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Identification of ZMIZ1-related Neurodevelopmental Disorder in Neonates with Atrioventricular Septal Defects: Expansion of Phenotypes and Implications for Counseling

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
ZMIZ1 is a gene linked to a rare, dominant, syndromic neurodevelopmental disorder. Features of ZMIZ1-related neurodevelopmental disorder (ZND) include intellectual disability, developmental delays, growth failure, feeding difficulties, microcephaly, dysmorphic features, and variable congenital malformations. Cardiac anomalies have been reported but are not typical of currently described individuals.



Three neonates in Seattle Children’s intensive care units were identified to have de novo pathogenic variants in ZMIZ1 on exome or genome sequencing. Testing was prompted for congenital anomalies including atrioventricular septal defect (AVSD). This case presentation will highlight two of these individuals who gave permission to share additional clinical information.



With the expansion of exome and genome as a first line test in critical care services, these cases will highlight how phenotypes are rapidly expanding for rare disorders and how these diagnoses impact families. In this instance, we may be observing ZMIZ1 as having a stronger impact on cardiac development than previously observed.

 

Case Presentation
Patient 1

Patient 1 was a term female who presented to the NICU and was evaluated at the second day of life. She had a diagnosis of severe ventriculomegaly, arachnoid cyst, dysmorphic features, and AVSD. Family history was non-contributory to the assessment.



Patient 2

Patient 2 was a term male who presented to the CICU and was evaluated at the third day of life. He was diagnosed with congenital heart disease which included an AV canal defect and hypoplastic aortic arch. Family history noted a paternal aunt with WAGR syndrome and hearing loss on the maternal side of the family.

 

Diagnostic Workup
Trio rapid genome sequencing with concurrent mitochondrial analysis was recommended for both patients. Truncating, de novo, pathogenic variants in ZMIZ1 were identified in both individuals. No other variants were identified for either patient.

 

Treatment and Management
Diagnosis of ZND increased risk of potential ophthalmologic concerns and reinforced need for early intervention services for both patients. This result also provided anticipatory guidance to families and providers about growth failure and feeding difficulties. For patient 2, a lower threshold for referring to neurology was recommended due to potential risk of seizures.

 

Outcome and Follow-Up
Due to age, some long-term impacts have not yet been appreciated. For patient 1, the feeding difficulties that can be associated with ZMIZ1-related disorder may have influenced the decision to proceed with G-tube placement. Ophthalmology exam was completed for patient 1 which noted moderate hyperopia. Patient 2 has limited data for follow up at this time.

Discussion
In the described cohort of individuals with ZMIZ1-related disorder through the Carapito study in 2019, cardiac manifestations have been documented in a small number of individuals (4 of 19). These cases highlight cardiac anomalies, particularly AVSD, may be more common than previously known. With broad genetic testing becoming more typical in critical care units, we are observing an expansion of phenotypes with rare disease more rapidly.



These cases highlight the challenges of counseling an early diagnosis of a rare neurodevelopmental syndrome. Due to limited information, there are challenges in predicting the degree of developmental impact in the future and navigating uncertainty. This is made more complex by the well documented delays that many neonates experience after hospitalization and early surgical intervention.

 

Conclusion
Broad genetic testing in critical care units can lead to expansion of phenotypes for rare disease. These cases illustrate an example of how pathogenic variants in ZMIZ1 may more commonly impact cardiac development. As we identify rare disorders such as ZND, this leads to challenges in counseling and navigating uncertainty with families whose child is discovered to have a neurodevelopmental disorder at an early age.

 

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