Clinical characteristics.

IRF2BPL-related disorder is characterized by mild-to-profound developmental delay (with regression in many individuals), intellectual disability, seizures (generalized tonic-clonic, myoclonic, absence, focal tonic-clonic, complex partial, infantile spasms, and/or atonic seizures), movement disorder (ataxia, dystonia, tremor, and parkinsonism), spasticity, and neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis). Feeding issues, gastrointestinal dysmotility, and ophthalmologic manifestations are also reported. Brain MRI can show focal or diffuse cortical and/or subcortical atrophy, cerebellar atrophy (particularly of the vermis), brainstem atrophy, and corpus callosum abnormalities including thinning/atrophy or thickening. Onset is highly variable and can be in the first year of life through the sixth decade. In some individuals the course of the disorder is progressive or debilitating.

Diagnosis/testing.

The diagnosis of IRF2BPL-related disorder is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in IRF2BPL identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental and educational support; standard treatment of epilepsy and movement disorder by an experienced neurologist; standard treatment of spasticity per orthopedist, neurologist, physical medicine and rehabilitation specialist, physical therapist, and occupational therapist; feeding support for poor weight gain; standard treatment for gastric dysmotility; treatment of vision deficits per ophthalmologist with treatment of more complex findings per ophthalmic subspecialist; treatment of pubertal delay per endocrinologist; family and social work support.

Surveillance: At each visit, assess developmental progress, educational needs, cognitive function, seizures, movement disorder, spasticity, contractures, behavioral issues, growth, nutritional status, gastrointestinal dysmotility, and family needs; physical medicine and/or occupational and physical therapy assessment for mobility and self-help skills at each visit; dilated eye exam per treating ophthalmologist; assessment of pubertal development at each visit through adolescence.

Genetic counseling.

IRF2BPL-related disorder is inherited in an autosomal dominant manner. The majority of individuals diagnosed with IRF2BPL-related disorder have the disorder as the result of a de novo pathogenic variant; approximately 9% of individuals reported to date have an affected parent. Each child of an individual with IRF2BPL-related disorder has a 50% chance of inheriting the IRF2BPL pathogenic variant. Once the IRF2BPL pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

IRF2BPL-related disorder should be considered in probands with the following clinical and imaging findings and family history.

Clinical findings in individuals presenting at age <18 years

• Mild-to-profound developmental delay (Developmental regression has been described in 50% of individuals.)
• Intellectual disability
• Epilepsy (generalized tonic-clonic, myoclonic [with photoparoxsymal response], absence, focal tonic-clonic, complex partial, infantile spasms, and/or atonic seizures)
• Movement disorders (ataxia, dystonia, tremor, and parkinsonism; less commonly, athetosis, chorea, and myoclonus)
• Neurobehavioral/psychiatric manifestations (autism spectrum disorder, autistic features, anxiety, depression, and psychosis)
• Ophthalmologic manifestations (dysconjugate gaze, ophthalmoplegia, gaze palsy, slow saccades; less commonly, keratoconus, cataracts, and retinal pigmentary anomalies)

Clinical findings in individuals presenting in adolescence and adulthood

• Epilepsy (generalized tonic-clonic, myoclonic, absence, and focal tonic-clonic seizures)
• Movement disorders (dystonia with or without dysarthria, ataxia, choreoathetosis)
• Cognitive decline
• Anarthria, aphonia
• Psychiatric manifestations (recurrent psychosis)
• Ophthalmologic manifestations (macular degeneration, gaze palsy, and abnormal saccades)

Note: Presentation can be as late as the sixth decade.

Imaging findings on brain MRI

• Focal or diffuse cortical and/or subcortical atrophy
• Cerebellar atrophy (particularly of the vermis)
• Brainstem atrophy
• Corpus callosum abnormalities (thinning/atrophy, thickening)

Note: Brain MRI can be normal, particularly in early childhood.

Family history. Because IRF2BPL-related disorder is often caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations).

Establishing the Diagnosis

The diagnosis of IRF2BPL-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in IRF2BPL 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 IRF2BPL variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome sequencing / genome sequencing [Manickam et al 2021, van der Sanden et al 2023]. Other options include the use of chromosomal microarray analysis (CMA) or a multigene panel. Note: In the absence of a family history of IRF2BPL-related disorder, single-gene testing (sequence analysis of IRF2BPL, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An intellectual disability / epilepsy / movement disorders multigene panel that includes IRF2BPL 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 IRF2BPL-related disorder, 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.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an intellectual disability multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing intellectual disability, whereas some multigene panels may not. To date, the majority of IRF2BPL pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing. 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.

Clinical Description

IRF2BPL-related disorder is characterized by mild-to-profound developmental delay with or without regression, intellectual disability, seizures, movement disorder (ataxia, dystonia, tremor, parkinsonism), spasticity, and autism spectrum disorder. Feeding issues, gastrointestinal dysmotility, and ophthalmologic manifestations are also reported. Onset is highly variable and can be in the first year of life through the sixth decade. To date, more than 60 individuals have been identified with a pathogenic variant in IRF2BPL. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay occurs in most individuals and is mild to profound. There is no information regarding specific developmental domains that could be more severely affected. Hypotonia is common and contributes to gross motor delays.

Some individuals have progressive loss of gross motor, fine motor, and self-help skills. Early signs of developmental regression can include dysarthria, dysphagia, and dysconjugate gaze. Lack of balance and coordination with frequent falls is also described. Increased difficulty with walking and/or sitting is reported in 38% of individuals, increased falls in 25%, progressive articulation difficulties in 19%, and loss of speech in 6%. Regression has been described as early as age eight months and can occur throughout early adulthood.

Intellectual disability. Cognitive assessment may be hindered by the lack of communication skills. Cognitive decline has been inferred in several individuals but is difficult to ascertain due to lack of systematic evaluations [Heide et al 2023, Horovitz et al 2023].

Epilepsy. Seizures are common and are reported by 43% of affected individuals and/or families [LDM Pena, personal communication]. The types of seizures reported include generalized tonic-clonic, myoclonic, absence, focal tonic-clonic, complex partial, infantile spasms, and atonic seizures. Approximately 40%-50% of those with epilepsy have multiple seizure types. Progressive myoclonic epilepsy phenotypes have been described [Costa et al 2023]. Seizures can arise throughout the life span, including in adulthood [Costa et al 2023, Gardella et al 2023].

Movement disorders can include ataxia, dystonia, tremor, and parkinsonism. Onset can occur as late as young adulthood [Ganos et al 2014]. Other less frequently described movement disorders include athetosis, chorea, and myoclonus [Shelkowitz et al 2019].

Additional cerebellar signs include eye movement abnormalities and dysdiadochokinesia.

Spasticity. Some individuals develop increased muscle tone, particularly of the lower extremities. Hyperreflexia and joint contractures have also been described.

Neurobehavioral/psychiatric manifestations. Some individuals are diagnosed with autism spectrum disorder or have autistic features without a diagnosis of autism. Attention-deficit/hyperactivity disorder, anxiety, depression, and psychosis have also been reported [Spagnoli et al 2020, Sainio et al 2022].

Feeding and gastrointestinal manifestations include swallowing difficulties, gastrointestinal dysmotility, and feeding intolerance.

Ophthalmologic involvement. Dysconjugate gaze, ophthalmoplegia, gaze palsy, and slow saccades have been reported. Keratoconus has rarely been described [Ganos et al 2019, Prilop et al 2020], as have cataracts [Prilop et al 2020], retinal pigmentary anomalies [Shelkowitz et al 2019], and macular degeneration in one individual [Marcogliese et al 2018].

Neuroimaging. Commonly reported brain imaging findings include focal or diffuse cortical and/or subcortical atrophy, cerebellar atrophy (particularly of the vermis), brainstem atrophy, and thinning/atrophy of the corpus callosum [Pisano et al 2022]. Less commonly, thickening of the corpus callosum has been observed. Other nonspecific findings include supratentorial T₂ hyperintensities. Some individuals with normal initial brain imaging demonstrate progressive atrophy with cerebral and/or cerebellar volume loss on subsequent imaging. Brain imaging is reportedly normal in 30%-50% of individuals in published reports [Shelkowitz et al 2019, Pisano et al 2022, Chen et al 2024].

Growth. No consistent abnormality of growth is reported.

Other. IRF2BPL pathogenic variants (a missense variant and an in-frame deletion of one amino acid) have been reported in individuals with delayed puberty from two families [Mancini et al 2019]. Further studies are needed to assess the potential involvement of IRF2BPL in delayed puberty.

Adult onset. Although IRF2BPL-related disorder does not show clearly defined early- vs late-onset presentations, several individuals with adult onset have been described. The phenotype in those with later onset includes ataxia, dystonia, and dysarthria [Ganos et al 2014, Ganos et al 2019, Prilop et al 2020, Antonelli et al 2022, Sainio et al 2022, Horovitz et al 2023]. In general, the adults who have epilepsy developed seizures earlier in life.

Prognosis. Several adults with IRF2BPL-related disorder have been reported. Data on progression of behavior abnormalities or neurologic findings are limited. In some individuals, the course of the disorder is progressive or debilitating, and care may require mechanical ventilation due to respiratory insufficiency, gastrostomy tube feeding, supportive equipment to maintain independence, and therapies to maintain mobility and/or prevent disuse sequelae.

Genotype-Phenotype Correlations

Pathogenic variants (including missense and nonsense) located downstream of the nuclear localization signal may be associated with a less severe phenotype without a progressive loss of milestones or movement disorder. However, the precise genomic location for this genotype-phenotype correlation is currently unknown.

To date, three variants have been associated with a concordant phenotype of NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures) reported in at least three different families (NM_024496.4): c.496G>T (p.Glu166Ter), c.519C>G (p.Tyr173Ter), and c.562C>T (p.Arg188Ter) [Marcogliese et al 2018, Tran Mau-Them et al 2019, Hong et al 2020, Qian et al 2021, Costa et al 2023, Yang et al 2023].

Penetrance

Penetrance for IRF2BPL-related disorder appears to be high; however, substantial intrafamilial and interfamilial variability in age of onset and clinical features has been observed. Developmental delay and intellectual disability were reported in a female with an IRF2BPL pathogenic variant inherited from her apparently unaffected mother who died at age 45 years of an unrelated cause [Heide et al 2023]. Possible reduced penetrance has been observed in several additional families [LDM Pena & P Marcogliese, personal observations].

Prevalence

Prevalence is unknown. To date, more than 60 affected individuals have been described.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with IRF2BPL-related disorder, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

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).

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.

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.

Mode of Inheritance

IRF2BPL-related disorder is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The majority of individuals diagnosed with IRF2BPL-related disorder have the disorder as the result of a de novo IRF2BPL pathogenic variant.
• Approximately 9% of individuals with IRF2BPL-related disorder reported to date have an affected parent.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• 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 has a de novo pathogenic variant.
  • 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.
    * A parent with somatic and gonadal mosaicism for an IRF2BPL pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with IRF2BPL-related disorder may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

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

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• While penetrance for IRF2BPL-related disorder appears to be high, substantial variability in age of onset and clinical features has been reported among affected individuals within the same family (see Penetrance).
• If the IRF2BPL pathogenic variant identified 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 possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for IRF2BPL-related disorder because of the possibility of reduced penetrance or late onset in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with IRF2BPL-related disorder has a 50% chance of inheriting the IRF2BPL 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 IRF2BPL 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 young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the IRF2BPL pathogenic variant has been identified in an affected family member, 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.

Molecular Pathogenesis

IRF2BPL is an intronless gene that encodes probable E3 ubiquitin-protein ligase IRF2BPL (IRF2BPL), a transcriptional regulator that may also have E3 ubiquitin ligase activity [Higashimori et al 2018]. It has been shown to bind the promoter of the gonadotropin-releasing hormone [Mancini et al 2019]. IRF2BPL binds to casein kinase I isoform alpha, a Wnt/beta-catenin antagonist. Loss of IRF2BPL in Drosophila, zebra fish, and cells of individuals with IRF2BPL-related disorder leads to increased proto-oncogene Wnt-1 (encoded by WNT1) transcription and Wnt/beta-catenin signaling. Some neurobehavioral phenotypes in Drosophila and zebra fish can be ameliorated by pharmacologic or genetic Wnt/beta-catenin inhibition [Marcogliese et al 2022]. In cancer cell lines, IRF2BPL may ubiquitinate beta-catenin directly, leading to its degradation, but to date there has yet to be a link between IRF2BPL activity and oncogenesis [Higashimori et al 2018]. Cells from affected individuals display abnormal mitochondrial respiration and morphology that can be rescued by clearing damaged mitochondria pharmacologically [Sinha Ray et al 2022].

To date, all seven pathogenic frameshift or nonsense variants (six lead to truncation prior to the nuclear localization signal [NLS], and one leads to truncation after the NLS) in IRF2BPL that have been assessed biochemically escape nonsense-mediated decay and lead to the production of a truncated protein [Marcogliese et al 2018, Tran Mau-Them et al 2019, Sinha Ray et al 2022]. These truncated alleles result in loss of IRF2BPL function [Marcogliese et al 2018, Marcogliese et al 2022]. However, truncated IRF2BPL has also been shown to have dominant-negative activity, sequestering full-length IRF2BPL from the nucleus to the cytoplasm [Sinha Ray et al 2022].

Although no clear genotype-phenotype correlation has been confirmed, pathogenic variants causing truncation proximal to the polyglutamine tract (amino acids 103-127) may be associated with increased severity, and pathogenic variants causing truncation downstream of the NLS (amino acids 542-545) display more variability with milder presentation and/or later onset.

Mechanism of disease causation. Haploinsufficiency and/or dominant-negative effect

IRF2BPL-specific laboratory technical considerations. IRF2BPL has a glutamine-rich domain, a polyalanine repeat, and is guanine/cytosine rich in general, which may cause technical difficulties with sequence analysis. The authors recommend consideration of pathogenic variant confirmation, particularly variants in these domains, by an orthogonal method.

Author Notes

Contact Dr Paul Marcogliese ([email protected]) to inquire about review of IRF2BPL variants of uncertain significance.

Acknowledgments

The authors would like to gratefully acknowledge the families and affected individuals for their interest, support, and participation in research initiatives to understand the scope of the phenotypes and the function of the IRF2BPL gene product.

Revision History

• 21 November 2024 (sw) Review posted live
• 31 May 2024 (ldmp/pm) Original submission

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