U.S. flag

An official website of the United States government

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

Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

EED-Related Overgrowth

, PhD and , MD, PhD, FRCPC, FCCMG, FACMG, FRSM (UK).

Author Information and Affiliations

Initial Posting: ; Last Update: May 8, 2025.

Estimated reading time: 30 minutes

Summary

Clinical characteristics.

EED-related overgrowth is characterized by fetal or early childhood overgrowth (tall stature, macrocephaly, large hands and feet, and advanced bone age) and intellectual disability that ranges from mild to severe.

Diagnosis/testing.

The diagnosis of EED-related overgrowth is established in a proband with suggestive findings and a heterozygous germline EED pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental delay / intellectual disability requires early referral for developmental support and educational interventions tailored to the child's needs. Seizures, cervical spine instability, palatal abnormalities, kyphoscoliosis, congenital heart defects, cryptorchidism, and ophthalmologic findings are treated per standard practice.

Surveillance: Routine assessment of the following: development; spine for scoliosis or deformities; joint range of motion for joint contractures; and eyes for refractive errors, myopia, and strabismus.

Agents/circumstances to avoid: Activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks) because of the possible increased risk for cervical spine instability.

Genetic counseling.

EED-related overgrowth is an autosomal dominant disorder. Most probands whose parents have undergone molecular genetic testing have the disorder as the result of a de novo EED pathogenic variant. Transmission of an EED pathogenic variant from an affected mother to affected children has been reported in two families. Each child of an individual with EED-related overgrowth has a 50% chance of inheriting the EED pathogenic variant. Once a family member has a confirmed molecular diagnosis of EED-related overgrowth, prenatal and preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

EED-related overgrowth should be suspected in individuals with the following clinical and radiographic findings.

Clinical findings

  • Overgrowth manifesting as:
    • Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean)
      Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth.
    • Macrocephaly (z score ≥2 for age)
    • Large hands and feet (length z score ≥2 for age)
  • Intellectual disability, developmental delay
    • Delay of gross motor skills
    • Delay of fine motor skills
    • Delay of speech acquisition
    • Delay of social development
    • Intellectual disability (by clinical assessment and/or formal testing)

Skeletal radiographic findings

  • Advanced bone age (bone age z score ≥2 for chronologic age)
  • Abnormalities of the cervical spine are uncommon but significant when present.
  • Metaphyses may be widened, flared, and/or abnormally lucent.
  • Skeletal surveys have variously revealed flattened glenoid fossae, humeral heads, femoral heads, and flattened acetabulum. Other findings include small iliac wings and coxa valga or congenital dislocation of the hips, as well as asymmetric limb lengths (1 individual) and flaring of the distal clavicles and distal ribs (1 individual).
  • Osteopenia has been documented on skeletal survey; however, to date no increased risk of fractures has been documented.

Supportive findings include characteristic craniofacial features that are more evident in infancy and childhood and tend to become less evident with age (see Figure 1): a round face; prominent (tall, wide, or broad) forehead; hypertelorism; low, wide, and/or depressed nasal bridge; large ears (with or without posterior helical pits and earlobe creases), which may appear low set; prominent and/or long philtrum; horizontal chin crease; and retrognathia. Facial hypotonia may contribute to an open-mouthed appearance. Published photographs showing the characteristic craniofacial features of EED-related overgrowth are accessible (with registration or institutional access) in Cohen et al [2015] (full text; see Figure 1), Cohen & Gibson [2016] (full text; see Figure 2), Cooney et al [2017] (full text; see Figure 1), Imagawa et al [2017] (full text; see Figure 2), Smigiel et al [2018] (full text; see Figure 1), Griffiths et al [2019] (full text; see Figure 1), and Goel et al [2024] (full text; see Figure 1).

Figure 1. . Photographs of a male with EED-related overgrowth at age one day (A), 3.

Figure 1.

Photographs of a male with EED-related overgrowth at age one day (A), 3.5 weeks (B), three months (C), six months (D), one year (E), two years (F), seven years (G), 11 years (H), 12 years (I), and 33 years (J, K, L, M, N, O, P) Note round face with prominent (more...)

Establishing the Diagnosis

The diagnosis of EED-related overgrowth is established in a proband with suggestive findings and a heterozygous germline pathogenic (or likely pathogenic) variant in EED identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous EED variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the scenario.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of disorders of overgrowth with intellectual disability (OGID) can be indistinguishable, children with the distinctive findings described in Suggestive Findings who have not undergone previous genetic testing are likely to be diagnosed using a multigene panel or genomic testing (see Scenario 1), whereas children with OGID who have previously undergone genetic testing that did not include sequence analysis of EED may be diagnosed using single-gene testing (see Scenario 2).

Scenario 1

When the phenotype of a child with a disorder of OGID does not strongly suggest a specific diagnosis, molecular genetic testing approaches can include use of a multigene panel for OGID disorders or comprehensive genomic testing:

  • A multigene panel that includes EED and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of EED overgrowth, some panels for overgrowth and intellectual disability disorders may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Scenario 2

When the phenotypic findings suggest the diagnosis of EED-related overgrowth in an individual who has already had molecular genetic testing for other common OGID disorders (see Differential Diagnosis), single-gene testing of EED is an option.

  • Single-gene testing. Sequence analysis of EED is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Typically, if no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications; however, to date such variants have not been identified as a cause of this disorder.

Table 1.

Molecular Genetic Testing Used in EED-Related Overgrowth

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
EED Sequence analysis 3100% 4, 5
Gene-targeted deletion/duplication analysis 6None reported 5
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

EED coding region sequence analysis has detected a pathogenic variant in all individuals reported to date [Cohen et al 2015, Cohen & Gibson 2016, Cooney et al 2017, Imagawa et al 2017, Tatton-Brown et al 2017, Smigiel et al 2018]. However, causative noncoding variants may exist; in the case of an individual with a phenotype strongly evocative of EED-related overgrowth, the predictive value of a negative test is unknown.

5.

Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Epigenetic signature analysis / methylation array. A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with EED-related overgrowth [Choufani et al 2020]. Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1) suggestive findings of EED-related overgrowth but in whom no pathogenic variant in EED has been identified via sequence analysis or genomic testing; or (2) suggestive findings of EED-related overgrowth and a EED variant of uncertain clinical significance identified by molecular genetic testing. For an introduction to epigenetic signature analysis click here.

Clinical Characteristics

Clinical Description

EED-related overgrowth is characterized by fetal or early childhood overgrowth (tall stature, macrocephaly, large hands and feet, and advanced osseous maturation), psychomotor delay, and intellectual disability that ranges from mild to severe. Characteristic craniofacial features are more evident in infancy and childhood and tend to become less evident with age (see Figure 1 for photographs of one individual from age one day to 33 years). Other common features include scoliosis, hernias, cryptorchidism in males, and cardiovascular, genitourinary, and ophthalmologic manifestations. To date, EED-related overgrowth has been reported in 19 individuals [Cohen et al 2015, Cohen & Gibson 2016, Cooney et al 2017, Imagawa et al 2017, Tatton-Brown et al 2017, Smigiel et al 2018, Griffiths et al 2019, Spellicy et al 2019, Kang & Kim 2021, Hetzelt et al 2022, Goel et al 2024].

Table 2.

EED-Related Overgrowth: Frequency of Select Features

Feature% of Persons w/Feature 1Comment
Overgrowth15/16 for whom growth data are reportedPrenatal &/or postnatal in onset
Psychomotor delay100%Mild to severe
Intellectual disability100%Mild to severe
Scoliosis6/19Kyphosis & other spinal anomalies may be present.
Hernias6/19Multiple hernias may be present.
Cardiovascular manifestations9/19Small ASDs, VSDs, & PDAs may close spontaneously; major malformations are rare.
Cryptorchidism6/10 malesMay be unilateral or bilateral
Ophthalmologic findings12 out of 19Myopia, Strabismus, Ptosis

ASD = atrial septal defect; PDA = patent ductus arteriosus; VSD = ventricular septal defect

1.

Prenatal overgrowth. Gestational age at delivery has ranged from 36 to 42 weeks.

Birth weight ranges from appropriate to large for gestational age, with weights ranging from 3,550 g (male, 38 weeks' gestation [Smigiel et al 2018]) to 5,160 g (male, 40 weeks' gestation [Spellicy et al 2019]) with z scores from 0 to 4.2. To date, birth weights below the mean for gestational age have not been reported.

Birth length typically ranges from 52 cm (z score = 0.5) to 57 cm (z score = 3.0).

Birth head circumference ranges from 35 cm (z score = 0) to 37.2 cm (z score = 2.0).

Postnatal overgrowth. During childhood and adolescence, increased height, weight, and head circumference manifest as increased z scores in height (0.84 to 5.1), weight (1.0 to 3.8), and head circumference (0.6 to 4.0). Z scores for body mass index vary from approximately 1.4 to 1.8; thus, based on data available to date, obesity does not appear to be a major feature of EED-related overgrowth. Large body weight is typically accompanied by tall stature.

Growth parameter z scores in adults using World Health Organization curves vary from 1.85 to 3.1 in height and 1.46 to 3.9 in head circumference. The two adults reported by Griffiths et al [2019] had body mass indices of 32.6 kg/m2 and 38.2 kg/m2 (in the obese range) in their mid-20s. Registry-based longitudinal growth curves are not yet available.

Psychomotor delay. Delay of gross motor, fine motor, and speech milestones is common.

Intellectual disability, present in all individuals reported to date, may be mild [Cohen et al 2015], moderate [Cooney et al 2017], or severe [Tatton-Brown et al 2017]. Difficulties with coordination and balance may persist into adulthood.

Two affected individuals had relatively sociable, friendly personalities; a third was somewhat hyperactive and lacking inhibition, with occasional aggression toward peers at school. In one individual who had had more detailed testing, specific weaknesses were noted in problem solving and memory, whereas visual memory was a relative strength.

Craniofacial features. The voice may be hypernasal, low, or hoarse.

Characteristic craniofacial features that are more evident in infancy and childhood and tend to become less evident with age (see Figure 1 for photographs of one individual from age one day to 33 years) include a round face; prominent (tall, wide, or broad) forehead; hypertelorism; low, wide, and/or depressed nasal bridge; large ears (with or without posterior helical pits and earlobe creases), which may appear low set; prominent and/or long philtrum; horizontal chin crease; and retrognathia. Facial hypotonia may contribute to an open-mouthed appearance. Published photographs showing the characteristic craniofacial features of EED-related overgrowth are accessible (with registration or institutional access) in Cohen et al [2015] (full text; see Figure 1), Cohen & Gibson [2016] (full text; see Figure 2), Cooney et al [2017] (full text; see Figure 1), Imagawa et al [2017] (full text; see Figure 2), Smigiel et al [2018] (full text; see Figure 1), Griffiths et al [2019] (full text; see Figure 1), and Goel et al [2024] (full text; see Figure 1).

Bilateral cleft palate has been reported in one individual, and bifid uvula has been reported in another.

Musculoskeletal findings. Large hands and feet are notable in childhood and into adulthood. Fingers may be long and slender. Broad thumbs were seen in two individuals. Camptodactyly, joint contractures, flat feet (pes planovalgus), and/or clubfoot may be seen.

Scoliosis and/or kyphoscoliosis of the thoracic spine have been reported frequently.

Hypermobility of the small joints of the hands, recurrent patellar subluxation, and dislocation have also been described; with reported skin fragility (poor wound healing, fragile nails), these suggest more generalized laxity of connective tissue.

Stenosis of the cervical spine has been reported in three individuals, one of whom required laminectomy and arthrodesis; another had associated myelopathy at the level of the third cervical vertebra. Laminectomy and fusion have also been required in a fourth individual, in the context of atlantoaxial instability with C1-C2 instability. Lumbar spinal stenosis or spondylolisthesis has also been reported in two individuals.

Osteopenia, reported in two individuals, was a secondary finding on bone age radiographs or skeletal survey.

Neurologic findings. Low muscle tone with delayed gross motor milestones is common. Gait may appear clumsy; coordination is often poor.

Epilepsy has been reported in six individuals; one of them had seizures associated with hyperinsulinemic hypoglycemia (see Endocrine in this section).

Cerebral imaging has shown nonspecific enlargement of the ventricles, white matter volume loss, an arachnoid cyst, a cyst of the septum pellucidum that required surgical decompression, and a pituitary microadenoma in one individual each. Thinning or shortening of the corpus callosum has been described in two individuals. Cerebral imaging has also been normal in several individuals.

Skin and nail findings have included the following:

  • Multiple pigmented nevi (3 individuals)
  • Soft, doughy skin with increased elasticity (1 individual)
  • Small nails (2 individuals)
  • Fragile fingernails and toenails (1 individual)
  • Poor wound healing with hyperpigmentation and keloid overgrowth of a surgical scar (1 individual)

Hernias. Inguinal and femoral hernias may be seen. Umbilical hernias may be large enough to require surgical management.

Cardiovascular manifestations. Structural cardiac anomalies (patent ductus arteriosus, septal defects, and mild or moderate mitral valve prolapse) have been reported.

Genitourinary manifestations. Bilateral cryptorchidism has been reported in males and may require surgical correction.

One female had nephromegaly and a duplicated collecting system.

Ophthalmologic findings. Ocular findings have included hypertelorism; narrow and/or short palpebral fissures with a downward slant to the lateral aspect of the upper eyelid have also been reported. Eversion of the lateral lower eyelid has also been suggested, based on panel review of published photographs.

The following were reported in one individual each:

  • Ptosis requiring surgical correction
  • Early-onset cataracts (age 30 years)
  • Chororetinal degeneration

Hearing loss

  • Bilateral hypoacusis of 50 dB (frequencies not specified) (1 individual)
  • Mild-to-moderate conductive hearing loss (1 individual)

Endocrine manifestations

  • Neonatal hyperinsulinemic hypoglycemia; treated by glucose infusion and resolved at 21 days (1 individual)
  • Childhood-onset hyperinsulinemic hypoglycemia; treated with octreotide (1 individual).
  • Calcification of one of the adrenal glands with hypocortisolism (1 individual)

Respiratory issues. Neonatal respiratory distress may be seen. One individual had significant tracheomalacia requiring surgical intervention, as well as frequent respiratory infections. One individual was readmitted to hospital in the first weeks of life for pneumonia.

Feeding/gastrointestinal findings include:

  • Gastrostomy tube feeds in infancy, later requiring partial bowel resection for obstruction (the latter possibly associated with anticholinergic medications) (1 individual)
  • Chronic constipation (1 individual)
  • Intestinal malrotation and Hirschsprung disease (1 individual)

Cancer predisposition. No instances of benign or malignant tumors in childhood among individuals with germline EED pathogenic variants have been reported to date. One adult was reported with an anal squamous cell carcinoma at age 61 years [Goel et al 2024]. The risk for certain cancers, such as hematologic cancers and malignant peripheral nerve sheath tumors, could theoretically be increased (see Genetically Related Disorders, Cancer and Benign Tumors).

Genotype-Phenotype Correlations

With only 19 probands reported to date, data are insufficient to consider genotype-phenotype correlations.

Penetrance

Because most germline EED coding variants associated with overgrowth are de novo, penetrance is expected to be high. Estimates of penetrance for inherited EED coding variants are not yet available.

Differential Diagnosis

Significant overlap in findings is observed between EED-related overgrowth, EZH2-related overgrowth, Sotos syndrome (associated with pathogenic variants in NSD1), and Imagawa-Matsumoto syndrome (associated with pathogenic variants in SUZ12) (see Table 3).

Additional disorders of interest in the differential diagnosis of EED-related overgrowth are summarized in Table 3.

Table 3.

Disorders with Macrocephaly and Intellectual Disability of Interest in the Differential Diagnosis of EED-Related Overgrowth

Gene / Genetic MechanismDisorderMOIFeatures of Disorder
Overlapping w/EED-related overgrowthDistinguishing from EED-related overgrowth
EZH2 EZH2-related overgrowth (incl Weaver syndrome)AD
  • Macrosomia
  • Craniofacial dysmorphism similar to EED-related overgrowth
  • Advanced bone age
  • Hematologic malignancies occur at a slightly ↑ frequency.
  • Less frequent cervical spine anomalies
NSD1 (intragenic PV or deletion encompassing NSD1) Sotos syndrome AD
  • Macrosomia
  • Craniofacial dysmorphism similar to EED-related overgrowth
  • Advanced bone age
Tumors occur in ~3% of affected persons.
SUZ12 SUZ12-related overgrowth (Imagawa-Matsumoto syndrome) (OMIM 618786)AD
  • Postnatal overgrowth
  • Craniofacial dysmorphism similar to EED-related overgrowth
  • Advanced bone age
  • Prenatal overgrowth apparently less severe
  • Postnatal overgrowth apparently more severe
Other disorders of interest
Abnormal regulation of gene transcription in 2 imprinted domains at 11p15.5 1 Beckwith-Wiedemann syndrome See footnote 2.
  • Macrosomia
  • Neonatal hypoglycemia
  • Umbilical hernia
  • ↑ risk for variety of tumors, in particular Wilms tumor & hepatoblastoma
  • Organomegaly
  • Macroglossia
DNMT3A Tatton-Brown-Rahman syndrome (DNMT3A-related overgrowth syndrome)AD
  • Macrosomia
  • Craniofacial dysmorphism may be similar to EED-related overgrowth in childhood.
  • Craniofacial dysmorphism in adulthood is distinct from EED-related overgrowth.
  • Dilatation of aortic root is more common in DNMT3A-related overgrowth syndrome.
FBN1 FBN1-related Marfan syndrome AD
  • Tall stature in childhood
  • Scoliosis
  • Camptodactyly
  • Dilatation of aortic root is more common in Marfan syndrome.
  • Lack of intellectual disability
FBN2 Congenital contractural arachnodactyly (CCA) (Beals syndrome)AD
  • Scoliosis
  • Kyphosis
  • Camptodactyly
  • "Crumpled" ears
  • True joint contractures are rare in EED-related overgrowth.
  • Hypertelorism & macrocephaly are more common in EED-related overgrowth.
GPC3 (intragenic PV or deletion encompassing GPC33 Simpson-Golabi-Behmel syndrome type 1 XL
  • Macrosomia
  • Macrocephaly
  • Hernias
  • Vertebral fusion
  • Scoliosis
  • Large hands
  • Postaxial polydactyly
  • Significant risk of embryonal tumors
H1-4 (HIST1H1E) HIST1H1E syndrome AD
  • Camptodactyly
  • Kyphoscoliosis
Abnormal tone (hypotonia in neonatal period or early childhood; ↑ tone described in 2 neonates)
NFIX (intragenic PV or deletion encompassing NFIX) NFIX-related Malan syndrome AD
  • Macrosomia
  • Craniofacial dysmorphism
  • Advanced bone age
  • 1 person w/rib osteosarcoma & another w/Wilms tumor have been reported (overall prevalence of malignancy of ~2%).
  • Less frequent cervical spine anomalies
PTEN PTEN hamartoma tumor syndrome AD
  • Macrocephaly
  • Intellectual disability
  • Cancer predisposition
  • Mucocutaneous lesions
1.

A constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5, a copy number variant of chromosome 11p15.5, or a heterozygous CDKN1C pathogenic variant

2.

Recurrence risk depends on the genetic mechanism in the proband that underlies the abnormal expression of imprinted genes in the Beckwith-Wiedemann syndrome critical region.

3.

Contiguous deletions of GPC3 and GPC4 have been identified in multiple families with Simpson-Golabi-Behmel syndrome type 1.

Management

No clinical practice guidelines for EED-related overgrowth have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EED-related overgrowth, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

EED-Related Overgrowth: Recommended Evaluations Following Initial Diagnosis

System/
Concern
EvaluationComment
Growth Plot prenatal ultrasound &/or birth parameters according to gestational age at assessment or deliveryZ scores may be unusually high relative to norms for gestational age (e.g., birth head circumference of 2.4 SD above the mean at 36 wks).
Neurologic DevelopmentConsider eval by speech therapist, occupational therapist, & physiotherapist.
Neuropsychological assessmentFor behavioral issues
EEG if seizures are suspected
  • Refer to neurologist for seizure disorder mgmt.
  • Rule out hyperinsulinism.
CT of cervical spine to assess for spinal cord impingement & spinal stenosisOnly if signs or symptoms warrant; refer to neurosurgeon as needed.
Brain MRIMay be done electively to look for structural brain abnormalities; because infants & very young children may require sedation or anesthesia for MRI, additional clinical indications (e.g., seizures) may inform timing of imaging.
Oropharynx Exam for palatal anomaliesRefer to craniofacial team or otolaryngologist as needed.
Musculoskeletal Assessment for musculoskeletal anomalies (e.g., scoliosis, kyphosis, limited joint mobility, recurrent dislocations)Refer to orthopedist as needed.
Assessment for osteopeniaIf fracture has occurred, consider bone mineral density scan to quantify risk of future fractures.
Skin Exam for pigmented neviExamine for change in size/shape/color over time.
Cardiac EchocardiogramTo assess for structural heart defects
Hernias Examine for inguinal & umbilical hernias
Genitourinary Males: examine for undescended testes.
Kidney ultrasound examAssess for structural kidney abnormalities.
Eyes Ophthalmologic evalAssess for strabismus, myopia, & refractive error.
Hearing Audiologic evalNewborn audiology screening may be insufficient; consider additional audiology screening if speech is delayed & possibly also at school entry.
Endocrine Glucose level in neonatal period
  • If lethargy &/or poor feeding
  • If seizures occur, measure glucose & insulin simultaneously.
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of EED-related overgrowth to facilitate medical & personal decision making
1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Treatment is symptomatic; no therapy specific to the disorder is available. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Table 5.

EED-Related Overgrowth: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Developmental delay / Intellectual disability / Neurobehavioral issues See Developmental Delay / Intellectual Disability Management Issues.
Seizure disorder Standardized treatment w/ASM by experienced neurologist
  • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Cleft palate
  • Mgmt by cleft/craniofacial team
  • Surgical correction of cleft palate
  • Orthodontic interventions to correct retrognathia (overbite) as needed
Scoliosis/Kyphosis Standard treatment per orthopedist
Cervical spine instability Surgical intervention if instability is severe & neurologic compromise is present or likelyExpert neurosurgical advice recommended, particularly for prophylactic intervention
Other musculoskeletal manifestations (e.g., joint contractures, clubfoot) PT/surgery as needed
Undescended testes, inguinal hernia Standard treatment per urologist
Cardiovascular manifestations Standard therapy per cardiologist
Strabismus, refractive error, cataracts Standard treatment per ophthalmologist
Hearing loss Standard treatment per audiologist/ENT
Hyperinsulinemic hypoglycemia Glucose; consider octreotide.Endocrine eval recommended if hypoglycemia persists &/or insulin levels ↑

ASM = antiseizure medication; PT = physical therapy

1.

Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states and provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.

Autism or other major behavior problems have not been reported to date in EED-related overgrowth. The presence of autistic spectrum disorders, major behavioral difficulties, and/or another significant neuropsychiatric phenotype in an individual with EED-related overgrowth may prompt a search for an additional underlying cause for these features.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Table 6.

EED-Related Overgrowth: Recommended Surveillance

System/ConcernEvaluationFrequency/Comment
Neurologic Developmental assessmentsAnnually or as needed, to adjust therapies & adapt educational needs
Assessment by neurologistPer routine for persons w/epilepsy
Screening for cervical spine instability 1 / spinal stenosisAs dictated by signs & symptoms; see also footnote 1.
Musculoskeletal Eval for scoliosis, spine deformities, joint contracturesAt each visit
Skin Assess for changes in nevi concerning for potential malignancyAnnually or as needed
Eyes Ophthalmologist to screen for refractive errors, myopia, & strabismus
Endocrine Glucose/insulin levels to assess for hyperinsulinemic hypoglycemia 2In infancy & as needed in those w/lethargy, poor feeding, seizures, & other clinical manifestations of hypoglycemia
1.

Though to date data are insufficient to recommend routine imaging of the cervical spine to screen for atlantoaxial instability or spinal canal stenosis, practitioners should have a low threshold for imaging when signs and symptoms are consistent with cord impingement, such as gait deterioration (particularly when of rapid onset). Elective cervical spine imaging should be considered when activities involve possible sudden movement of the neck and/or head and neck (e.g., contact sports, amusement park thrill rides).

2.

Hyperinsulinemic hypoglycemia was confirmed in two individuals (1 as a neonate); infants showing evidence of poor neonatal adaptation should have their serum glucose measured, and insulin levels measured if circulating glucose is low.

Although malignant peripheral nerve sheath tumors (MPNSTs) have not been reported to date in individuals with EED-related overgrowth caused by germline EED pathogenic variants, the observation of somatic EED pathogenic variants in malignant MPNSTs [Lee et al 2014] suggests that lesions with features suspicious for MPNSTs should be followed with clinical examination and/or imaging as per guidelines for such lesions in individuals with neurofibromatosis type 1.

Agents/Circumstances to Avoid

In one individual, neurologic compromise resulting from neck motion during gymnastics required surgical intervention. Caution is advised for activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks).

Side effects of pharmacologic agents that inhibit the activity of polycomb repressive complex 2 (PRC2) (which includes the polycomb protein EED, encoded by EED) may be increased (e.g., tazemetostat). In addition, the efficacy of such agents in individuals with EED-related overgrowth may differ from that in other individuals.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

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

Mode of Inheritance

EED-related overgrowth is an autosomal dominant disorder.

Risk to Family Members

Parents of a proband

  • Most probands reported to date with EED-related overgrowth whose parents have undergone molecular genetic testing have the disorder as a result of a de novo EED pathogenic variant.
  • Some individuals diagnosed with EED-related overgrowth have an affected parent. Two families with multiple affected individuals have been reported; in each of these, an affected mother gave birth to more than one affected child [Kang & Kim 2021, Goel et al 2024].
  • If a parent of an individual with an identified EED pathogenic variant does not have any clinical features of EED-related overgrowth, that parent is unlikely to have a pathogenic variant in EED. However, molecular genetic testing of both parents for the EED pathogenic variant identified in the proband is generally advisable.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
    • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
      * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with EED-related overgrowth has a 50% chance of inheriting the EED pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the EED pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once a family member has a confirmed molecular diagnosis of EED-related overgrowth, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

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

Molecular Genetics

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

Table A.

EED-Related Overgrowth: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
EED 11q14​.2 Polycomb protein EED EED EED

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

Table B.

OMIM Entries for EED-Related Overgrowth (View All in OMIM)

605984EMBRYONIC ECTODERM DEVELOPMENT; EED
617561COHEN-GIBSON SYNDROME; COGIS

Molecular Pathogenesis

EED encodes polycomb protein EED, a highly conserved, ubiquitously expressed protein that is a core member of the polycomb repressive complex 2 (PRC2). Other PRC2 members include EZH2, SUZ12, RBBP7, and RBBP4; their complex with EED is thought to be necessary for the lysine methyltransferase activity of PRC2.

There are seven WD40 domains, though whether these domains have redundant or distinct functions is not yet known. The C-terminal domain of EED binds specifically to trimethylated H3K27 (i.e., H3K27me3) histone tails, and this function is thought to be necessary for the propagation of H3K27me3 marks to daughter cells that initially lack sufficient H3K27 marks after mitosis. In so doing, EED is believed to provide the epigenetic reader function of the PRC2 complex’s epigenetic reader-writer function.

In general, PRC2 is a key chromatin modifier involved in the maintenance of transcriptional silencing. PRC2-mediated trimethylation of H3K27 is thought to correlate with transcriptional repression of local DNA. Correct propagation of H3K27me3 marks is in turn thought necessary in order for repressive domains to persist in the newly synthesized chromatin [Margueron et al 2009].

In an ex vivo assay, a lymphoblastoid cell line derived from a Japanese individual with EED pathogenic variant p.Arg236Thr showed reduced levels of H3K27 trimethylation by Western blotting, consistent with reduced methyltransferase activity of the mutated PRC2 complex toward this substrate [Imagawa et al 2017]. These data suggest that EED-related overgrowth is caused by partial loss of function of EED protein.

Mechanism of disease causation. Loss of function

Table 7.

EED Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_003797​.4
NP_003788​.2
c.707G>Cp.Arg236ThrSee Molecular Pathogenesis.

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Dr William T Gibson's clinical and laboratory research focuses on Cohen-Gibson syndrome, Weaver syndrome, and similar rare disorders, including rare genetic versions of common, complex diseases.

Dr Gibson (ac.rhccb@nosbigtw) is actively involved in clinical research regarding individuals with EED-related overgrowth. He would be happy to communicate with persons who have any questions regarding diagnosis of EED-related overgrowth or other considerations.

Dr Gibson is also interested in hearing from clinicians treating families affected by childhood overgrowth and intellectual disability disorders in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Dr Gibson to inquire about review of EED, EZH2, and SETD1B variants of uncertain significance.

Acknowledgments

We gratefully acknowledge the patients and their families who have generously participated in the research described and referenced here. We also gratefully acknowledge the contributions of Professor Steven JM Jones and Dr Yaoqing Shen for helpful discussions of EED variation recorded in online databases of human cancers.

Dr Gibson gratefully acknowledges both research salary support and laboratory support provided by the British Columbia Children's Hospital Foundation through the BC Children's Hospital Research Institute's IGAP Intramural Salary Award program, as well as various Childhood Diseases Theme and Diabetes Theme funding programs. Dr Gibson is also grateful for the operating funds provided competitively through various programs run by the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI), Genome Canada, and Genome British Columbia.

Dr Cohen would like to thank the generous gifts to Children's Mercy Research Institute and the Genomic Answers for Kids program at Children's Mercy Kansas City.

Revision History

  • 8 May 2025 (sw) Comprehensive updated posted live
  • 11 April 2019 (bp) Review posted live
  • 8 April 2018 (wtg) Original submission

References

Literature Cited

  • Choufani S, Gibson WT, Turinsky AL, Chung BHY, Wang T, Garg K, Vitriolo A, Cohen ASA, Cyrus S, Goodman S, Chater-Diehl E, Brzezinski J, Brudno M, Ming LH, White SM, Lynch SA, Clericuzio C, Temple IK, Flinter F, McConnell V, Cushing T, Bird LM, Splitt M, Kerr B, Scherer SW, Machado J, Imagawa E, Okamoto N, Matsumoto N, Testa G, Iascone M, Tenconi R, Caluseriu O, Mendoza-Londono R, Chitayat D, Cytrynbaum C, Tatton-Brown K, Weksberg R. DNA methylation signature for EZH2 functionally classifies sequence variants in three PRC2 complex genes. Am J Hum Genet. 2020;106:596-610. [PMC free article: PMC7212265] [PubMed: 32243864]
  • Cohen AS, Gibson WT. EED-associated overgrowth in a second male patient. J Hum Genet. 2016;61:831-4. [PubMed: 27193220]
  • Cohen AS, Tuysuz B, Shen Y, Bhalla SK, Jones SJ, Gibson WT. A novel mutation in EED associated with overgrowth. J Hum Genet. 2015;60:339-42. [PubMed: 25787343]
  • Cooney E, Bi W, Schlesinger AE, Vinson S, Potocki L. Novel EED mutation in patient with Weaver syndrome. Am J Med Genet A. 2017;173:541-5. [PubMed: 27868325]
  • Fu JM, Satterstrom FK, Peng M, Brand H, Collins RL, Dong S, Wamsley B, Klei L, Wang L, Hao SP, Stevens CR, Cusick C, Babadi M, Banks E, Collins B, Dodge S, Gabriel SB, Gauthier L, Lee SK, Liang L, Ljungdahl A, Mahjani B, Sloofman L, Smirnov AN, Barbosa M, Betancur C, Brusco A, Chung BHY, Cook EH, Cuccaro ML, Domenici E, Ferrero GB, Gargus JJ, Herman GE, Hertz-Picciotto I, Maciel P, Manoach DS, Passos-Bueno MR, Persico AM, Renieri A, Sutcliffe JS, Tassone F, Trabetti E, Campos G, Cardaropoli S, Carli D, Chan MCY, Fallerini C, Giorgio E, Girardi AC, Hansen-Kiss E, Lee SL, Lintas C, Ludena Y, Nguyen R, Pavinato L, Pericak-Vance M, Pessah IN, Schmidt RJ, Smith M, Costa CIS, Trajkova S, Wang JYT, Yu MHC, Aleksic B, Artomov M, Benetti E, Biscaldi-Schafer M, Børglum AD, Carracedo A, Chiocchetti AG, Coon H, Doan RN, Fernández-Prieto M, Freitag CM, Gerges S, Guter S, Hougaard DM, Hultman CM, Jacob S, Kaartinen M, Kolevzon A, Kushima I, Lehtimäki T, Rizzo CL, Maltman N, Manara M, Meiri G, Menashe I, Miller J, Minshew N, Mosconi M, Ozaki N, Palotie A, Parellada M, Puura K, Reichenberg A, Sandin S, Scherer SW, Schlitt S, Schmitt L, Schneider-Momm K, Siper PM, Suren P, Sweeney JA, Teufel K, del Pilar Trelles M, Weiss LA, Yuen R, Cutler DJ, De Rubeis S, Buxbaum JD, Daly MJ, Devlin B, Roeder K, Sanders SJ, Talkowski ME, The Autism Sequencing C, Broad Institute Center for Common Disease G, i P-BC. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nature Genetics. 2022;54:1320-31. [PMC free article: PMC9653013] [PubMed: 35982160]
  • Kang YJ, Kim YO. Cohen-Gibson syndrome in a family: the first familial case report. J Genet Med. 2021;18:70-4.
  • Goel H, O'Donnell S, Edwards M. EED related overgrowth: first report of multiple members in a single family. Am J Med Genet A. 2024;194:374-82. [PubMed: 37840385]
  • Griffiths S, Loveday C, Zachariou A, Behan LA, Chandler K, Cole T, D'Arrigo S, Dieckmann A, Foster A, Gibney J, Hunter M, Milani D, Pantaleoni C, Roche E, Sherlock M, Springer A, White SM, Tatton-Brown K, et al. EED and EZH2 constitutive variants: a study to expand the Cohen-Gibson syndrome phenotype and contrast it with Weaver syndrome. Am J Med Genet A. 2019;179:588-94. [PubMed: 30793471]
  • Hetzelt KLML, Winterholler M, Kerling F, Rauch C, Ekici AB, Winterpacht A, Vasileiou G, Uebe S, Thiel CT, Kraus C, Reis A, Zweier C. Manifestation of epilepsy in a patient with EED-related overgrowth (Cohen-Gibson syndrome). Am J Med Genet A. 2022;188:292-7. [PubMed: 34533271]
  • Imagawa E, Higashimoto K, Sakai Y, Numakura C, Okamoto N, Matsunaga S, Ryo A, Sato Y, Sanefuji M, Ihara K, Takada Y, Nishimura G, Saitsu H, Mizuguchi T, Miyatake S, Nakashima M, Miyake N, Soejima H, Matsumoto N. Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. Hum Mutat. 2017;38:637-48. [PubMed: 28229514]
  • Lee W, Teckie S, Wiesner T, Ran L, Prieto Granada CN, Lin M, Zhu S, Cao Z, Liang Y, Sboner A, Tap WD, Fletcher JA, Huberman KH, Qin LX, Viale A, Singer S, Zheng D, Berger MF, Chen Y, Antonescu CR, Chi P. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet. 2014;46:1227-32. [PMC free article: PMC4249650] [PubMed: 25240281]
  • Margueron R, Justin N, Ohno K, Sharpe ML, Son J, Drury WJ III, Voigt P, Martin SR, Taylor WR, De Marco V, Pirrotta V, Reinberg D, Gamblin SJ. Role of the polycomb protein EED in the propagation of repressive histone marks. Nature. 2009; 461:762-7. [PMC free article: PMC3772642] [PubMed: 19767730]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016; 48:126-33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Smigiel R, Biernacka A, Biela M, Murcia-Pienkowski V, Szmida E, Gasperowicz P, Kosinska J, Kostrzewa G, Koppolu AA, Walczak A, Wawrzuta D, Rydzanicz M, Sasiadek M, Ploski R. Novel de novo mutation affecting two adjacent amino acids in the EED gene in a patient with Weaver syndrome. J Hum Genet. 2018;63:517-20. [PubMed: 29410511]
  • Spellicy CJ, Peng Y, Olewiler L, Cathey SS, Rogers RC, Bartholomew D, Johnson J, Alexov E, Lee JA, Friez MJ, Jones JR. Three additional patients with EED-associated overgrowth: potential mutation hotspots identified? J Hum Genet. 2019;64:561-72. [PubMed: 30858506]
  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • Tatton-Brown K, Loveday C, Yost S, Clarke M, Ramsay E, Zachariou A, Elliott A, Wylie H, Ardissone A, Rittinger O, Stewart F, Temple IK, Cole T, Mahamdallie S, Seal S, Ruark E, Rahman N, et al. Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability. Am J Hum Genet. 2017;100:725-36. [PMC free article: PMC5420355] [PubMed: 28475857]
  • Wassef M, Margueron R. The multiple facets of PRC2 alterations in cancers. J Mol Biol. 2017;429:1978-93. [PubMed: 27742591]
  • Zhou X, Feliciano P, Shu C, Wang T, Astrovskaya I, Hall JB, Obiajulu JU, Wright JR, Murali SC, Xu SX, Brueggeman L, Thomas TR, Marchenko O, Fleisch C, Barns SD, Snyder LG, Han B, Chang TS, Turner TN, Harvey WT, Nishida A, O'Roak BJ, Geschwind DH, Consortium S, Michaelson JJ, Volfovsky N, Eichler EE, Shen Y, Chung WK. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. Nat Genet. 2022;54:1305-19. [PMC free article: PMC9470534] [PubMed: 35982159]
Copyright © 1993-2025, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2025 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

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

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

Bookshelf ID: NBK540017PMID: 30973693

Views

Tests in GTR by Gene

Related information

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

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...