Summary
Clinical characteristics.
RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and mild sensorineural hearing loss. Hypotonia and feeding problems are common among affected individuals. Developmental delay and intellectual disability range from mild to profound. Behavior problems may include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder. A variety of eye anomalies (coloboma, optic nerve anomalies, microphthalmia, and/or Peter's anomaly) and vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia) have been reported. Congenital heart defects, most commonly septal defects, have also been described. Genitourinary abnormalities include vesicoureteral reflux, and cryptorchidism and hypospadias in males. Sensorineural hearing loss can be unilateral or bilateral.
Diagnosis/testing.
The diagnosis of RERE-related disorders is established in a proband by identification of a heterozygous pathogenic variant in RERE by molecular genetic testing.
Management.
Treatment of manifestations: Feeding difficulties may require the use of feeding therapy and/or thickened liquids; in severe cases, a nasogastric or gastrostomy tube may be considered. Seizure disorders, abnormal vision and/or strabismus, hearing loss, congenital heart defects, gastroesophageal reflux, genitourinary anomalies, scoliosis, congenital hip dysplasia, developmental delay, and behavioral problems are treated in the standard manner.
Surveillance: At least annual monitoring of developmental progress / educational needs and for scoliosis (until growth is complete). Annual (or as clinically indicated) ophthalmologic and audiologic evaluations. Routine follow up with a cardiologist and a urologist, as indicated for those who have anomalies involving these organ systems. Monitoring of seizure activity and behavioral issues as needed.
Genetic counseling.
RERE-related disorders are inherited in an autosomal dominant manner and are typically caused by a de novo pathogenic variant. If the RERE pathogenic variant identified in the proband is not identified in one of the parents, the risk to sibs is low (~1%) but greater than that of the general population because of the possibility of parental germline mosaicism for the pathogenic variant. Once the RERE pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
No clinical diagnostic criteria have been published.
Suggestive Findings
RERE-related disorders should be considered in individuals presenting with the following clinical and brain MRI findings.
Clinical findings. Mild-to-profound developmental delay, intellectual disability, and/or autism spectrum disorder; AND any of the following features presenting in infancy or childhood:
- Behavioral issues, including attention-deficit/hyperactivity disorder and self-injurious behavior
- Generalized hypotonia of infancy
- Infant feeding difficulties
- Eye/vision problems:
- Structural eye defects (coloboma, optic nerve atrophy/hypoplasia, micropthalmia, and/or Peter's anomaly)
- Vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia, and/or ptosis)
- Sensorineural hearing loss
- Congenital heart defects, especially septal defects
- Epilepsy
- Genitourinary anomalies including vesicoureteral reflux, hypospadias, and cryptorchidism
- Choanal atresia
Brain MRI findings. Brain MRI may be normal or may reveal a range of related abnormalities including diminished white matter volume, abnormalities of or thin corpus callosum, and ventriculomegaly.
Establishing the Diagnosis
The diagnosis of RERE-related disorders is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in RERE by molecular genetic testing (see Table 1).
Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of RERE, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.
- Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including RERE) that cannot be detected by sequence analysis.
- An intellectual disability (ID) multigene panel that includes RERE and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants of uncertain significance and pathogenic variants 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 RERE-related disorders, some panels for intellectual disability 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.
- Exome sequencing, which does not require the clinician to determine which gene is likely involved, yields results similar to an ID multigene panel but has two advantages: (1) a multigene panel may not include all rare genes recently identified as causing ID; and (2) exome sequencing may be able to detect pathogenic variants in genes which – for technical reasons – do not sequence well.
Table 1.
Molecular Genetic Testing Used in RERE-Related Disorders
Clinical Characteristics
Clinical Description
RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and sensorineural hearing loss.
To date, 19 individuals have been identified with a pathogenic variant in RERE [Fregeau et al 2016, Jordan et al 2018]. The following description of the phenotypic features associated with this condition is based on these reported cases.
Developmental delay (DD) and intellectual disability (ID) have been documented in most individuals with RERE-related disorders and can vary from mild to profound. Some affected individuals may have normal early developmental milestones.
Other neurodevelopmental features including hypotonia and feeding problems (which may be caused by brain stem or cranial nerve abnormalities) are common among affected individuals.
Behavioral problems are often noted and can include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder.
Sensory impairments are common.
- 6/19 (~30%) of affected individuals have structural eye anomalies (see Suggestive Findings). Both iris and chorioretinal colobomas have been described, although none of the reported individuals to date are blind. Other eye/vision problems such as myopia, anisometropia, astigmatism, exotropia, esotropia, and ptosis have also been documented.
- 4/19 (~20%) of affected individuals have sensorineural hearing loss. Hearing loss has been described as mild and can be unilateral or bilateral. One affected individual had progressive hearing loss that became severe, but it is unclear if this is typical.
Congenital heart defects are seen in 8/19 (~40%) of affected individuals, with ventricular septal defects being particularly common.
Epilepsy has been diagnosed in 2/19 (~10%) of affected individuals. Given the small numbers, it is not yet known if there is a predominant seizure type.
Neuroimaging reveals central nervous system anomalies in 13/19 (approximately 70%) of affected individuals. Typical findings include diminished white matter volume, abnormalities of or thin corpus callosum, and ventriculomegaly (see Suggestive Findings).
Other associated features
- Gastrointestinal problems, especially gastroesophageal reflux disease, is present in a minority of affected individuals. Some affected individuals have poor suck and swallow without true dysphagia. One person required tube feeding as an infant.
- Genitourinary abnormalities including vesicoureteral reflux, and cryptorchidism and hypospadias in males
- Musculoskeletal features including congenital hip dysplasia (2/19 individuals; approximately 10%) and scoliosis without vertebral anomalies (3/19 individuals; ~15%). Some affected individuals are still very young, so the true incidence of scoliosis may be higher than reported.
- Facial features. No specific dysmorphic features have been observed. If present, dysmorphic features are nonspecific.
- Choanal atresia has been identified only in individuals with the c.4313_4318dupTCCACC, p.(Leu1438_His1439dup) pathogenic variant (see Genotype/Phenotype Correlations).
- Cranial nerve dysfunction has been identified in one affected individual.
Prognosis. It is unknown if life span in RERE-related disorders is abnormal. Two reported individuals are alive in their early twenties [Jordan et al 2018], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
Genotype-Phenotype Correlations
In general, pathogenic missense variants affecting the atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, genitourinary anomalies, and sensorineural hearing loss when compared with loss-of-function variants [Jordan et al 2018]. This suggests that some changes in this domain may represent dominant negative alleles.
The c.4313_4318dupTCCACC, p.(Leu1438_His1439dup) variant is associated with a unique phenotypic presentation that includes many features commonly seen in individuals with CHARGE syndrome including coloboma, choanal atresia, congenital heart defects, growth deficiency, genitourinary anomalies, and DD/ID.
Prevalence
The prevalence of this condition is unknown. Approximately 19 individuals with RERE-related disorders have been identified and published in the literature [Fregeau et al 2016, Jordan et al 2018].
Genetically Related (Allelic) Disorders
1p36 deletion syndrome (OMIM 607872). RERE is located in the proximal critical region for the 1p36 deletion syndrome. It is likely that RERE haploinsufficiency contributes to many of the phenotypic features associated with proximal 1p36 deletions (see Differential Diagnosis).
Differential Diagnosis
Because the phenotypic features associated with RERE-related disorders are not sufficient to diagnose this condition, all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See OMIM Autosomal Dominant, Autosomal Recessive, Nonsyndromic X-Linked, and Syndromic X-Linked Intellectual Developmental Disorder Phenotypic Series.
Table 2.
Disorders to Consider in the Differential Diagnosis of RERE-Related Disorders
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with RERE-related disorders, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with RERE-Related Disorders
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with RERE-Related Disorders
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. In the US, early intervention is a federally funded program available in all states.
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.
Ages 5-21 years
- In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can assist with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a 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.
- Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy, typically from an occupational or speech therapist, is recommended for affected individuals who have difficulty feeding as a result of poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication) for individuals who have expressive language difficulties, particularly those for whom this is a motor deficit.
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, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
Table 5.
Recommended Surveillance for Individuals with RERE-Related Disorders
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
RERE-related disorders are inherited in an autosomal dominant manner and are typically caused by a de novo pathogenic variant.
Risk to Family Members
Parents of a proband
- All probands reported to date with RERE-related disorders whose parents have undergone molecular genetic testing have the disorder as a result of a de novo RERE pathogenic variant.
- Theoretically, if the parent is the individual in whom the RERE pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. Therefore, molecular genetic testing should be considered in cases where the parents appear clinically asymptomatic.
- If the RERE pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of germline mosaicism have been reported to date.
Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the RERE pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
Offspring of a proband. No individuals with an RERE-related disorder have been reported to have had children. However, many are not yet of reproductive age and there is no reason to assume that reproduction would not be biologically possible.
Other family members. Given that all probands with an RERE-related disorder reported to date have the disorder as a result of a de novo RERE pathogenic variant, the risk to other family members is presumed to be low.
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
Risk to future pregnancies is presumed to be low as the proband most likely has a de novo RERE pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal and preimplantation genetic testing may be considered.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal 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.
- National Library of Medicine Genetics Home Reference
- American Association on Intellectual and Developmental Disabilities (AAIDD)Phone: 202-387-1968
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.
RERE-Related Disorders: Genes and Databases
Table B.
OMIM Entries for RERE-Related Disorders (View All in OMIM)
Molecular Pathogenesis
RERE is a nuclear receptor coregulator that functions in protein complexes to both positively and negatively modulate the transcription of target genes.
Gene structure. RERE, previously called the arginine-glutamic dipeptide repeats encoding gene (NM_012102.3), contains 22 coding exons and two noncoding exons. Alternative transcripts and splice isoforms have been identified.
See Table A, Gene for a detailed summary of gene and protein information.
Pathogenic variants. A large percentage of the pathogenic variants reported in RERE are missense variants in the histidine-rich region of the 21-amino acid atrophin-1 domain (p.His1425_p.1445Pro). The amino acid sequence in this region is highly conserved, but the functional significance of this domain is currently unknown.
Table 6.
RERE Pathogenic Variants Discussed in This GeneReview
Normal gene product. RERE encodes the 1,566-amino acid protein RERE, which has a predicted molecular weight of 172 kd and contains BAH-MTA, ELM2, SANT, ZnF_GATA, and atrophin-1 domains. Within the atrophin-1 domain, there are two arginine-glutamic acid dipeptide repeat regions. RERE protein has previously been known as atrophin 1-associated protein, atrophin-related protein, and atrophin 2.
Abnormal gene product. Loss-of-function variants in RERE are likely to cause disease by haploinsufficiency. Missense variants may also cause disease by generating a nonfunctioning protein; however, some evidence suggests that they may produce an abnormal protein product that functions in a dominant negative fashion [Jordan et al 2018].
Chapter Notes
Author Notes
Daryl A Scott, MD, PhD
Baylor College of Medicine
Texas Children's Hospital
R813, One Baylor Plaza
BCM225
Houston, TX 77030
Dr Scott is a pediatric clinical geneticist whose research interests focus on identifying and characterizing genes that cause common, life-threatening birth defects.
Elliott H Sherr MD, PhD
University of California, San Francisco
Department of Neurology
675 Nelson Rising Lane
San Francisco, CA 94158
Dr Sherr is a child neurologist whose research focuses on autism and other disorders of neurodevelopment, including malformations of cortical development.
Revision History
- 21 March 2019 (ma) Review posted live
- 31 July 2018 (ds) Original submission
References
Literature Cited
- Fregeau B, Kim BJ, Hernández-García A, Jordan VK, Cho MT, Schnur RE, Monaghan KG, Juusola J, Rosenfeld JA, Bhoj E, Zackai EH, Sacharow S, Barañano K, Bosch DGM, de Vries BBA, Lindstrom K, Schroeder A, James P, Kulch P, Lalani SR, van Haelst MM, van Gassen KLI, van Binsbergen E, Barkovich AJ, Scott DA, Sherr EH. De novo mutations of RERE cause a genetic syndrome with features that overlap those associated with proximal 1p36 deletions. Am J Hum Genet. 2016;98:963–70. [PMC free article: PMC4863473] [PubMed: 27087320]
- Jordan VK, Fregeau B, Ge X, Giordano J, Wapner RJ, Balci TB, Carter MT, Bernat JA, Moccia AN, Srivastava A, Martin DM, Bielas SL, Pappas J, Svoboda MD, Rio M, Boddaert N, Cantagrel V, Lewis AM, Scaglia F, Kohler JN, Bernstein JA, Dries AM, Rosenfeld JA, DeFilippo C, Thorson W, Yang Y, Sherr EH, Bi W, Scott DA. Genotype-phenotype correlations in individuals with pathogenic RERE variants. Hum Mutat. 2018;39:666–75. [PMC free article: PMC5903952] [PubMed: 29330883]
- 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]
Publication Details
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Publication History
Initial Posting: March 21, 2019.
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NLM Citation
Scott DA, Sherr EH. RERE-Related Disorders. 2019 Mar 21. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.