Expanding the Phenotype of Newly Described ZBTB47-related Neurodevelopmental Disorder
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
ZBTB47, encoding zinc finger and BTBdomain-containing protein 47, has been recently linked with a newly described autosomal dominant neurodevelopmental disorder. Evidence has implicated that alterations in zinc finger transcription factors (ZNFs) play a role in the development of several diseases, including a neurodevelopmental phenotype and other features spanning across multiple organ systems. ZBTB47, a ZNF protein, is widely expressed throughout the body’s tissues, with highest expression in the cardiovascular, skeletal, and central nervous system. To date, only one cohort of five participants, ages five to thirteen years, with a ZBTB47 pathogenic variant has been reported. Participants were heterozygous for de novo missense variants in the ZBTB47 gene, of which four were heterozygous for the c.1429G>A (p.Glu477Lys) pathogenic variant.
Case Presentation
A 30-year-old male participant was seen in the Adult Cardiology clinic following a recent diagnosis of a non-ischemic dilated cardiomyopathy (NICM) with severe left ventricular systolic dysfunction. The participant's expanded medical history included developmental regression, intellectual disability, epilepsy, recurrent infections, hypotonia, poor coordination, and intestinal malrotation. The participant presented with chronic abdominal pain attributed to small bowel malrotation and infrarenal duplication of the inferior vena cava (IVC). During his workup for surgery, an incidental finding of reduced left ventricle (LV) (30-35%) was identified and characterized as moderately to severely reduced overall global left ventricular systolic function. Prior to this finding, the participant did not have any symptoms of congestive heart failure.
Diagnostic Workup
The complex history prompted the decision to order a Fragile X assay, Chromosomal Microarray (CMA), and a trio exome sequencing. Fragile X testing revealed a normal hemizygous allele and CMA was consistent with a typical male and did not identify any copy number changes of clinical significance. Exome sequencing identified a heterozygous de novo missense pathogenic variant (c.1429G>A; p.Glu477Lys) variant in ZBTB47.
Treatment and Management
Genetic counseling was provided regarding the new diagnosis along with referral to clinical genetics for further evaluation and to establish care. Participant continues to receive specialized services for his diagnosis of intellectual disability. Metoprolo tartare was discontinued in favor of metoprolol succinate (Toprol) for guideline-directed medical therapy for LV dysfunction.
Outcome and Follow-Up
The participant continues to receive appropriate care without new major health outcomes. Consistent LV monitoring is in place through Echocardiogram screening.
Discussion
While the previous cohort reported various cardiovascular and gastrointestinal abnormalities, the combination of NICM and and intestinal malrotation has not been described, or may have been under-evaluated currently due to the younger ages of prior participants. Given that our clinic’s participant is heterozygous for the same de novo missense variant identified in the prior cohort, it is possible that these are adult-onset manifestations that should be evaluated and screened for in other ZBTB47 heterozygotes if not indicated prior. This will broaden the current understanding of the impact of pathogenic ZBTB47 variants and enable appropriate monitoring of both existing and future participants who undergo genetic testing.
Conclusion
In conclusion, our participant offers additional evidence supporting the role of the ZBTB47 gene in the development of a neurodevelopmental disorder and contributes new data on the cardiac and gastrointestinal phenotypes associated with the same genotype found in the majority of participants from the original cohort. Broader genetic testing should be considered when a participant has a constellation of medical findings that appear to be significant beyond the initial reason for specialty evaluation.
ZBTB47, encoding zinc finger and BTBdomain-containing protein 47, has been recently linked with a newly described autosomal dominant neurodevelopmental disorder. Evidence has implicated that alterations in zinc finger transcription factors (ZNFs) play a role in the development of several diseases, including a neurodevelopmental phenotype and other features spanning across multiple organ systems. ZBTB47, a ZNF protein, is widely expressed throughout the body’s tissues, with highest expression in the cardiovascular, skeletal, and central nervous system. To date, only one cohort of five participants, ages five to thirteen years, with a ZBTB47 pathogenic variant has been reported. Participants were heterozygous for de novo missense variants in the ZBTB47 gene, of which four were heterozygous for the c.1429G>A (p.Glu477Lys) pathogenic variant.
Case Presentation
A 30-year-old male participant was seen in the Adult Cardiology clinic following a recent diagnosis of a non-ischemic dilated cardiomyopathy (NICM) with severe left ventricular systolic dysfunction. The participant's expanded medical history included developmental regression, intellectual disability, epilepsy, recurrent infections, hypotonia, poor coordination, and intestinal malrotation. The participant presented with chronic abdominal pain attributed to small bowel malrotation and infrarenal duplication of the inferior vena cava (IVC). During his workup for surgery, an incidental finding of reduced left ventricle (LV) (30-35%) was identified and characterized as moderately to severely reduced overall global left ventricular systolic function. Prior to this finding, the participant did not have any symptoms of congestive heart failure.
Diagnostic Workup
The complex history prompted the decision to order a Fragile X assay, Chromosomal Microarray (CMA), and a trio exome sequencing. Fragile X testing revealed a normal hemizygous allele and CMA was consistent with a typical male and did not identify any copy number changes of clinical significance. Exome sequencing identified a heterozygous de novo missense pathogenic variant (c.1429G>A; p.Glu477Lys) variant in ZBTB47.
Treatment and Management
Genetic counseling was provided regarding the new diagnosis along with referral to clinical genetics for further evaluation and to establish care. Participant continues to receive specialized services for his diagnosis of intellectual disability. Metoprolo tartare was discontinued in favor of metoprolol succinate (Toprol) for guideline-directed medical therapy for LV dysfunction.
Outcome and Follow-Up
The participant continues to receive appropriate care without new major health outcomes. Consistent LV monitoring is in place through Echocardiogram screening.
Discussion
While the previous cohort reported various cardiovascular and gastrointestinal abnormalities, the combination of NICM and and intestinal malrotation has not been described, or may have been under-evaluated currently due to the younger ages of prior participants. Given that our clinic’s participant is heterozygous for the same de novo missense variant identified in the prior cohort, it is possible that these are adult-onset manifestations that should be evaluated and screened for in other ZBTB47 heterozygotes if not indicated prior. This will broaden the current understanding of the impact of pathogenic ZBTB47 variants and enable appropriate monitoring of both existing and future participants who undergo genetic testing.
Conclusion
In conclusion, our participant offers additional evidence supporting the role of the ZBTB47 gene in the development of a neurodevelopmental disorder and contributes new data on the cardiac and gastrointestinal phenotypes associated with the same genotype found in the majority of participants from the original cohort. Broader genetic testing should be considered when a participant has a constellation of medical findings that appear to be significant beyond the initial reason for specialty evaluation.