EPG5-Related Disorder

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.