512
    reference_title: "Opitz syndrome: improving clinical interpretation of intronic variants in MID1 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MID1 is not expressed in blood and mRNA studies are hardly accessible in
      routine diagnostics.
    explanation: This explains why a proxy functional splicing assay may be needed for intronic MID1 variant interpretation.
  - reference: PMID:35953512
    reference_title: "Opitz syndrome: improving clinical interpretation of intronic variants in MID1 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Minigene assay is an alternative for assessing the effect of intronic
      variants on splicing.
    explanation: This directly supports minigene assay as a functional diagnostic adjunct.
- name: Prenatal genetic testing
  description: >-
    Targeted prenatal testing can be offered in pregnancies at risk when the
    familial MID1 variant is known, especially when prenatal ultrasound shows
    multiple midline defects.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:31630581
    reference_title: "First trimester ultrasound features of X-linked Opitz syndrome and early molecular diagnosis: case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal genetic testing is offered for pregnancies at risk, in which the
      mutation in the family has been identified.
    explanation: This directly supports targeted prenatal genetic testing when a familial MID1 mutation is known.
treatments:
- name: Surgical repair of congenital anomalies
  description: >-
    Management is primarily anomaly-directed, including staged hypospadias
    repair and repair of clefting or other structural defects when present.
  treatment_term:
    preferred_term: surgical repair
    term:
      id: MAXO:0009072
      label: surgical repair
  target_phenotypes:
  - preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  - preferred_term: orofacial cleft
    term:
      id: HP:0000202
      label: Orofacial cleft
  evidence:
  - reference: PMID:37181966
    reference_title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient underwent surgery for first-stage hypospadias correction and
      was advised to follow up for additional surgery and maintenance
      procedures before being discharged.
    explanation: This directly supports staged surgical correction for hypospadias in an affected child.
- name: Multidisciplinary supportive care
  description: >-
    Affected individuals require coordinated supportive management across
    pediatrics, urology or pediatric surgery, cardiology, craniofacial or oral
    surgery, and other specialties depending on organ involvement.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  - preferred_term: Laryngeal cleft
    term:
      id: HP:0008751
      label: Laryngeal cleft
  evidence:
  - reference: PMID:37181966
    reference_title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A multidisciplinary approach involved pediatricians, oral surgeons,
      cardiologists, and pediatric surgeons.
    explanation: This supports multidisciplinary supportive management for multisystem disease.
- name: Genetic counseling
  description: >-
    Families with an identified MID1 variant should receive counseling about
    X-linked recurrence risk, carrier testing, and prenatal diagnostic options.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:31630581
    reference_title: "First trimester ultrasound features of X-linked Opitz syndrome and early molecular diagnosis: case report and review of the literature."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prenatal genetic testing is offered for pregnancies at risk, in which the
      mutation in the family has been identified.
    explanation: This supports the genetic-counseling context for recurrence-risk and prenatal-testing discussions.
differential_diagnoses:
- name: SPECC1L-related syndrome
  description: >-
    SPECC1L-related craniofacial syndromes can overlap with Opitz G/BBB through
    hypertelorism and clefting, but recent nosology work argues that pathogenic
    SPECC1L presentations should be kept distinct because canonical laryngeal
    malformations and male genital anomalies are generally absent.
  evidence:
  - reference: PMID:30472488
    reference_title: "Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the phenotype of individuals with SPECC1L mutations shows
      overlap with Opitz syndrome in its craniofacial anomalies, the canonical
      laryngeal malformations and male genital anomalies are not observed.
    explanation: This directly supports SPECC1L-related syndrome as an overlapping but distinguishable differential.
  - reference: PMID:30472488
    reference_title: "Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, we suggest that patients with pathogenic variants in
      SPECC1L should not be described as "dominant (or type 2) Opitz GBBB
      syndrome", and instead should be referred to as "SPECC1L syndrome"
    explanation: This supports keeping SPECC1L-related disease separate in the differential diagnosis section.
- name: Teebi hypertelorism syndrome
  disease_term:
    preferred_term: Teebi hypertelorism syndrome
    term:
      id: MONDO:0030639
      label: Teebi hypertelorism syndrome
  description: >-
    Teebi hypertelorism syndrome overlaps through craniofacial hypertelorism,
    but the broader pattern of malformations differs from canonical MID1-related
    Opitz G/BBB syndrome.
- name: Baraitser-Winter cerebrofrontofacial syndrome
  disease_term:
    preferred_term: Baraitser-Winter cerebrofrontofacial syndrome
    term:
      id: MONDO:0017579
      label: Baraitser-Winter cerebrofrontofacial syndrome
  description: >-
    Baraitser-Winter cerebrofrontofacial syndrome overlaps through
    craniofacial anomalies and neurodevelopmental findings, but it is an
    actin-related disorder with distinct neurologic and muscular features.
clinical_trials: []
datasets: []
references:
- reference: PMID:35953512
  title: "Opitz syndrome: improving clinical interpretation of intronic variants in MID1 gene."
  findings: []
- reference: PMID:37181966
  title: A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
  findings: []
- reference: PMID:31630581
  title: "First trimester ultrasound features of X-linked Opitz syndrome and early molecular diagnosis: case report and review of the literature."
  findings: []
- reference: PMID:35205294
  title: SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome.
  findings: []
- reference: PMID:30472488
  title: "Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes."
  findings: []
- reference: PMID:38238086
  title: Absence of the RING domain in MID1 results in patterning defects in the developing human brain.
  findings: []
- reference: PMID:32926417
  title: "Hydrothorax in fetal cases of Opitz G/BBB diagnosis: Extending the phenotype?"
  findings: []
📚

References & Deep Research

References

7
PMID:35953512
Opitz syndrome: improving clinical interpretation of intronic variants in MID1 gene.
No top-level findings curated for this source.
PMID:37181966
A Rare Case of Telecanthus-Hypospadias Syndrome in a Pediatric Patient.
No top-level findings curated for this source.
PMID:31630581
First trimester ultrasound features of X-linked Opitz syndrome and early molecular diagnosis: case report and review of the literature.
No top-level findings curated for this source.
PMID:35205294
SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome.
No top-level findings curated for this source.
PMID:30472488
Phenotypic spectrum associated with SPECC1L pathogenic variants: new families and critical review of the nosology of Teebi, Opitz GBBB, and Baraitser-Winter syndromes.
No top-level findings curated for this source.
PMID:38238086
Absence of the RING domain in MID1 results in patterning defects in the developing human brain.
No top-level findings curated for this source.
PMID:32926417
Hydrothorax in fetal cases of Opitz G/BBB diagnosis: Extending the phenotype?
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 34 citations 2026-05-09T11:06:46.978319

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Opitz G/BBB syndrome
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Opitz G/BBB syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Opitz G/BBB syndrome (Opitz syndrome; telecanthus-hypospadias syndrome): Disease characteristics research report

Target disease

  • Disease name: Opitz G/BBB syndrome (also “Opitz syndrome,” “telecanthus-hypospadias syndrome,” “BBB syndrome,” “G syndrome,” “Opitz-Frias syndrome”) (baldini2019understandingthemolecular pages 97-101, vagha2023ararecase pages 1-5)
  • Category: Mendelian / multiple congenital anomaly syndrome with midline developmental defects (migliore2022specc1lmutationsare pages 1-2, micale2023opitzsyndromeimproving pages 1-2)
  • MONDO ID: Not found in retrieved sources (see Limitations)

1) Disease information

Definition and current understanding

Opitz G/BBB syndrome (OS) is a rare, genetically heterogeneous congenital malformation syndrome in which midline structures are primarily affected, classically presenting with hypertelorism/telecanthus and genitourinary anomalies (especially hypospadias in males), with variable involvement of the airway/foregut, heart, anorectal region, and central nervous system (migliore2022specc1lmutationsare pages 1-2, micale2023opitzsyndromeimproving pages 1-2).

A 2023 peer-reviewed review in Pediatric Research summarizes OS as “a rare, genetically heterogeneous disorder that primarily affects midline structures,” listing key features including hypertelorism/telecanthus, cleft lip/palate, laryngo-tracheo-esophageal anomalies, congenital heart defects, anorectal anomalies, and hypospadias (micale2023opitzsyndromeimproving pages 1-2).

Key identifiers (from retrieved evidence)

  • OMIM/“MIM” disease IDs: 300000 (X-linked), 145410 (autosomal dominant) (migliore2022specc1lmutationsare pages 1-2, wang2025heartfailurecaused pages 1-3, sarno2021firsttrimesterultrasound pages 1-3)
  • MID1 gene OMIM/“MIM”: 300552 (migliore2022specc1lmutationsare pages 1-2, sarno2021firsttrimesterultrasound pages 1-3)
  • Orphanet / ICD-10 / ICD-11 / MeSH / MONDO: Not found in retrieved sources.

Synonyms and alternative names

Synonyms reported in the retrieved sources include: BBB syndrome, G syndrome, Opitz-G, Opitz-Frias, and telecanthus-hypospadias syndrome (baldini2019understandingthemolecular pages 97-101).

Evidence provenance

The retrieved evidence is primarily from aggregated disease-level resources and literature synthesis (peer-reviewed review/research articles) plus case reports and prenatal case studies (micale2023opitzsyndromeimproving pages 1-2, sarno2021firsttrimesterultrasound pages 1-3, vagha2023ararecase pages 1-5).

2) Etiology

Disease causal factors

Primary cause: germline genetic variants affecting midline development.

Genetic heterogeneity and subtypes - X-linked Opitz G/BBB syndrome (XLOS): due to hemizygous pathogenic variants in MID1 (also referred to as TRIM18) at Xp22.2 (migliore2022specc1lmutationsare pages 1-2, micale2023opitzsyndromeimproving pages 1-2). - Autosomal dominant Opitz G/BBB / “type 2” historical locus: linked to 22q11.2 genomic losses; some families reported with SPECC1L pathogenic variants at 22q11.23 (migliore2022specc1lmutationsare pages 1-2, bhoj2019phenotypicspectrumassociated pages 1-5). Multiple sources emphasize that SPECC1L-associated disease may be better conceptualized as a partially overlapping, distinct “SPECC1L syndrome” rather than canonical Opitz G/BBB (migliore2022specc1lmutationsare pages 1-2, bhoj2019phenotypicspectrumassociated pages 1-5).

Risk factors

  • Sex: X-linked form predominates in males; female carriers can be mildly affected (often hypertelorism only) but severe fetal female presentations have been reported, potentially influenced by X-inactivation (tessier2020hydrothoraxinfetal pages 1-2).
  • Family history: in XLOS, carrier mothers are common (listyasari2022clinicallessonlearned pages 3-3).

No environmental/toxic/infectious risk factors were identified in the retrieved sources.

Protective factors / gene–environment interactions

No protective factors or gene–environment interactions were identified in the retrieved sources.

3) Phenotypes (with HPO suggestions)

Core phenotype spectrum (MID1-related Opitz G/BBB)

Across review and case-based evidence, the most recurrent features are:

1) Ocular hypertelorism / telecanthus
- Type: clinical sign / craniofacial dysmorphism
- HPO: HP:0000316 (Hypertelorism), HP:0000506 (Telecanthus)
- Notes/frequency: described as a main sign (migliore2022specc1lmutationsare pages 1-2).

2) Hypospadias (and other male genital anomalies)
- Type: congenital urogenital malformation
- HPO: HP:0000047 (Hypospadias), HP:0000028 (Cryptorchidism), HP:0000033 (Bifid scrotum)
- Notes: listed among major findings of OS (migliore2022specc1lmutationsare pages 1-2).

3) Laryngo–tracheo–esophageal defects (including laryngeal cleft / TE fistula in some descriptions)
- Type: congenital airway/foregut malformations
- HPO (examples): HP:0008750 (Laryngeal cleft), HP:0100835 (Tracheoesophageal fistula), HP:0002776 (Feeding difficulties)
- Notes: emphasized as “main clinical signs” in an OS genetics review (migliore2022specc1lmutationsare pages 1-2).

4) Cleft lip and/or palate
- Type: craniofacial malformation
- HPO: HP:0000204 (Cleft upper lip), HP:0000175 (Cleft palate)
- Frequency (reported in a 2023 case-report synthesis): “over half” of individuals had cleft lip/palate (vagha2023ararecase pages 1-5).

5) Congenital heart defects
- Type: structural cardiovascular malformations
- HPO (examples): HP:0001629 (Ventricular septal defect), HP:0001631 (Atrial septal defect), HP:0001708 (Coarctation of aorta), HP:0001643 (Patent ductus arteriosus)
- Notes: CHD is repeatedly listed in OS clinical summaries (migliore2022specc1lmutationsare pages 1-2, vagha2023ararecase pages 1-5).

6) Anorectal anomalies (imperforate/ectopic anus)
- Type: gastrointestinal malformation
- HPO: HP:0002023 (Anal atresia) / HP:0002037 (Anorectal malformation)
- Notes: described in multiple OS summaries (migliore2022specc1lmutationsare pages 1-2).

7) Central nervous system malformations and neurodevelopmental phenotype
- Type: congenital CNS malformations + neurodevelopmental disorder
- HPO (examples): HP:0001274 (Agenesis of corpus callosum), HP:0001305 (Dandy-Walker malformation), HP:0002079 (Ventriculomegaly), HP:0001263 (Global developmental delay), HP:0001249 (Intellectual disability)
- Frequency: developmental delay reported as ~one-third of affected males in a fetal-case letter (tessier2020hydrothoraxinfetal pages 1-2) and about 50% in a prenatal case report/review (sarno2021firsttrimesterultrasound pages 1-3), indicating variability and/or ascertainment differences.

8) Rare fetal/early-life features expanding phenotype - Fetal hydrothorax has been proposed as a rare additional prenatal feature based on two fetal cases with de novo MID1 variants (tessier2020hydrothoraxinfetal pages 1-2).

SPECC1L-related (autosomal dominant) phenotype (overlap and distinctions)

A critical nosology review emphasizes that SPECC1L-related disease overlaps with Opitz-like craniofacial findings (hypertelorism, prominent forehead, broad nasal bridge, anteverted nares, cleft lip/palate), but canonical laryngeal malformations and male genital anomalies are reportedly absent in SPECC1L cohorts (bhoj2019phenotypicspectrumassociated pages 1-5). Instead, characteristic findings include: - Branchial fistulae (HPO: HP:0009794) - Omphalocele / abdominal wall defects (HPO: HP:0001539) - Congenital diaphragmatic hernia (CDH) (HPO: HP:0000776) - Müllerian anomalies such as bicornuate uterus/uterus didelphys (HPO: HP:0000136 / HP:0000130)
These are specifically emphasized in a 2020 AJMG A paper concluding that “SPECC1L is a bona fide CDH gene” and recommending consideration of SPECC1L-related Opitz-like syndrome in CDH patients with compatible craniofacial findings (wild2020congenitaldiaphragmatichernia pages 1-2).

Quality of life impact

Quality-of-life instruments (e.g., EQ-5D/SF-36) were not reported in the retrieved sources. Clinical impact is inferred from multisystem anomalies requiring multidisciplinary care and surgical interventions (vagha2023ararecase pages 1-5).

4) Genetic / molecular information

Causal genes

  • MID1 (TRIM18) — X-linked form (Xp22.2) (migliore2022specc1lmutationsare pages 1-2, micale2023opitzsyndromeimproving pages 1-2)
  • SPECC1L — reported in autosomal dominant families with Opitz-like phenotypes (22q11.23) (micale2023opitzsyndromeimproving pages 1-2, bhoj2019phenotypicspectrumassociated pages 1-5)

Pathogenic variant classes (MID1)

MID1 disease-causing variants are distributed across the locus and include missense, nonsense, indels/frameshifts, splice variants, and large deletions/duplications (baldini2019understandingthemolecular pages 9-13, micale2023opitzsyndromeimproving pages 1-2). A 2023 diagnostic-focused review notes: “MID1 is not expressed in blood and mRNA studies are hardly accessible in routine diagnostics,” and highlights minigene assays for splicing effects (micale2023opitzsyndromeimproving pages 1-2).

Observed/implicated mechanism: Many MID1 alleles are predicted loss-of-function (LoF), and LoF is stated to be the likely mechanism in a genetic heterogeneity review (migliore2022specc1lmutationsare pages 1-2).

Population frequency / carrier frequency

Allele frequencies in gnomAD or similar resources were not extractable from the retrieved sources.

Modifier genes / epigenetics

A review notes phenotypic variability and mentions possible interactions between MID1 and MID2 in shaping phenotype (migliore2022specc1lmutationsare pages 8-10), but no specific validated modifier variants were extractable from the retrieved sources.

5) Environmental information

No specific environmental or lifestyle contributors were identified in the retrieved sources.

6) Mechanism / pathophysiology

Key molecular functions of MID1 relevant to disease

MID1 is a TRIM family E3 ubiquitin ligase that associates with microtubules and forms complexes affecting signaling and translation (baldini2019understandingthemolecular pages 13-18, baldini2019understandingthemolecular pages 9-13). Mechanistic summaries in the retrieved sources support the following chain:

Upstream genetic lesion → MID1 loss/dysfunction → PP2A dysregulation and microtubule/RNP perturbation → altered developmental patterning and tissue fusion → midline malformations.

Key mechanistic elements: - MID1–PP2A axis and translation control: MID1 ubiquitinates components of the PP2A regulatory axis, and loss/depletion of MID1 increases PP2A and can disrupt mTORC1 signaling, consistent with a MID1–PP2A–mTOR functional axis (baldini2019understandingthemolecular pages 13-18). - Microtubule association: MID1 microtubule binding depends on the C-terminal region (B30.2/COS/PRY-SPRY-containing), and truncating variants can disrupt microtubule association and transport (baldini2019understandingthemolecular pages 9-13). In a 2024 human organoid paper, a C-terminal patient variant affecting the B30.2 region “showed no filamentous organization and no co-localization with the microtubule cytoskeleton” (frank2024absenceofthe pages 2-4).

2024 organoid and transcriptomic evidence (recent development)

A key 2024 advance is the use of genome-edited human iPSC-derived brain organoids to interrogate MID1 isoform-function: the Life Science Alliance paper reports that absence of RING-domain-containing MID1 isoforms causes early patterning defects and neurogenic deficits, with transcriptome deregulation preceding neural induction (frank2024absenceofthe pages 1-2, frank2024absenceofthe pages 2-4). The figures directly illustrate reduced neural tissue, PCA transcriptome separation, and expanded choroid plexus-like (TTR-positive) structures (frank2024absenceofthe media 7494b3f8, frank2024absenceofthe media 8e0af7e5, frank2024absenceofthe media f851948f, frank2024absenceofthe media 42fc7635).

Suggested ontology mappings (mechanism)

  • GO biological process (examples):
  • GO:0007275 (multicellular organism development)
  • GO:0007067 (mitotic nuclear division) / broader neurogenesis-related processes (supported by organoid “neurogenic deficit”) (frank2024absenceofthe pages 2-4)
  • GO:0016567 (protein ubiquitination) (supported by MID1 E3 ligase function) (baldini2019understandingthemolecular pages 13-18, frank2024absenceofthe pages 1-2)
  • GO:0008017 (microtubule binding) / GO:0007018 (microtubule-based movement) (supported by MID1 microtubule association/transport) (baldini2019understandingthemolecular pages 9-13)
  • GO:0032008 (positive regulation of TOR signaling) / GO:0031929 (TOR signaling) (supported by MID1–PP2A–mTORC1 axis) (baldini2019understandingthemolecular pages 13-18, frank2024absenceofthe pages 1-2)
  • GO cellular component (examples):
  • GO:0005874 (microtubule)
  • GO:0005829 (cytosol)
  • Cell Ontology (CL) (examples for neurodevelopmental context):
  • CL:0000540 (neuron)
  • CL:0000679 (glial cell) / CL:0000127 (astrocyte) (as downstream candidate; not directly enumerated in retrieved evidence)
  • CL:0000125 (ventricular zone neural progenitor / broadly neural stem/progenitor) consistent with organoid VZ-like regions (frank2024absenceofthe pages 2-4)
  • UBERON (examples):
  • UBERON:0000955 (brain)
  • UBERON:0001893 (cerebellum) (supported by cerebellar vermis anomalies) (baldini2019understandingthemolecular pages 9-13, tessier2020hydrothoraxinfetal pages 1-2)
  • UBERON:0002367 (larynx), UBERON:0003126 (trachea), UBERON:0001043 (esophagus) (supported by laryngo-tracheo-esophageal malformations) (migliore2022specc1lmutationsare pages 1-2)
  • UBERON:0000056 (urethra/urogenital tract) (supported by hypospadias and genital anomalies) (migliore2022specc1lmutationsare pages 1-2)

Immune system involvement

No human OS immunophenotyping evidence was found in the retrieved sources. (A 2024 EAE model paper links Mid1 to T cell migration via mTOR/microtubule pathways, but this is not presented as OS pathogenesis evidence.) (wei2024midline1regulateseffector pages 13-13).

7) Anatomical structures affected

Primary systems: craniofacial midline, urogenital, airway/foregut, cardiovascular, CNS (migliore2022specc1lmutationsare pages 1-2).

Examples (UBERON): - Face/craniofacial region (hypertelorism; clefting) - Larynx–trachea–esophagus axis (laryngo-tracheo-esophageal anomalies) (migliore2022specc1lmutationsare pages 1-2) - Heart (congenital heart defects) (migliore2022specc1lmutationsare pages 1-2) - Brain (corpus callosum/cerebellar vermis anomalies) (migliore2022specc1lmutationsare pages 1-2, tessier2020hydrothoraxinfetal pages 1-2)

8) Temporal development

Onset: typically congenital; many features detectable prenatally (sarno2021firsttrimesterultrasound pages 1-3, tessier2020hydrothoraxinfetal pages 1-2).

Prenatal imaging findings (examples): - First-trimester ultrasound (12 weeks) in XLOS: increased nuchal translucency, heart defects, cleft lip/palate, enlarged fourth ventricle, absence of ductus venosus (sarno2021firsttrimesterultrasound pages 1-3). - Fetal hydrothorax/hydrops in MID1 de novo cases at ~24–25 weeks, with clefting and CNS anomalies (tessier2020hydrothoraxinfetal pages 1-2).

Course is typically lifelong, with outcomes depending on severity of airway/cardiac/CNS involvement (vagha2023ararecase pages 1-5).

9) Inheritance and population

Inheritance

  • X-linked (MID1): males primarily affected; heterozygous females can be mildly affected and may show hypertelorism (tessier2020hydrothoraxinfetal pages 1-2, listyasari2022clinicallessonlearned pages 3-3).
  • Autosomal dominant (22q11.2 losses; SPECC1L in some families): reported in the literature and discussed as a distinct but overlapping spectrum (migliore2022specc1lmutationsare pages 1-2, bhoj2019phenotypicspectrumassociated pages 1-5).

Epidemiology

Two sources cite a male incidence of approximately 1:50,000–1:100,000 for X-linked Opitz G/BBB syndrome (sarno2021firsttrimesterultrasound pages 1-3, vagha2023ararecase pages 5-6).

Diagnostic yield statistic: MID1 pathogenic variants were reported to explain ~20–30% of screened OS cases in one review, highlighting genetic heterogeneity and the need for broader testing when MID1 is negative (migliore2022specc1lmutationsare pages 1-2).

10) Diagnostics

Clinical recognition

Suspicion arises from the combination of hypertelorism/telecanthus with hypospadias and/or airway/foregut malformations, often with clefting and CHD (migliore2022specc1lmutationsare pages 1-2, vagha2023ararecase pages 1-5).

Genetic testing approaches (evidence-based elements)

  • MID1 sequencing (XLOS): standard approach when X-linked phenotype suspected; family segregation helps interpret uncertain variants (listyasari2022clinicallessonlearned pages 3-3).
  • CNV/structural variant testing: OS can be caused by “whole gene or intragenic large deletions” of MID1 (micale2023opitzsyndromeimproving pages 1-2). In prenatal evaluation, chromosomal microarray (aCGH) was used before confirming a familial MID1 variant (sarno2021firsttrimesterultrasound pages 1-3).
  • Splicing/intronic variant interpretation: A 2023 paper emphasizes the diagnostic challenge that “MID1 is not expressed in blood,” and supports minigene assays to functionally test intronic/splice-altering variants for ACMG/AMP classification (micale2023opitzsyndromeimproving pages 1-2).
  • 22q11.2 evaluation / SPECC1L testing: autosomal dominant cases may involve 22q11.2 genomic losses; SPECC1L pathogenic variants are reported in some families but are “not common in sporadic cases,” and missense interpretation can be challenging (migliore2022specc1lmutationsare pages 1-2).

Prenatal diagnostics

When a familial MID1 variant is known, prenatal genetic testing (e.g., chorionic villus sampling with targeted PCR) can enable early molecular diagnosis (sarno2021firsttrimesterultrasound pages 1-3).

Differential diagnosis (from retrieved sources)

SPECC1L-related phenotypes overlap with Teebi hypertelorism and Baraitser–Winter spectrum; the literature explicitly discusses nosology and overlap, emphasizing that SPECC1L cases may lack canonical laryngeal and male genital findings (bhoj2019phenotypicspectrumassociated pages 1-5, migliore2022specc1lmutationsare pages 1-2).

11) Outcome / prognosis

Prognosis depends on severity of airway/feeding complications, congenital heart disease, and CNS involvement (vagha2023ararecase pages 1-5). Severe cardiac involvement can occur; a 2025 case report describes heart failure in a patient with MID1-related OS (wang2025heartfailurecaused pages 1-3). Quantitative survival or life-expectancy estimates were not found in the retrieved sources.

12) Treatment / management (applications and real-world implementation)

No disease-specific pharmacotherapy was identified in the retrieved sources; management is primarily supportive and surgical, tailored to malformations.

Surgical/interventional management (examples)

  • Hypospadias repair often requires staged surgery; a 2023 clinical case underscores coordinated care across pediatrics, urology/pediatric surgery, cardiology, and craniofacial surgery (vagha2023ararecase pages 1-5).

Supportive/multidisciplinary care

A 2023 clinical summary stresses “multidisciplinary” evaluation and attention to cardiovascular, neurologic, and respiratory involvement (vagha2023ararecase pages 5-6).

Experimental/clinical trials

No interventional trials specific to Opitz G/BBB syndrome were identified in the retrieved trial set. One trial was retrieved for 22q11.2 deletion syndrome (NCT05149898; completed Phase 2; transdermal cannabidiol gel), which may be relevant to a subset of autosomal dominant Opitz-like presentations linked to 22q11.2; however, this is not an Opitz-specific trial and no Opitz subgroup results were available from retrieved evidence.

MAXO suggestions (management actions; conceptual mapping)

  • MAXO:0000495 (surgical repair of congenital anomaly) — e.g., hypospadias repair, cleft repair
  • MAXO:0000747 (genetic counseling)
  • MAXO:0000127 (diagnostic genetic testing)
  • MAXO:0001020 (multidisciplinary care)

13) Prevention

Primary prevention is not established because the disorder is genetic. Prevention in practice is reproductive risk management: - Genetic counseling and cascade testing in families with known MID1 variants (listyasari2022clinicallessonlearned pages 3-3). - Prenatal diagnosis when familial mutation is known (sarno2021firsttrimesterultrasound pages 1-3).

14) Other species / natural disease

No naturally occurring veterinary syndrome explicitly corresponding to Opitz G/BBB was identified in the retrieved sources.

15) Model organisms

A MID1 knockout mouse model is described as reproducing key neuroanatomical features: Mid1 knockout (Mid1-/Y) mice show cerebellar abnormalities consistent with patient findings, with defects evident during embryogenesis (baldini2019understandingthemolecular pages 1-9, baldini2019understandingthemolecular pages 9-13). Mechanistic investigations in these models implicate altered subcellular localization of RNA exosome components and reduced SNARE proteins/complex assembly in embryonic cerebella, suggesting disrupted RNA regulation and vesicular trafficking during development (baldini2019understandingthemolecular pages 1-9).

Model type: mammalian genetic model (mouse) and human iPSC-derived brain organoids (frank2024absenceofthe pages 2-4, baldini2019understandingthemolecular pages 9-13).

Recent developments (2023–2024 highlights)

1) Improved clinical interpretation of MID1 intronic variants (2023): emphasizes limited accessibility of patient mRNA studies (“MID1 is not expressed in blood”) and supports functional minigene assays for splicing effects and ACMG/AMP reclassification (micale2023opitzsyndromeimproving pages 1-2). Publication: Aug 2023; https://doi.org/10.1038/s41390-022-02237-y. 2) Human brain organoid disease modeling of MID1 isoform mechanisms (2024): absence of RING-domain-containing isoforms causes early patterning defects, reduced neural tissue, and increased choroid plexus-like structures with early transcriptomic changes (frank2024absenceofthe pages 1-2, frank2024absenceofthe pages 2-4). Publication: Jan 2024; https://doi.org/10.26508/lsa.202302288. Representative figure evidence in the retrieved paper is shown in (frank2024absenceofthe media 7494b3f8, frank2024absenceofthe media 8e0af7e5, frank2024absenceofthe media f851948f, frank2024absenceofthe media 42fc7635).

Data/knowledge gaps and limitations (based on retrieved corpus)

  • Ontology/terminology IDs: MONDO, Orphanet (ORPHA), ICD-10/ICD-11, and MeSH identifiers were not present in the retrieved sources; therefore they cannot be asserted with citations here.
  • Epidemiology: only a coarse male incidence range was available; prevalence, sex ratio across subtypes, and population-specific estimates were not available.
  • Variant-level statistics: specific recurrent variants, allele frequencies (gnomAD), and penetrance estimates were not extractable.
  • Treatment outcomes: no controlled treatment studies specific to Opitz G/BBB were retrieved; management evidence is largely clinical practice/case-based.

Quick-reference summary table

Disease / synonym(s) Key identifiers in retrieved evidence Genetic form / locus / gene Hallmark clinical features supported in retrieved evidence Representative recent references (year; DOI URL)
Opitz G/BBB syndrome; Opitz syndrome; BBB syndrome; G syndrome; Opitz-Frias syndrome; telecanthus-hypospadias syndrome (baldini2019understandingthemolecular pages 97-101, vagha2023ararecase pages 1-5) OMIM/MIM: 300000 (X-linked Opitz G/BBB / XLOS), 145410 (autosomal dominant Opitz syndrome / OS); MID1 gene OMIM/MIM: 300552; MONDO: not found in retrieved sources; Orphanet: not found in retrieved sources; ICD-10/ICD-11: not found in retrieved sources; MeSH: not found in retrieved sources (migliore2022specc1lmutationsare pages 1-2, micale2023opitzsyndromeimproving pages 1-2, wang2025heartfailurecaused pages 1-3, sarno2021firsttrimesterultrasound pages 1-3) Genetically heterogeneous disorder affecting midline development. X-linked form caused by hemizygous pathogenic variants in MID1/TRIM18 at Xp22.2; autosomal-dominant form linked to 22q11.2 genomic losses, with some families carrying heterozygous SPECC1L variants at 22q11.23 (migliore2022specc1lmutationsare pages 1-2, micale2023opitzsyndromeimproving pages 1-2) Hypertelorism/telecanthus; hypospadias; laryngo-tracheo-esophageal defects; cleft lip and/or palate; congenital heart defects; anorectal anomalies; cryptorchidism/bifid or hypoplastic scrotum; CNS anomalies including Dandy-Walker malformation and agenesis/hypoplasia of corpus callosum or cerebellar vermis; developmental delay/intellectual disability with variable expressivity (migliore2022specc1lmutationsare pages 1-2, micale2023opitzsyndromeimproving pages 1-2, vagha2023ararecase pages 1-5, tessier2020hydrothoraxinfetal pages 1-2) Micale et al., 2023; https://doi.org/10.1038/s41390-022-02237-y (micale2023opitzsyndromeimproving pages 1-2) · Vagha et al., 2023; https://doi.org/10.7759/cureus.37411 (vagha2023ararecase pages 1-5)
X-linked Opitz G/BBB syndrome (XLOS) (sarno2021firsttrimesterultrasound pages 1-3) OMIM/MIM: 300000; MID1 OMIM/MIM: 300552; prevalence in males reported as 1:50,000-1:100,000 in retrieved sources; other identifiers not found in retrieved sources (sarno2021firsttrimesterultrasound pages 1-3, vagha2023ararecase pages 5-6) X-linked inheritance; MID1/TRIM18 loss-of-function variants including missense, nonsense, indels, splice-site variants, and whole-gene/intragenic deletions (micale2023opitzsyndromeimproving pages 1-2, vagha2023ararecase pages 5-6) Core findings include hypertelorism/telecanthus and hypospadias, often with cleft lip/palate, heart defects, laryngo-tracheo-esophageal anomalies, genital anomalies, and variable neurodevelopmental involvement; prenatal findings reported include increased nuchal translucency, cleft lip/palate, heart defects, enlarged fourth ventricle, absent ductus venosus, hydrothorax, and vermis defects (vagha2023ararecase pages 1-5, tessier2020hydrothoraxinfetal pages 1-2, sarno2021firsttrimesterultrasound pages 1-3) Sarno et al., 2021; https://doi.org/10.1080/14767058.2019.1677594 (sarno2021firsttrimesterultrasound pages 1-3) · Micale et al., 2023; https://doi.org/10.1038/s41390-022-02237-y (micale2023opitzsyndromeimproving pages 1-2)
Autosomal dominant Opitz syndrome; 22q11.2-related / SPECC1L-related Opitz G/BBB syndrome (migliore2022specc1lmutationsare pages 1-2, wild2020congenitaldiaphragmatichernia pages 1-2) OMIM/MIM: 145410 in retrieved sources; 22q11.2 region implicated; MONDO/Orphanet/ICD/MeSH not found in retrieved sources (migliore2022specc1lmutationsare pages 1-2) Autosomal dominant form linked to 22q11.2 genomic losses; some families reported with heterozygous SPECC1L pathogenic variants at 22q11.23, though retrieved evidence notes SPECC1L mutations are not common in sporadic OS and may represent a distinct SPECC1L syndrome spectrum (migliore2022specc1lmutationsare pages 1-2, bhoj2019phenotypicspectrumassociated pages 1-5) Overlaps with Opitz craniofacial phenotype (hypertelorism, prominent forehead, broad nasal bridge, anteverted nares, cleft lip/palate), but canonical laryngeal malformations and male genital anomalies may be absent; relatively characteristic SPECC1L-associated findings include branchial fistulae, omphalocele, congenital diaphragmatic hernia, bicornuate uterus/uterus didelphys, umbilical hernia, vesicoureteral reflux, and deafness (bhoj2019phenotypicspectrumassociated pages 1-5, wild2020congenitaldiaphragmatichernia pages 1-2, bhoj2019phenotypicspectrumassociated pages 11-14) Migliore et al., 2022; https://doi.org/10.3390/genes13020252 (migliore2022specc1lmutationsare pages 1-2) · Wild et al., 2020; https://doi.org/10.1002/ajmg.a.61878 (wild2020congenitaldiaphragmatichernia pages 1-2)

Table: This table compacts the retrieved evidence on Opitz G/BBB syndrome into names, identifiers, genetic subtypes, hallmark features, and representative references. It is useful as a quick-reference artifact for disease knowledge base population and cross-checking genotype-phenotype distinctions.

References

  1. (baldini2019understandingthemolecular pages 97-101): R Baldini. Understanding the molecular mechanisms underlying the pathogenesis of opitz g/bbb syndrome exploiting the mid1 knock-out …. Unknown journal, 2019.

  2. (vagha2023ararecase pages 1-5): Jayant Vagha, Ajinkya Wazurkar, Keta Vagha, Sham Lohiya, and Ashish Varma. A rare case of telecanthus-hypospadias syndrome in a pediatric patient. Cureus, Apr 2023. URL: https://doi.org/10.7759/cureus.37411, doi:10.7759/cureus.37411. This article has 0 citations.

  3. (migliore2022specc1lmutationsare pages 1-2): Chiara Migliore, Anna Vendramin, Shane McKee, Paolo Prontera, Francesca Faravelli, Rani Sachdev, Patricia Dias, Martina Mascaro, Danilo Licastro, and Germana Meroni. Specc1l mutations are not common in sporadic cases of opitz g/bbb syndrome. Genes, 13:252, Jan 2022. URL: https://doi.org/10.3390/genes13020252, doi:10.3390/genes13020252. This article has 4 citations.

  4. (micale2023opitzsyndromeimproving pages 1-2): Lucia Micale, Federica Russo, Martina Mascaro, Silvia Morlino, Grazia Nardella, Carmela Fusco, Luigi Bisceglia, Germana Meroni, and Marco Castori. Opitz syndrome: improving clinical interpretation of intronic variants in mid1 gene. Pediatric Research, 93:1208-1215, Aug 2023. URL: https://doi.org/10.1038/s41390-022-02237-y, doi:10.1038/s41390-022-02237-y. This article has 4 citations and is from a domain leading peer-reviewed journal.

  5. (wang2025heartfailurecaused pages 1-3): Yu Wang, Xiang Wu, and Kun Wang. Heart failure caused by opitz syndrome: a case report and literature review. BMC Cardiovascular Disorders, Dec 2025. URL: https://doi.org/10.1186/s12872-025-05297-0, doi:10.1186/s12872-025-05297-0. This article has 0 citations and is from a peer-reviewed journal.

  6. (sarno2021firsttrimesterultrasound pages 1-3): Laura Sarno, Giuseppe Maria Maruotti, Antonella Izzo, Cristina Mazzaccara, Luigi Carbone, Giuseppina Esposito, Marco Di Cresce, Gabriele Saccone, Angelo Sirico, Rita Genesio, Nunzia Mollo, Pasquale Martinelli, Anna Conti, Fulvio Zullo, and Giulia Frisso. First trimester ultrasound features of x-linked opitz syndrome and early molecular diagnosis: case report and review of the literature. The Journal of Maternal-Fetal & Neonatal Medicine, 34:3089-3093, Oct 2021. URL: https://doi.org/10.1080/14767058.2019.1677594, doi:10.1080/14767058.2019.1677594. This article has 3 citations.

  7. (bhoj2019phenotypicspectrumassociated pages 1-5): Elizabeth J. Bhoj, Damien Haye, Annick Toutain, Dominique Bonneau, Irene Kibæk Nielsen, Ida Bay Lund, Pauline Bogaard, Stine Leenskjold, Kadri Karaer, Katherine T. Wild, Katheryn L. Grand, Mirena C. Astiazaran, Luis A. Gonzalez-Nieto, Ana Carvalho, Daphné Lehalle, Shivarajan M. Amudhavalli, Elena Repnikova, Carol Saunders, Isabelle Thiffault, Irfan Saadi, Dong Li, Hakon Hakonarson, Yoann Vial, Elaine Zackai, Patrick Callier, Séverine Drunat, and Alain Verloes. Phenotypic spectrum associated with specc1l pathogenic variants: new families and critical review of the nosology of teebi, opitz gbbb, and baraitser-winter syndromes. European Journal of Medical Genetics, 62:103588, Dec 2019. URL: https://doi.org/10.1016/j.ejmg.2018.11.022, doi:10.1016/j.ejmg.2018.11.022. This article has 39 citations and is from a peer-reviewed journal.

  8. (tessier2020hydrothoraxinfetal pages 1-2): Aude Tessier, Lucile Boutaud, Ange‐Line Bruel, Christel Thauvin‐Robinet, Philippe Roth, Valérie Malan, Marie‐Paule Beaujard, Amale Achaiaa, Judite de Oliveira, Julie Steffann, Ferechte Encha‐Razavi, Laurence Faivre, Bettina Bessières, and Tania Attié‐Bitach. Hydrothorax in fetal cases of opitz g/bbb diagnosis: extending the phenotype? Clinical Genetics, 98:620-621, Sep 2020. URL: https://doi.org/10.1111/cge.13840, doi:10.1111/cge.13840. This article has 1 citations and is from a peer-reviewed journal.

  9. (listyasari2022clinicallessonlearned pages 3-3): Nurin A. Listyasari, Gorjana Robevska, Katie L. Ayers, Tiong Yang Tan, Andrew H. Sinclair, and Sultana M.H. Faradz. Clinical lesson learned from genetic analysis in patients prior to surgical repair of hypospadias. Asian Journal of Urology, 9:186-189, Apr 2022. URL: https://doi.org/10.1016/j.ajur.2022.02.006, doi:10.1016/j.ajur.2022.02.006. This article has 0 citations.

  10. (wild2020congenitaldiaphragmatichernia pages 1-2): K. Taylor Wild, Tia Gordon, Elizabeth J. Bhoj, Haowei Du, Shalini N. Jhangiani, Jennifer E. Posey, James R. Lupski, Daryl A. Scott, and Elaine H. Zackai. Congenital diaphragmatic hernia as a prominent feature of a specc1l‐related syndrome. American Journal of Medical Genetics Part A, 182:2919-2925, Sep 2020. URL: https://doi.org/10.1002/ajmg.a.61878, doi:10.1002/ajmg.a.61878. This article has 12 citations.

  11. (baldini2019understandingthemolecular pages 9-13): R Baldini. Understanding the molecular mechanisms underlying the pathogenesis of opitz g/bbb syndrome exploiting the mid1 knock-out …. Unknown journal, 2019.

  12. (migliore2022specc1lmutationsare pages 8-10): Chiara Migliore, Anna Vendramin, Shane McKee, Paolo Prontera, Francesca Faravelli, Rani Sachdev, Patricia Dias, Martina Mascaro, Danilo Licastro, and Germana Meroni. Specc1l mutations are not common in sporadic cases of opitz g/bbb syndrome. Genes, 13:252, Jan 2022. URL: https://doi.org/10.3390/genes13020252, doi:10.3390/genes13020252. This article has 4 citations.

  13. (baldini2019understandingthemolecular pages 13-18): R Baldini. Understanding the molecular mechanisms underlying the pathogenesis of opitz g/bbb syndrome exploiting the mid1 knock-out …. Unknown journal, 2019.

  14. (frank2024absenceofthe pages 2-4): Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, and Susann Schweiger. Absence of the ring domain in mid1 results in patterning defects in the developing human brain. Life Science Alliance, 7:e202302288, Jan 2024. URL: https://doi.org/10.26508/lsa.202302288, doi:10.26508/lsa.202302288. This article has 8 citations and is from a peer-reviewed journal.

  15. (frank2024absenceofthe pages 1-2): Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, and Susann Schweiger. Absence of the ring domain in mid1 results in patterning defects in the developing human brain. Life Science Alliance, 7:e202302288, Jan 2024. URL: https://doi.org/10.26508/lsa.202302288, doi:10.26508/lsa.202302288. This article has 8 citations and is from a peer-reviewed journal.

  16. (frank2024absenceofthe media 7494b3f8): Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, and Susann Schweiger. Absence of the ring domain in mid1 results in patterning defects in the developing human brain. Life Science Alliance, 7:e202302288, Jan 2024. URL: https://doi.org/10.26508/lsa.202302288, doi:10.26508/lsa.202302288. This article has 8 citations and is from a peer-reviewed journal.

  17. (frank2024absenceofthe media 8e0af7e5): Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, and Susann Schweiger. Absence of the ring domain in mid1 results in patterning defects in the developing human brain. Life Science Alliance, 7:e202302288, Jan 2024. URL: https://doi.org/10.26508/lsa.202302288, doi:10.26508/lsa.202302288. This article has 8 citations and is from a peer-reviewed journal.

  18. (frank2024absenceofthe media f851948f): Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, and Susann Schweiger. Absence of the ring domain in mid1 results in patterning defects in the developing human brain. Life Science Alliance, 7:e202302288, Jan 2024. URL: https://doi.org/10.26508/lsa.202302288, doi:10.26508/lsa.202302288. This article has 8 citations and is from a peer-reviewed journal.

  19. (frank2024absenceofthe media 42fc7635): Sarah Frank, Elisa Gabassi, Stephan Käseberg, Marco Bertin, Lea Zografidou, Daniela Pfeiffer, Heiko Brennenstuhl, Sven Falk, Marisa Karow, and Susann Schweiger. Absence of the ring domain in mid1 results in patterning defects in the developing human brain. Life Science Alliance, 7:e202302288, Jan 2024. URL: https://doi.org/10.26508/lsa.202302288, doi:10.26508/lsa.202302288. This article has 8 citations and is from a peer-reviewed journal.

  20. (wei2024midline1regulateseffector pages 13-13): Yingying Wei, Wenjuan Li, Jie Huang, Zachary Braunstein, Xinxin Liu, Xinlu Li, Jeffrey Deiuliis, Jun Chen, Xinwen Min, Handong Yang, Quan Gong, Leya He, Zheng Liu, Lingli Dong, and Jixin Zhong. Midline-1 regulates effector t cell motility in experimental autoimmune encephalomyelitis via mtor/microtubule pathway. Theranostics, 14:1168-1180, Jan 2024. URL: https://doi.org/10.7150/thno.87130, doi:10.7150/thno.87130. This article has 14 citations and is from a domain leading peer-reviewed journal.

  21. (vagha2023ararecase pages 5-6): Jayant Vagha, Ajinkya Wazurkar, Keta Vagha, Sham Lohiya, and Ashish Varma. A rare case of telecanthus-hypospadias syndrome in a pediatric patient. Cureus, Apr 2023. URL: https://doi.org/10.7759/cureus.37411, doi:10.7759/cureus.37411. This article has 0 citations.

  22. (baldini2019understandingthemolecular pages 1-9): R Baldini. Understanding the molecular mechanisms underlying the pathogenesis of opitz g/bbb syndrome exploiting the mid1 knock-out …. Unknown journal, 2019.

  23. (bhoj2019phenotypicspectrumassociated pages 11-14): Elizabeth J. Bhoj, Damien Haye, Annick Toutain, Dominique Bonneau, Irene Kibæk Nielsen, Ida Bay Lund, Pauline Bogaard, Stine Leenskjold, Kadri Karaer, Katherine T. Wild, Katheryn L. Grand, Mirena C. Astiazaran, Luis A. Gonzalez-Nieto, Ana Carvalho, Daphné Lehalle, Shivarajan M. Amudhavalli, Elena Repnikova, Carol Saunders, Isabelle Thiffault, Irfan Saadi, Dong Li, Hakon Hakonarson, Yoann Vial, Elaine Zackai, Patrick Callier, Séverine Drunat, and Alain Verloes. Phenotypic spectrum associated with specc1l pathogenic variants: new families and critical review of the nosology of teebi, opitz gbbb, and baraitser-winter syndromes. European Journal of Medical Genetics, 62:103588, Dec 2019. URL: https://doi.org/10.1016/j.ejmg.2018.11.022, doi:10.1016/j.ejmg.2018.11.022. This article has 39 citations and is from a peer-reviewed journal.