Evaluation of the Genotypic and Phenotypic Spectrum of Pediatric ABCC6 Deficiency
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
ABCC6 is a transmembrane protein involved in the metabolic pyrophosphate (PPi)-adenosine pathway that produces PPi, an inhibitor of skeletal mineralization, and adenosine, a regulator of vascular intimal proliferation. Dysfunctional ABCC6 results in accumulation of mineralized deposits in the soft tissue and arterial intimal proliferation. Pseudoxanthoma elasticum (PXE) due to ABCC6 Deficiency is characterized by calcification of the skin, retina, and peripheral arteries, with symptom onset typically in adolescence or early adulthood. Generalized arterial calcification of infancy type 2 (GACI2) due to ABCC6 Deficiency is characterized by severe cardiovascular calcification or stenosis and is typically diagnosed in infants. Children (aged 0-18 years) with monoallelic or biallelic variants in ABCC6 have been diagnosed with PXE or GACI2, but to date their genotypes and phenotypes have not been systematically collated. This study evaluated the genotypic and phenotypic spectrum of pediatric ABCC6 Deficiency.
Methods:
A comprehensive literature search was performed to identify patients with ≥1 variant in ABCC6 and clinical manifestations recorded during childhood (age 0-18 years) using Mastermind, a database of variants with evidence cited in the medical literature. Children without a reported phenotype were excluded. Additional children were included from 2 natural history studies (NCT03478839 and NCT03758534). ABCC6 variants were interpreted according to the 2015 American College of Medical Genetics and Genomics guidelines.
Results:
In total, 95 children met the inclusion criteria (82 from published literature and 19 from natural history studies); 54.7% were diagnosed with PXE and 46.3% with GACI2. The median age at symptom onset was ≈5 months (range, 0-17 years), while median age at diagnosis was 3 years. Median age at symptom onset was greater in PXE vs GACI2 (PXE 8.2 years, GACI2 ≈8 months). Most children had ectopic calcification, most commonly affecting the arteries (56%). Patients exhibited multisystem complications including cardiovascular (51%), dermatologic (37%), ocular (22%), and neurological (21%) phenotypes. Except for skin manifestations, the majority of calcification and organ-system manifestations were reported within the first year of life; however, medical complications continued to be reported with relatively high frequency through 6 years of age and with lower frequency from ages 7 to 18 years. Unfortunately, 25% of children required hospitalization, and 12% had died by a median age of ≈1.4 months.
Analysis of ABCC6 variants revealed a total of 132 variants, of which 57.6% were predicted to be pathogenic (P), 26.5% likely pathogenic (LP), and 10.6% variants of uncertain significance (VUS). Among all variants, biallelic ABCC6 variants occurred in 61.1% of children, and monoallelic variants were found in 26.3%. Forty-six percent of children harbored biallelic P/LP variants. The P/LP variants were most frequently missense (35.1%), nonsense (22.5%), and frameshift deletions (18.9%). The location of the variants along the ABCC6 protein had a high degree of heterogeneity.
Four pathogenic variants (R518Q/R518*, R1141*, W1259fs, R1314W) occurred at a high frequency (>10 alleles), but no definitive correlation could be deduced when the associated phenotypes were examined.
Conclusion:
Patients with pediatric (age 0-18 years) ABCC6 Deficiency exhibit a high burden of calcification and multisystem complications, which often manifest within the first year of life. Most ABCC6 variants were P/LP (84%) with a high degree of heterogeneity in location and type, and no genotypic hot spots associated with particular phenotypes could be deduced. Due to the variability of clinical presentations and the lack of systematic characterization of their phenotypes, pediatric ABCC6 Deficiency is likely underdiagnosed. The elevated risk of cardiovascular and neurological complications from infancy through childhood underscores the need for guidelines on diagnosis, including genetic testing, and monitoring of pediatric ABCC6 Deficiency.
ABCC6 is a transmembrane protein involved in the metabolic pyrophosphate (PPi)-adenosine pathway that produces PPi, an inhibitor of skeletal mineralization, and adenosine, a regulator of vascular intimal proliferation. Dysfunctional ABCC6 results in accumulation of mineralized deposits in the soft tissue and arterial intimal proliferation. Pseudoxanthoma elasticum (PXE) due to ABCC6 Deficiency is characterized by calcification of the skin, retina, and peripheral arteries, with symptom onset typically in adolescence or early adulthood. Generalized arterial calcification of infancy type 2 (GACI2) due to ABCC6 Deficiency is characterized by severe cardiovascular calcification or stenosis and is typically diagnosed in infants. Children (aged 0-18 years) with monoallelic or biallelic variants in ABCC6 have been diagnosed with PXE or GACI2, but to date their genotypes and phenotypes have not been systematically collated. This study evaluated the genotypic and phenotypic spectrum of pediatric ABCC6 Deficiency.
Methods:
A comprehensive literature search was performed to identify patients with ≥1 variant in ABCC6 and clinical manifestations recorded during childhood (age 0-18 years) using Mastermind, a database of variants with evidence cited in the medical literature. Children without a reported phenotype were excluded. Additional children were included from 2 natural history studies (NCT03478839 and NCT03758534). ABCC6 variants were interpreted according to the 2015 American College of Medical Genetics and Genomics guidelines.
Results:
In total, 95 children met the inclusion criteria (82 from published literature and 19 from natural history studies); 54.7% were diagnosed with PXE and 46.3% with GACI2. The median age at symptom onset was ≈5 months (range, 0-17 years), while median age at diagnosis was 3 years. Median age at symptom onset was greater in PXE vs GACI2 (PXE 8.2 years, GACI2 ≈8 months). Most children had ectopic calcification, most commonly affecting the arteries (56%). Patients exhibited multisystem complications including cardiovascular (51%), dermatologic (37%), ocular (22%), and neurological (21%) phenotypes. Except for skin manifestations, the majority of calcification and organ-system manifestations were reported within the first year of life; however, medical complications continued to be reported with relatively high frequency through 6 years of age and with lower frequency from ages 7 to 18 years. Unfortunately, 25% of children required hospitalization, and 12% had died by a median age of ≈1.4 months.
Analysis of ABCC6 variants revealed a total of 132 variants, of which 57.6% were predicted to be pathogenic (P), 26.5% likely pathogenic (LP), and 10.6% variants of uncertain significance (VUS). Among all variants, biallelic ABCC6 variants occurred in 61.1% of children, and monoallelic variants were found in 26.3%. Forty-six percent of children harbored biallelic P/LP variants. The P/LP variants were most frequently missense (35.1%), nonsense (22.5%), and frameshift deletions (18.9%). The location of the variants along the ABCC6 protein had a high degree of heterogeneity.
Four pathogenic variants (R518Q/R518*, R1141*, W1259fs, R1314W) occurred at a high frequency (>10 alleles), but no definitive correlation could be deduced when the associated phenotypes were examined.
Conclusion:
Patients with pediatric (age 0-18 years) ABCC6 Deficiency exhibit a high burden of calcification and multisystem complications, which often manifest within the first year of life. Most ABCC6 variants were P/LP (84%) with a high degree of heterogeneity in location and type, and no genotypic hot spots associated with particular phenotypes could be deduced. Due to the variability of clinical presentations and the lack of systematic characterization of their phenotypes, pediatric ABCC6 Deficiency is likely underdiagnosed. The elevated risk of cardiovascular and neurological complications from infancy through childhood underscores the need for guidelines on diagnosis, including genetic testing, and monitoring of pediatric ABCC6 Deficiency.
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