A Novel Truncating Variant in PRDM16 Causes Severe Familial Cardiomyopathy with Variable Clinical Presentations
Laboratory Genetics and Genomics
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Primary Categories:
- Genomic Medicine
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Secondary Categories:
- Genomic Medicine
Introduction
PRDM16 (PR domain containing 16) is a zinc-finger transcription regulator and has been suspected to be responsible for the cardiomyopathy features in 1p36 deletion syndrome. Recent retrospective studies showed that about 29% to 34% of patients with a PRDM16 deletion developed cardiomyopathy, compared to about only 10% of patients without the deletion.
Case Presentation
Here we report a 10-year-old girl, who was previously healthy and no developmental concerns, diagnosed with dilated cardiomyopathy, decompensated heart failure, and evidence of global end organ hypoperfusion in the setting of severely depressed biventricular systolic function. The patient had developed shortness of breath and persistent cough and was brought to the emergency department where echocardiogram revealed dilated left ventricle (LV) with severely depressed LV systolic function with estimated LV ejection fraction 17-18%. She was admitted for further workup while her heart failure progressed, and she received a heart transplant.
Diagnostic Workup
Pathological examination of the heart biopsy found cardiomegaly (449 grams), biventricular mural thickening, biventricular diffuse cardiomyocyte hypertrophy, and focal interventricular septum interstitial fibrosis. The coronary arteries are patent and within normal limits. There is no evidence of inflammation or viral cytopathic changes.
Exome sequencing analysis of her peripheral blood sample identified a novel heterozygous frameshift variant resulting from 2 base pair (2-bp) deletion, c.1496_1497del (p.Pro499Leufs*104) in the PRDM16 gene (reference sequence: NM_022114.4). This 2-bp deletion occurs in exon 9 of 17 of the PRDM16 gene and is predicted to result in a truncated protein with potential loss of PRDM16 function. Loss-of-function variants in PRDM16 are highly constrained with pLI = 1 (expected value: 99.4, observed value: 21, o/e: 0.21, confidence interval: 0.15-0.3) based on the variants observed in the gnomAD database, the largest human population allele frequency database (https://gnomad.broadinstitute.org/). This variant has not been reported either as a benign or disease-causing variant in humans. It has not been observed in the gnomAD database or ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/). This variant was not detected in her healthy father’s blood sample. Her mother is not available for testing as she had passed away from congestive heart failure with a similar dilated cardiomyopathy phenotype with onset in her twenties. The same heterozygous variant was detected in her maternal aunt who reported having hypertrophic cardiomyopathy and atrial fibrillation diagnosed at 25 years old.
Treatment and Management
Subsequent genetic counseling revealed an extensive maternal family history with cardiac symptom onset in adulthood and subsequent heart failure in multiple generations including both affected male and female relatives. Further targeted mutation analysis completed on available unaffected individuals in the family confirmed the absence of the same PRDM16 frameshift variant. Except the maternal aunt, all other affected relatives have passed away (no DNA available for testing). The consistency with segregation of the variant and the disease in the family suggests this novel PRDM16 germline variant is likely responsible for the family’s extensive cardiomyopathy and heart failure history.
Outcome and Follow-Up
The patient appeared to be stable after receiving the heart transplantation. She was followed up by the cardiac specialties, geneticists and other important care management.
Discussion
A recent cohort study of PRDM16 loss in 1p36 deletion syndrome suggests PRDM16 loss may associate with sex-dependent cardiomyopathy and cardiac mortality. In contrast, our patient family has affected male and female members with variable presentation of cardiomyopathy with no obvious sex preference. Additionally, there is no clearly established molecular basis behind this observation in human. Instead, we hypothesize that loss of PRDM16 in hearts may lead to mitochondrial dysfunction as suggested in a mouse model. The function evaluation of this novel PRDM16 variant is on-going.
Conclusion
In summary, our exome findings of the heterozygous likely loss-of-function PRDM16 variant (p. p.Pro499Leufs*104) combined with the inheritance and extensive family history of cardiac failure provide evidence that PRDM16 loss of function causes cardiomyopathy and heart failure with variable presentations and onset ages. The variant will be useful in diagnosis/prognosis. Elucidation of pathophysiological pathways involving PRDM16 in human heart development is essential for developing drugs targeting PRDM16-related cardiomyopathy.
PRDM16 (PR domain containing 16) is a zinc-finger transcription regulator and has been suspected to be responsible for the cardiomyopathy features in 1p36 deletion syndrome. Recent retrospective studies showed that about 29% to 34% of patients with a PRDM16 deletion developed cardiomyopathy, compared to about only 10% of patients without the deletion.
Case Presentation
Here we report a 10-year-old girl, who was previously healthy and no developmental concerns, diagnosed with dilated cardiomyopathy, decompensated heart failure, and evidence of global end organ hypoperfusion in the setting of severely depressed biventricular systolic function. The patient had developed shortness of breath and persistent cough and was brought to the emergency department where echocardiogram revealed dilated left ventricle (LV) with severely depressed LV systolic function with estimated LV ejection fraction 17-18%. She was admitted for further workup while her heart failure progressed, and she received a heart transplant.
Diagnostic Workup
Pathological examination of the heart biopsy found cardiomegaly (449 grams), biventricular mural thickening, biventricular diffuse cardiomyocyte hypertrophy, and focal interventricular septum interstitial fibrosis. The coronary arteries are patent and within normal limits. There is no evidence of inflammation or viral cytopathic changes.
Exome sequencing analysis of her peripheral blood sample identified a novel heterozygous frameshift variant resulting from 2 base pair (2-bp) deletion, c.1496_1497del (p.Pro499Leufs*104) in the PRDM16 gene (reference sequence: NM_022114.4). This 2-bp deletion occurs in exon 9 of 17 of the PRDM16 gene and is predicted to result in a truncated protein with potential loss of PRDM16 function. Loss-of-function variants in PRDM16 are highly constrained with pLI = 1 (expected value: 99.4, observed value: 21, o/e: 0.21, confidence interval: 0.15-0.3) based on the variants observed in the gnomAD database, the largest human population allele frequency database (https://gnomad.broadinstitute.org/). This variant has not been reported either as a benign or disease-causing variant in humans. It has not been observed in the gnomAD database or ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/). This variant was not detected in her healthy father’s blood sample. Her mother is not available for testing as she had passed away from congestive heart failure with a similar dilated cardiomyopathy phenotype with onset in her twenties. The same heterozygous variant was detected in her maternal aunt who reported having hypertrophic cardiomyopathy and atrial fibrillation diagnosed at 25 years old.
Treatment and Management
Subsequent genetic counseling revealed an extensive maternal family history with cardiac symptom onset in adulthood and subsequent heart failure in multiple generations including both affected male and female relatives. Further targeted mutation analysis completed on available unaffected individuals in the family confirmed the absence of the same PRDM16 frameshift variant. Except the maternal aunt, all other affected relatives have passed away (no DNA available for testing). The consistency with segregation of the variant and the disease in the family suggests this novel PRDM16 germline variant is likely responsible for the family’s extensive cardiomyopathy and heart failure history.
Outcome and Follow-Up
The patient appeared to be stable after receiving the heart transplantation. She was followed up by the cardiac specialties, geneticists and other important care management.
Discussion
A recent cohort study of PRDM16 loss in 1p36 deletion syndrome suggests PRDM16 loss may associate with sex-dependent cardiomyopathy and cardiac mortality. In contrast, our patient family has affected male and female members with variable presentation of cardiomyopathy with no obvious sex preference. Additionally, there is no clearly established molecular basis behind this observation in human. Instead, we hypothesize that loss of PRDM16 in hearts may lead to mitochondrial dysfunction as suggested in a mouse model. The function evaluation of this novel PRDM16 variant is on-going.
Conclusion
In summary, our exome findings of the heterozygous likely loss-of-function PRDM16 variant (p. p.Pro499Leufs*104) combined with the inheritance and extensive family history of cardiac failure provide evidence that PRDM16 loss of function causes cardiomyopathy and heart failure with variable presentations and onset ages. The variant will be useful in diagnosis/prognosis. Elucidation of pathophysiological pathways involving PRDM16 in human heart development is essential for developing drugs targeting PRDM16-related cardiomyopathy.