Unveiling a Dual Diagnosis: The Role of Exome Reanalysis in Evolving Pediatric Phenotypes
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction
Exome reanalysis is a valuable tool for addressing complex phenotypes, particularly as clinical presentations evolve and genetic knowledge expands. By incorporating new clinical data, reevaluating variants, and employing multidisciplinary interpretation, this process enhances diagnostic accuracy. This report highlights how exome reanalysis uncovered a dual diagnosis in a pediatric patient with an evolving phenotype.
Case Presentation
A 14-year-old female presented with a history of peeling skin syndrome diagnosed 10 years ago through exome sequencing, which identified a homozygous variant, c.85G>C (p.Gly29Ala), in the CDSN gene. At the time, there were no concerns about myopathies or neuromuscular complications. Recently, she presented with new symptoms, including one week of fatigue, proximal muscle weakness, loss of ambulation, tingling, numbness, and hypoglycemia.
Diagnostic Workup
Laboratory evaluations revealed borderline low glucose (70 mg/dL), elevated creatinine kinase (1040 U/L), and lactate dehydrogenase (533 U/L). Liver function tests were abnormal, with AST (214 U/L) and ALT (121 U/L). A liver biopsy demonstrated extensive macrosteatosis with increased mitochondria but was inconclusive for mitochondriopathy or glycogen storage disorder. The mitochondrial genome test was negative. The patient’s parents are first cousins of West African descent with no significant family history. Given her new symptoms, the differential diagnosis expanded to include idiopathic inflammatory myopathy or a genetic/mitochondrial etiology, prompting exome reanalysis focusing on genes associated with myopathies.
Discussion
Exome reanalysis identified a homozygous missense variant, c.440G>A (p.Arg147His), in the SLC25A32 gene, in addition to the previously known homozygous variant in the CDSN gene. The SLC25A32 gene encodes a mitochondrial transporter for flavin adenine dinucleotide (FAD) across the inner mitochondrial membrane. Variants in SLC25A32 reduce FAD availability for mitochondrial flavoenzymes, impairing fatty acid β-oxidation and respiratory-chain oxidative phosphorylation (PMID: 37845732).
The same SLC25A32 variant has been reported in the compound heterozygous state, along with a truncating variant, in a same-age girl with recurrent exercise intolerance and biochemical features of multiple acyl–coenzyme A dehydrogenase deficiency, who responded to riboflavin treatment (PMID: 26933868). However, in our patient, the lack of a positive acyl–coenzyme A dehydrogenase result limits a direct phenotypic comparison. Instead, our case focuses on overlapping features, particularly hypoglycemia and proximal muscle weakness, as potential manifestations of this variant. The c.440G>A (p.Arg147His) variant has been observed in 276 of 1,612,240 alleles (0.02%) in gnomAD v4.1.0, with no homozygotes identified, and the highest allele frequency in African/African American populations (22 of 74,888 alleles, 0.03%). Functional studies in yeast and the patient’s fibroblasts demonstrated significantly reduced enzymatic activity for this variant (PMID: 26933868). Our case represents the second reported occurrence of this missense variant with a similar phenotype. Follow-up serum biochemical testing is pending to clarify its impact.
Additionally, the reanalysis confirmed the previously identified c.85G>C (p.Gly29Ala) missense variant in the CDSN gene. CDSN encodes corneodesmosin, a key component of intercellular structures involved in desquamation. Homozygous nonsense and frameshift variants in CDSN are associated with peeling skin syndrome (PSS), an autosomal recessive condition characterized by superficial skin peeling from birth, severe pruritus, and atopy (PMID: 20643494). The overlap between the patient’s symptoms and PSS, along with segregation of the CDSN variant in an affected sister with ichthyosis, suggests that this variant contributed to her skin-related phenotype.
Conclusion
This case highlights a dual diagnosis: peeling skin syndrome due to a CDSN variant and a likely mitochondrial myopathy due to a SLC25A32 variant. While both variants are classified as variants of uncertain significance, clinically, they provide a molecular diagnosis that explains the patient’s evolving phenotype. This case underscores the importance of reanalyzing genomic data as phenotypes develop, emphasizing the utility of genomic reevaluation in identifying additional diagnoses that refine patient care and guide treatment strategies.
Exome reanalysis is a valuable tool for addressing complex phenotypes, particularly as clinical presentations evolve and genetic knowledge expands. By incorporating new clinical data, reevaluating variants, and employing multidisciplinary interpretation, this process enhances diagnostic accuracy. This report highlights how exome reanalysis uncovered a dual diagnosis in a pediatric patient with an evolving phenotype.
Case Presentation
A 14-year-old female presented with a history of peeling skin syndrome diagnosed 10 years ago through exome sequencing, which identified a homozygous variant, c.85G>C (p.Gly29Ala), in the CDSN gene. At the time, there were no concerns about myopathies or neuromuscular complications. Recently, she presented with new symptoms, including one week of fatigue, proximal muscle weakness, loss of ambulation, tingling, numbness, and hypoglycemia.
Diagnostic Workup
Laboratory evaluations revealed borderline low glucose (70 mg/dL), elevated creatinine kinase (1040 U/L), and lactate dehydrogenase (533 U/L). Liver function tests were abnormal, with AST (214 U/L) and ALT (121 U/L). A liver biopsy demonstrated extensive macrosteatosis with increased mitochondria but was inconclusive for mitochondriopathy or glycogen storage disorder. The mitochondrial genome test was negative. The patient’s parents are first cousins of West African descent with no significant family history. Given her new symptoms, the differential diagnosis expanded to include idiopathic inflammatory myopathy or a genetic/mitochondrial etiology, prompting exome reanalysis focusing on genes associated with myopathies.
Discussion
Exome reanalysis identified a homozygous missense variant, c.440G>A (p.Arg147His), in the SLC25A32 gene, in addition to the previously known homozygous variant in the CDSN gene. The SLC25A32 gene encodes a mitochondrial transporter for flavin adenine dinucleotide (FAD) across the inner mitochondrial membrane. Variants in SLC25A32 reduce FAD availability for mitochondrial flavoenzymes, impairing fatty acid β-oxidation and respiratory-chain oxidative phosphorylation (PMID: 37845732).
The same SLC25A32 variant has been reported in the compound heterozygous state, along with a truncating variant, in a same-age girl with recurrent exercise intolerance and biochemical features of multiple acyl–coenzyme A dehydrogenase deficiency, who responded to riboflavin treatment (PMID: 26933868). However, in our patient, the lack of a positive acyl–coenzyme A dehydrogenase result limits a direct phenotypic comparison. Instead, our case focuses on overlapping features, particularly hypoglycemia and proximal muscle weakness, as potential manifestations of this variant. The c.440G>A (p.Arg147His) variant has been observed in 276 of 1,612,240 alleles (0.02%) in gnomAD v4.1.0, with no homozygotes identified, and the highest allele frequency in African/African American populations (22 of 74,888 alleles, 0.03%). Functional studies in yeast and the patient’s fibroblasts demonstrated significantly reduced enzymatic activity for this variant (PMID: 26933868). Our case represents the second reported occurrence of this missense variant with a similar phenotype. Follow-up serum biochemical testing is pending to clarify its impact.
Additionally, the reanalysis confirmed the previously identified c.85G>C (p.Gly29Ala) missense variant in the CDSN gene. CDSN encodes corneodesmosin, a key component of intercellular structures involved in desquamation. Homozygous nonsense and frameshift variants in CDSN are associated with peeling skin syndrome (PSS), an autosomal recessive condition characterized by superficial skin peeling from birth, severe pruritus, and atopy (PMID: 20643494). The overlap between the patient’s symptoms and PSS, along with segregation of the CDSN variant in an affected sister with ichthyosis, suggests that this variant contributed to her skin-related phenotype.
Conclusion
This case highlights a dual diagnosis: peeling skin syndrome due to a CDSN variant and a likely mitochondrial myopathy due to a SLC25A32 variant. While both variants are classified as variants of uncertain significance, clinically, they provide a molecular diagnosis that explains the patient’s evolving phenotype. This case underscores the importance of reanalyzing genomic data as phenotypes develop, emphasizing the utility of genomic reevaluation in identifying additional diagnoses that refine patient care and guide treatment strategies.