Unusual Variants in NDUFAF6-Associated Mitochondrial Disease
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
NADH:ubiquinone oxidoreductase complex assembly factor 6 (NDUFAF6) plays an important role in mitochondrial complex I assembly by regulating ND1 biogenesis and facilitating the incorporation of NDAFS8. Variants in NDUFAF6 are associated with two OMIM disorders: Fanconi renotubular syndrome 5 (OMIM #618913) and Mitochondrial complex I deficiency, nuclear type 17 (OMIM #618239). The associated phenotype includes degeneration of the central nervous system and proximal tubule dysfunction. Studies revealed the role of NDUFAF6 in complex I deficiency as well as in the manifestation of Leigh syndrome, a progressive neurodegenerative disease. More recently, researchers discovered an intronic variant within NDUFAF6 in their cohort of Acadian patients representing the Acadian variant of renal Fanconi syndrome. Further analysis showed that this variant affected splicing and synthesis of NDUFAF6 isoforms and manifested as proximal tubule dysfunction, further expanding the phenotypes associated with variants in NDUFAF6.
Case Presentation
We present a 6-year-old female evaluated in the National Institutes of Health Undiagnosed Diseases Program who presented with global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction. The patient’s prenatal history was complicated by intrauterine growth restriction noted at 25 weeks followed by a premature birth at 35 weeks and 6 days via cesarean section for breech presentation. Following birth, the proband was admitted to the neonatal intensive care unit for respiratory distress and was placed on continuous positive air pressure. Developmental delay was evident by 3 months of age. At 3.5 months old, the patient began to refuse feeding and exhibited frequent emesis. She was subsequently diagnosed with failure to thrive and gastroesophageal reflux.
At 14 months old, the patient was noted to have chronic transaminitis and elevated plasma methionine and tyrosine levels, which prompted a liver biopsy that revealed mild microvesicular and macrovesicular steatosis, focally increased hepatocellular cytoplasmic eosinophilia, scattered acidophilic bodies, and mild sinusoidal fibrosis. During this time, urine amino acid analysis showed generalized aminoaciduria. The patient was found to have elevated blood lactate suggestive of mitochondrial disease. Growth differentiation factor 15 levels were also elevated. At 19 months she had glucosuria and an eGFR of <30 mL/min/1.73m2.
Diagnostic Workup
At 2 years and 2 months old, the proband was enrolled in the Clinical and Genetic Evaluation of Individuals with Undiagnosed Disorders Through the Undiagnosed Diseases Network. During this evaluation, she had elevated GDF15 levels, plasma lactate, and plasma pyruvate. Trio genome sequencing revealed two variants in NDUFAF6: a paternally inherited intronic variant NM_152416.3:c.298-768T>C and a maternally inherited 1.6 kb deletion NC_000008.11:g.95044573_95046180del encompassing all of exon 5. The intronic single nucleotide variant in this case has been previously reported to cause aberrant splicing, manifesting as renal Fanconi syndrome. Functional assays of complex I activity and assembly confirmed complex I deficiency. Based on this diagnosis, optimization of her mitochondrial cocktail and supplements was recommended before moving to a kidney or liver transplant.
Conclusion
In this case report, we utilized genome sequencing to diagnose complex I deficiency caused by NDUFAF6 compound heterozygous variants in an individual who presented with both global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction. We consider the implications that this case has for patients presenting with pathogenic variants in NDUFAF6 as it suggests a phenotypic spectrum between Leigh and Fanconi syndrome. This case also highlights the need to consider atypical variants, potentially missed by exome sequencing methods, during the planning of comprehensive diagnostic strategy.
NADH:ubiquinone oxidoreductase complex assembly factor 6 (NDUFAF6) plays an important role in mitochondrial complex I assembly by regulating ND1 biogenesis and facilitating the incorporation of NDAFS8. Variants in NDUFAF6 are associated with two OMIM disorders: Fanconi renotubular syndrome 5 (OMIM #618913) and Mitochondrial complex I deficiency, nuclear type 17 (OMIM #618239). The associated phenotype includes degeneration of the central nervous system and proximal tubule dysfunction. Studies revealed the role of NDUFAF6 in complex I deficiency as well as in the manifestation of Leigh syndrome, a progressive neurodegenerative disease. More recently, researchers discovered an intronic variant within NDUFAF6 in their cohort of Acadian patients representing the Acadian variant of renal Fanconi syndrome. Further analysis showed that this variant affected splicing and synthesis of NDUFAF6 isoforms and manifested as proximal tubule dysfunction, further expanding the phenotypes associated with variants in NDUFAF6.
Case Presentation
We present a 6-year-old female evaluated in the National Institutes of Health Undiagnosed Diseases Program who presented with global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction. The patient’s prenatal history was complicated by intrauterine growth restriction noted at 25 weeks followed by a premature birth at 35 weeks and 6 days via cesarean section for breech presentation. Following birth, the proband was admitted to the neonatal intensive care unit for respiratory distress and was placed on continuous positive air pressure. Developmental delay was evident by 3 months of age. At 3.5 months old, the patient began to refuse feeding and exhibited frequent emesis. She was subsequently diagnosed with failure to thrive and gastroesophageal reflux.
At 14 months old, the patient was noted to have chronic transaminitis and elevated plasma methionine and tyrosine levels, which prompted a liver biopsy that revealed mild microvesicular and macrovesicular steatosis, focally increased hepatocellular cytoplasmic eosinophilia, scattered acidophilic bodies, and mild sinusoidal fibrosis. During this time, urine amino acid analysis showed generalized aminoaciduria. The patient was found to have elevated blood lactate suggestive of mitochondrial disease. Growth differentiation factor 15 levels were also elevated. At 19 months she had glucosuria and an eGFR of <30 mL/min/1.73m2.
Diagnostic Workup
At 2 years and 2 months old, the proband was enrolled in the Clinical and Genetic Evaluation of Individuals with Undiagnosed Disorders Through the Undiagnosed Diseases Network. During this evaluation, she had elevated GDF15 levels, plasma lactate, and plasma pyruvate. Trio genome sequencing revealed two variants in NDUFAF6: a paternally inherited intronic variant NM_152416.3:c.298-768T>C and a maternally inherited 1.6 kb deletion NC_000008.11:g.95044573_95046180del encompassing all of exon 5. The intronic single nucleotide variant in this case has been previously reported to cause aberrant splicing, manifesting as renal Fanconi syndrome. Functional assays of complex I activity and assembly confirmed complex I deficiency. Based on this diagnosis, optimization of her mitochondrial cocktail and supplements was recommended before moving to a kidney or liver transplant.
Conclusion
In this case report, we utilized genome sequencing to diagnose complex I deficiency caused by NDUFAF6 compound heterozygous variants in an individual who presented with both global developmental delay, chronic kidney disease (stage III), and renal tubular dysfunction. We consider the implications that this case has for patients presenting with pathogenic variants in NDUFAF6 as it suggests a phenotypic spectrum between Leigh and Fanconi syndrome. This case also highlights the need to consider atypical variants, potentially missed by exome sequencing methods, during the planning of comprehensive diagnostic strategy.