Rere-Related Disorders

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.

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 variant in RERE by molecular genetic testing (see Table 1).

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 at the most reasonable cost 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.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• 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.
  For an introduction to exome sequencing click here. More detailed information for clinicians ordering genomic testing can be found here.

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 gastroesphageal 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].

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.

Treatment of Manifestations

Surveillance

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.