Clinical characteristics.

With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of EPG5-related disorder represents a continuum. At the most severe end of the spectrum is classic Vici syndrome (defined as a neurodevelopmental disorder with multisystem involvement characterized by the combination of agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive); at the milder end of the spectrum are attenuated neurodevelopmental phenotypes with variable multisystem involvement. Median survival in classic Vici syndrome appears to be 24 months, with only 10% of children surviving longer than age five years; the most common causes of death are respiratory infections as a result of primary immunodeficiency and/or cardiac insufficiency resulting from progressive cardiac failure. No data are available on life span in individuals at the milder end of the spectrum.

Diagnosis/testing.

The diagnosis of EPG5-related disorder is established in a proband with suggestive clinical findings and confirmed by identification of biallelic pathogenic (or likely pathogenic) variants in EPG5 on molecular testing.

Management.

Treatment of manifestations: There is no cure for EPG5-related disorder. Supportive multidisciplinary care to improve quality of life, optimize function, and reduce complications may include specialists in clinical genetics and pediatrics as well as allied health professionals in neurology, audiology, ophthalmology, development, feeding, cardiology, pulmonology, gastroenterology, immunology, endocrinology, and nephrology. Given the complexities of medical problems in affected individuals, input from experts in palliative care and medical ethics may be beneficial, particularly when invasive procedures are under consideration.

Of particular note, rigorous and early antibacterial and antifungal treatment (potentially in an intensive care unit setting) should be considered for chest infections to prevent episodes of life-threatening sepsis and organ failure due to the consequences of primary immunodeficiency.

Surveillance: To monitor disease progression, optimize functional abilities and communication skills, and address emerging disease manifestations, regular evaluations by the treating multidisciplinary specialists as well as assessments of developmental and educational needs are recommended.

Genetic counseling.

EPG5-related disorder is inherited in an autosomal recessive manner. Many individuals with EPG5-related disorder are born to consanguineous couples. If both parents are known to be heterozygous for an EPG5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the EPG5 pathogenic variants have been identified in an affected family member, carrier testing for at risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

At the more severe end of the spectrum of EPG5-related disorder, clinically defined classic Vici syndrome commonly involves the common combined presence of agenesis of corpus callosum, cataract, cardiomyopathy, hypopigmentation, primary immunodeficiency, failure to gain weight, and microcephaly. The milder end of the spectrum involves primarily neurodevelopmental and/or neurologic features with variable but (in general) less pronounced multisystem involvement [Kane et al 2019].

EPG5-related disorder should be suspected in individuals with the following suggestive findings across the phenotypic spectrum and family history.

Clinical Findings

Neurodevelopmental manifestations

• Developmental delay, typically with significant motor delay, absence of speech, and later severe intellectual disability
• Agenesis or dysgenesis of corpus callosum. Variable other central nervous system abnormalities include pontine hypoplasia and less frequently cerebellar hypoplasia, mild prominence of the cisterna magna, simplified sulcation pattern and neuronal migration abnormalities, reduced operculization, reduced white matter bulk, and delayed myelination [Byrne et al 2016a, Byrne et al 2016b].

Variably present highly suggestive multisystem findings

• Immunodeficiency manifesting as:
  • Thymic aplasia or hypoplasia [Byrne et al 2016b];
  • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [Piano Mortari et al 2018];
  • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [Finocchi et al 2012].
• Failure to gain weight, common after the first year of life despite adequate caloric intake [Byrne et al 2016b]
• (Oculo-)cutaneous hypopigmentation that is relative to familial and ethnic background; typically not complete albinism (Figure 1) [Byrne et al 2016b] (full text). Abnormal visual evoked potentials and retinal abnormalities on optical coherence tomography are consistent with ocular albinism [Filloux et al 2014].
• Progressive microcephaly, both congenital and (more commonly) acquired
• Early-onset epilepsy, in some cases refractory to pharmacologic treatment with progression to an epileptic encephalopathy
• Neuromuscular findings
  • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [Al-Owain et al 2010, McClelland et al 2010]. Note that a muscle biopsy is not required to confirm the diagnosis of EPG5-related disorder.
  • Peripheral neuropathy with absent reflexes [Byrne et al 2016b]
  • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders)
• Sensorineural hearing loss. Congenital hearing loss is likely to be detected on newborn hearing screening; hearing loss with later onset is likely to be detected when prompted by specific concerns.
• Ophthalmologic findings. Cataracts (congenital or acquired), optic nerve atrophy, retinopathy
• Cardiac involvement
  • Congenital structural cardiac abnormalities
  • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [Byrne et al 2016a, Byrne et al 2016b].

Figure 1.

Distinctive facial features in EPG5-related disorder. Note hypopigmentation in relation to ethnic and familial background. Some individuals present with myopathic facial features. In some individuals a recurrent, often confluent maculopapular rash is (more...)

Establishing the Diagnosis

The diagnosis of EPG5-related disorder is established in a proband with suggestive clinical findings and confirmed by identification of biallelic pathogenic (or likely pathogenic) variants in EPG5 on molecular testing (Table 1).

Note: (1) 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. (2) Identification of biallelic EPG5 variants of uncertain significance (or of one known EPG5 pathogenic variant and one EPG5 variant of uncertain significance) does not establish or rule out a 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).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. The diagnosis of EPG5-related disorder in individuals meeting the clinical definition of classic Vici syndrome is likely to be established using gene-targeted testing. At the other end of the spectrum, individuals with less distinctive findings are likely to be diagnosed through more comprehensive and less targeted genomic testing.

• Single-gene testing. This highly selective testing may be an option when the phenotypic findings suggest the diagnosis of classic Vici syndrome.
  This approach involves performing sequence analysis of EPG5 to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or 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.
• Multigene panels. EPG5 and other genes of interest may be included in multigene panels for developmental delay, microcephaly, developmental brain malformations, early-onset epileptic encephalopathies, mitochondrial disorders, and/or primary immunodeficiencies (see Differential Diagnosis). These panels are most likely to identify the genetic cause of the condition 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. (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.

Clinical Description

With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of biallelic EPG5 pathogenic variants causing EPG5-related disorder represents a continuum of variable severity. Vici syndrome (defined as a neurodevelopmental disorder with multisystem involvement characterized by the combination of agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive; see Suggestive Findings, Classic Vici Syndrome) is at the most severe end of the spectrum; however, milder, attenuated neurodevelopmental phenotypes with a variable degree of multisystem involvement are increasingly recognized.

To date, around 90 individuals have been identified with biallelic EPG5 pathogenic variants. These reports have mostly shown individuals toward the more severe end of the phenotypic spectrum, while reports of individuals with only neurologic disease but no more extensive multisystem involvement are scarce [Kane et al 2019]. Several sub-phenotypes (e.g., those presenting with predominantly immunologic features) remain very likely underdiagnosed and should be carefully evaluated in future genotype-phenotype correlation studies.

The description of the phenotypic spectrum associated with EPG5-related disorders is based on clinical reports published to date (see Table 2).

Antenatal presentation in the second trimester with agenesis of the corpus callosum, underdevelopment of the temporal lobes [Touraine et al 2017], and focal cortical microdysgenesis has been reported [Aggarwal et al 2018].

At the more severe end of the disorder spectrum, presentation is typically in the neonatal period or early infancy with callosal agenesis and (relative) hypopigmentation. (Severe) combined immunodeficiency, cardiomyopathy, and/or cataracts may or may not be present at birth but usually develop during the first year of life [Byrne et al 2016b].

At the less severe end of the disorder spectrum, presentations ranging from hypotonia and microcephaly in infancy to nonspecific global neurodevelopmental delay with associated movement disorders (but no other signs of multisystem involvement) during early childhood have been reported [Kane et al 2019].

Brain malformations. The most common brain malformation is agenesis of the corpus callosum, followed by pontine hypoplasia, enlargement of the cisterna magna, thalamic signal changes, and neuronal migration abnormalities [Byrne et al 2016b, Hori et al 2017].

Dysgenesis (rather than agenesis) of the corpus callosum has also been reported and may be more prominent in individuals with milder neurodevelopmental features [Kane et al 2019].

Neurologic

• Developmental delay. The severe end of the spectrum involves neurodevelopmental delay with failure to achieve ambulation, intellectual disability, and lack of speech in nearly all individuals [Byrne et al 2016a, Byrne et al 2016b]. The mildest presentation reported to date was delay in the attainment of motor and language skills at the age of 3.5 years, with speech and language development limited to a few words [Kane et al 2019].
• Neonatal muscular hypotonia. Presentation at birth may include profound generalized hypotonia with the combination of both central and peripheral hypotonia and associated respiratory and bulbar involvement [Byrne et al 2016b]. In some individuals at the severe end of the disorder spectrum, reduced fetal movements in utero and/or contractures of antenatal onset have been reported, potentially with an underlying myopathy and/or neuropathy. Currently there is only limited understanding of the pathogenesis and/or progression of neuromuscular features resulting from the lack of muscle or nerve biopsies in affected individuals.
• Seizures, mostly generalized tonic-clonic seizures, occur in the first two years of life in more than 60% of individuals, ranging from infrequent seizures to severe epileptic encephalopathy with burst-suppression patterns or hypsarrhythmia on EEG [Byrne et al 2016b]. Status epilepticus may occur in individuals at the more severe end of the spectrum.
  About 50% of affected individuals have seizures in response to fever, while individuals at the milder end of the spectrum may show transient loss of acquired skills with febrile seizures without long-term developmental regression [Kane et al 2019].
  Although seizures may be well-controlled with standard anti-seizure medications, the response varies.
• Movement disorders include spastic paraplegia and extrapyramidal movement disorders, particularly dystonia, choreoathetosis, and akinetic-rigid disorders.
• Neuromuscular features include variable myopathic features (including fiber size disproportion, type 1 predominance, increased central nuclei, vacuoles, and mitochondrial abnormalities) on muscle biopsy and features of an axonal neuropathy on nerve biopsy [McClelland et al 2010, Byrne et al 2016b].

Primary immunodeficiency. A combined immunodeficiency of variable severity as a result of defects in both T and B cells is common and may present with recurrent and unusual infections from the neonatal period or infancy onward. Immunologic studies may reveal prominent B cell involvement, characterized by lack of memory B cells, reduced immunoglobulin G2, deficient humoral response, and T4+ cell depletion. Bacterial and fungal agents (including Streptococcus viridans, Staphylococcus hominis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Candida albicans) may cause pneumonias, skin abscesses, oral mucocutaneous candidiasis, enterocolitis, and intractable diarrhea. Infections may quickly progress to septic shock and should be managed urgently and proactively (see Management, Treatment of Manifestations).

Recurrent episodes of otherwise unexplained fever without identification of a pathogenic organism also require proactive and immediate management (see Management, Treatment of Manifestations).

Thymus aplasia or hypoplasia has been reported in around one fifth of affected individuals.

Failure to gain weight. Poor weight gain despite adequate caloric intake is common, and profound failure to thrive is seen in a substantial proportion of affected individuals. Poor weight gain may be due to the principal underlying anabolic defect as a consequence of the primary autophagy defect; other potential causes may include gastrointestinal involvement with feeding difficulties, gastroesophageal reflux disease with risk for aspiration pneumonias, intractable diarrhea, and other features mimicking inflammatory bowel syndrome [Shimada et al 2018].

(Oculo-)cutaneous hypopigmentation. Cutaneous hypopigmentation is common but never complete and always relative to ethnic and familial background [Byrne et al 2016a, Byrne et al 2016b]. For ocular manifestations of hypopigmentation, see Ophthalmologic features in this section.

Cardiac involvement includes both structural congenital heart defects and acquired cardiomyopathies.

Cardiomyopathy is seen in 80%-90% of individuals with cardiac involvement in EPG5-related disorders and has a significant effect on morbidity and mortality. Both dilated and hypertrophic cardiomyopathy can be seen and usually develop in early childhood. Acute decompensation of cardiac function during infections / intercurrent illness is possible.

Congenital heart defects including patent foramen ovale, ventricular or atrial septal defects, hypoplastic aortic arch, and mitral valve insufficiency are seen in about 10%-20% of individuals with cardiac involvement.

Ophthalmologic features mainly include bilateral nuclear and anterior polar cataracts (70%), retinal abnormalities (35%; e.g., retinopathy), and bilateral optic nerve atrophy (30%). Other reported ocular abnormalities are mild fundus hypoplasia, evidence of misrouting of optic pathways in evoked potentials recorded across the mid-occipital scalp, and a poorly defined fovea demonstrating a lesser degree of foveal depression in optical coherence tomography [Filloux et al 2014]. This observation is similar to other congenital disorders of autophagy with ocular hypopigmentation, as noted in Table 3.

Sensorineural hearing loss (SNHL) may be detected after birth through brain auditory evoked responses in individuals at the severe end of the spectrum. To date, there have been no reports of hearing loss in individuals at the milder end of spectrum or in those with a progressive disease course; however, in individuals with severe disability, SHNL may not have been suspected and/or proactively investigated.

Hematologic abnormalities with anemia, low platelet counts, and idiopathic thrombocytopenic purpura can be triggered by infections without apparent bone marrow suppression. Onset, severity, and course are variable.

Other multisystem involvement (in <20% of affected individuals but probably underreported) [Byrne et al 2016a, Byrne et al 2016b] include the following:

• Thyroid abnormalities, including thyroid aplasia/hypoplasia or thyroid dysfunction in the presence of a normally formed thyroid gland [Byrne et al 2016a]
• Pulmonary hypoplasia
• Hepatomegaly and/or splenomegaly [Byrne et al 2016a]
• Kidney abnormalities with features suggestive of renal tubular acidosis or electrolyte imbalances (in particular hypokalemia)
• Morbilliform maculopapular rashes [Byrne et al 2016a, Huenerberg et al 2016, Hızal et al 2020]

Prognosis. Natural history data for individuals with classic Vici syndrome on the severe end of the EPG5-related disorder spectrum suggest a median survival time of 24 months, with only 10% of affected individuals surviving longer than age five years [Byrne et al 2016b]. The most common causes of death at the most severe end of the spectrum are respiratory infections as a result of primary immunodeficiency and/or cardiac insufficiency resulting from progressive cardiac failure.

While it may be expected that the disease course in individuals with phenotypes on the less severe end of the EPG5-related disorder spectrum may be milder and associated with a longer life span (in particular if cardiorespiratory and/or immunologic features are absent), to date no comprehensive follow-up data are available.

Genotype-Phenotype Correlations

Precise genotype-phenotype correlations are difficult to establish because of the relatively limited number of affected individuals and the lack of long-term natural history data.

Homozygosity for c.1007A>G (p.Gln336Arg), a likely founder variant in individuals of Ashkenazi Jewish background, is associated with a longer life expectancy and a less severe phenotype with apparently reduced cardiac and immunologic involvement, possibly due to a variable effect on EPG5 splicing with some residual expression of normal EPG5 protein [Byrne et al 2016b, Kane et al 2016]. Genotype-phenotype correlations for individuals compound heterozygous for the c.1007A>G (p.Gln336Arg) variant and a second (truncating) variant are less clear but probably are characterized by intermediate severity.

Other possible correlations. Emerging data suggest a correlation between severity of the phenotype and residual EPG5 protein expression. Median survival was nine months for infants with homozygous truncating EPG5 variants in comparison to 48 months for children with compound heterozygous variants, often involving at least one missense change [Byrne et al 2016b].

Bulk autophagy is at least partially impaired in fibroblasts from individuals with phenotypes on the severe end of the EPG5-related disorder spectrum who have EPG5 loss-of-function variants with decreased EPG5 protein expression [Cullup et al 2013, Byrne et al 2016a].

A milder decrease in mRNA and protein expression has been associated with a primarily neurologic phenotype without major multisystem involvement [Kane et al 2019].

Nomenclature

Classic Vici syndrome, a phenotype on the more severe end of the EPG5-related disorder spectrum, may also be referred to as EPG5-related Vici syndrome or immunodeficiency with cleft lip/palate, cataract, hypopigmentation, and absent corpus callosum.

Prevalence

The birth prevalence for EPG5-related disorder is unknown but is expected to be low, at least for phenotypes on the severe end of the phenotypic spectrum. While it is possible that less severe phenotypes with fewer specific features are more common, no reliable epidemiologic data are available to date.

The variant c.1007A>G (p.Gln336Arg) is a likely founder variant in individuals with Ashkenazi Jewish ancestry [Byrne et al 2016b, Kane et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with EPG5-related disorder, the evaluations summarized in Table 4 (if not performed as part of initial diagnostic process) are recommended.

Treatment of Manifestations

There is no cure for EPG5-related disorder.

Supportive care recommendations to improve quality of life, optimize function, and reduce complications are summarized in Table 5. This may include multidisciplinary care by specialists in clinical genetics and pediatric specialists and allied health professionals in neurology, audiology, ophthalmology, development, feeding, cardiology, pulmonology, gastroenterology, immunology, endocrinology, and nephrology. Considering the complexities of medical problems in some affected individuals, input from palliative care and medical ethics may also be beneficial, particularly when decisions about invasive procedures are made.

Consider rigorous and early antibacterial and antifungal treatment (potentially in an intensive care unit setting) for chest infections to prevent episodes of life-threatening sepsis and organ failure due to the consequences of primary immunodeficiency.

Surveillance

To identify the multidisciplinary evaluations (and their frequency) for assessing disease progression, optimizing functional abilities and communication skills, and addressing other disease manifestations, see Table 6.

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

EPG5-related disorder is inherited in an autosomal recessive manner.

Many individuals with EPG5-related disorder are born to consanguineous couples [Byrne et al 2016b].

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an EPG5 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EPG5 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon EPG5 deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes are not at risk of developing EPG5-related disorder. In one study, subtle clinical manifestations (including early-onset cataracts, vitiligo, and an increased incidence of certain tumor disorders) were described in families of individuals with EPG5 pathogenic variants [Byrne et al 2016a]. These preliminary observations require confirmation in larger series.

Sibs of a proband

• If both parents are known to be heterozygous for an EPG5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Heterozygotes are not at risk of developing EPG5-related disorder. In one study, subtle clinical manifestations (including early-onset cataracts, vitiligo, and an increased incidence of certain tumor disorders) were described in families of individuals with EPG5 pathogenic variants [Byrne et al 2016a]. These preliminary observations require confirmation in larger series.

Offspring of a proband. To date, individuals with EPG5-related disorder are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an EPG5 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the EPG5 pathogenic variants in the family.

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 the parents of affected children and young adults who are carriers or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if the reproductive partner is of the same ethnic background. An EPG5 founder variant has been identified in individuals of Ashkenazi Jewish heritage (see Genotype-Phenotype Correlations and Prevalence).

Prenatal Testing and Preimplantation Genetic Testing

Once the EPG5 pathogenic variants have 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 testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Macroautophagy (hereafter referred to as autophagy), a cellular degradation process, is pivotal for the recycling of proteins and organelles, specifically within post-mitotic cells such as neurons [Ebrahimi-Fakhari et al 2016]. The process of autophagy involves sequestration of cytoplasmic material into the double-membraned autophagosome and targeting to the lysosome for degradation. Ectopic P granules protein 5 homolog (EPG5), in concert with RAB7, serves as a tethering factor to facilitate autophagosome-lysosome fusion [Tian et al 2010], and probably also other intracellular fusion processes. EPG5-related disorder is thought to result from a defect in the late stages of the autophagy pathway, namely, autophagosome-lysosome fusion. Global reduction in autophagic flux leads to impaired development and function in a multitude of tissues and, thus, to a multisystem disease.

Mechanism of disease causation. Loss of function

Author Notes

Heinz Jungbluth, Darius Ebrahimi-Fakhari, Afshin Saffari, and Hormos Dafsari are actively involved in clinical and basic research regarding individuals with EPG5-related disorder. They would be happy to communicate with persons who have any questions regarding the diagnosis of EPG5-related disorder, other congenital disorders of autophagy, or similar considerations.

Contact Heinz Jungbluth and Hormos Dafsari to inquire about review of EPG5 variants of uncertain significance.

Heinz Jungbluth, Manolis Fanto, Celine Deneubourg, and Hormos Dafsari are interested in and work on the molecular biological research in EPG5-related disorder.

Acknowledgments

HSD was supported by the Cologne Clinician Scientist Program / Medical Faculty / University of Cologne and German Research Foundation (CCSP, DFG project no. 413543196).

HJ was supported by Action Medical Research, United Kingdom, the GOSH Charity / Sparks, and a European Commission H2020-MSCA-ITN-2017 grant.

Revision History

• 13 October 2022 (bp) Review posted live
• 19 April 2022 (def) Original submission

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