Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing
Abstract Trifunctional protein deficiency (TFP) is a disorder of fatty acid beta‐oxidation associated with metabolic, cardiac, and liver dysfunction in severe forms. We present two siblings diagnosed by newborn screening and confirmed by biochemical testing at birth. Their clinical course was compli...
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Wiley
2025-01-01
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| Series: | JIMD Reports |
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| Online Access: | https://doi.org/10.1002/jmd2.12459 |
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| author | Thomas Cassini Sarah Silverstein Molly Behan Cynthia J. Tifft May Christine Malicdan David R. Adams Undiagnosed Diseases Network Sun‐Young Ahn Debra S. Regier |
| author_facet | Thomas Cassini Sarah Silverstein Molly Behan Cynthia J. Tifft May Christine Malicdan David R. Adams Undiagnosed Diseases Network Sun‐Young Ahn Debra S. Regier |
| author_sort | Thomas Cassini |
| collection | DOAJ |
| description | Abstract Trifunctional protein deficiency (TFP) is a disorder of fatty acid beta‐oxidation associated with metabolic, cardiac, and liver dysfunction in severe forms. We present two siblings diagnosed by newborn screening and confirmed by biochemical testing at birth. Their clinical course was complicated by recurrent rhabdomyolysis, retinopathy, and hypoparathyroidism. Both siblings were also diagnosed with focal segmental glomerulosclerosis (FSGS) and bone marrow failure and ultimately died of hypoxemic respiratory failure. Initial sequencing of the TFP‐associated genes HADHA and HADHB showed only a paternally inherited variant in HADHB, NM_000183.3:c.1059del (p.Gly354AspfsTer10). Subsequent evaluation by the Undiagnosed Diseases Network with genome and transcriptome sequencing revealed a rare maternally inherited 17 base pair deletion in HADHB, NM_000183.3:c.1390‐515_1390‐499del, located in the final intron and resulting in a pseudoexon that harbors a premature termination codon. Both sisters were compound heterozygous for this and the paternal premature termination codon. No other variants were detected that were potentially causative for the FSGS and bone marrow failure on genome sequencing. A review of the literature at that time revealed several case reports of the uncommon clinical findings of FSGS, bone marrow failure, and pulmonary involvement in patients with TFP, confirming this clinical diagnosis as the complete explanation for these siblings. |
| format | Article |
| id | doaj-art-983f8b6f20854b53afe5c73e02f87ad4 |
| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| spelling | doaj-art-983f8b6f20854b53afe5c73e02f87ad42025-01-28T07:38:32ZengWileyJIMD Reports2192-83122025-01-01661n/an/a10.1002/jmd2.12459Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicingThomas Cassini0Sarah Silverstein1Molly Behan2Cynthia J. Tifft3May Christine Malicdan4David R. Adams5Undiagnosed Diseases NetworkSun‐Young Ahn6Debra S. Regier7Division of Medical Genetics and Genomic Medicine, Department of Pediatrics Vanderbilt University Medical Center Nashville Tennessee USANeuromuscular and Neurogenetics Diseases of Childhood Section NINDS, NIH Bethesda Maryland USAMedical Genetics Branch, National Human Genome Research Institute National Institutes of Health Bethesda Maryland USANIH Undiagnosed Diseases Program, NIH Intramural Research Program NIH Bethesda Maryland USANIH Undiagnosed Diseases Program, NIH Intramural Research Program NIH Bethesda Maryland USANIH Undiagnosed Diseases Program, NIH Intramural Research Program NIH Bethesda Maryland USADivision of Pediatric Nephrology Children's National Hospital Washington District of Columbia USADivision of Genetics and Metabolism Children's National Hospital Washington District of Columbia USAAbstract Trifunctional protein deficiency (TFP) is a disorder of fatty acid beta‐oxidation associated with metabolic, cardiac, and liver dysfunction in severe forms. We present two siblings diagnosed by newborn screening and confirmed by biochemical testing at birth. Their clinical course was complicated by recurrent rhabdomyolysis, retinopathy, and hypoparathyroidism. Both siblings were also diagnosed with focal segmental glomerulosclerosis (FSGS) and bone marrow failure and ultimately died of hypoxemic respiratory failure. Initial sequencing of the TFP‐associated genes HADHA and HADHB showed only a paternally inherited variant in HADHB, NM_000183.3:c.1059del (p.Gly354AspfsTer10). Subsequent evaluation by the Undiagnosed Diseases Network with genome and transcriptome sequencing revealed a rare maternally inherited 17 base pair deletion in HADHB, NM_000183.3:c.1390‐515_1390‐499del, located in the final intron and resulting in a pseudoexon that harbors a premature termination codon. Both sisters were compound heterozygous for this and the paternal premature termination codon. No other variants were detected that were potentially causative for the FSGS and bone marrow failure on genome sequencing. A review of the literature at that time revealed several case reports of the uncommon clinical findings of FSGS, bone marrow failure, and pulmonary involvement in patients with TFP, confirming this clinical diagnosis as the complete explanation for these siblings.https://doi.org/10.1002/jmd2.12459intronic variantnephrotic syndromeRNAseqtrifunctional protein deficiencyUndiagnosed Diseases Network |
| spellingShingle | Thomas Cassini Sarah Silverstein Molly Behan Cynthia J. Tifft May Christine Malicdan David R. Adams Undiagnosed Diseases Network Sun‐Young Ahn Debra S. Regier Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing JIMD Reports intronic variant nephrotic syndrome RNAseq trifunctional protein deficiency Undiagnosed Diseases Network |
| title | Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing |
| title_full | Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing |
| title_fullStr | Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing |
| title_full_unstemmed | Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing |
| title_short | Mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing |
| title_sort | mitochondrial trifunctional protein deficiency caused by a deep intronic deletion leading to aberrant splicing |
| topic | intronic variant nephrotic syndrome RNAseq trifunctional protein deficiency Undiagnosed Diseases Network |
| url | https://doi.org/10.1002/jmd2.12459 |
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