Incidence of PKAN determined by bioinformatic and population-based analysis of ~140,000 humans.
Panthothenate kinase-associated neurodegeneration (PKAN, OMIM 234200), is an inborn is an autosomal recessive inborn error of metabolism caused by pathogenic variants in PANK2. PANK2 encodes the enzyme pantothenate kinase 2 (EC 2.7.1.33), an essential regulatory enzyme in CoA biosynthesis. Clinical presentation includes dystonia, rigidity, bradykinesia, dysarthria, pigmentary retinopathy and dementia with variable age of onset ranging from childhood to adulthood. In order to provide an accurate incidence estimate of PKAN, we conducted a systematic review of the literature and databases for pathogenic mutations and constructed a bioinformatic profile for pathogenic missense variants in PANK2. We then studied the gnomAD cohort of ~140,000 unrelated adults from global populations to determine the allele frequency of the variants in PANK2 reported pathogenic for PKAN and for those additional variants identified in gnomAD that met bioinformatics criteria for being potentially pathogenic. Incidence was estimated based on three different models using the allele frequencies of pathogenic PKAN variants with or without those bioinformatically determined to be potentially pathogenic. Disease incidence calculations showed PKAN incidence ranging from 1:396,006 in Europeans, 1:1,526,982 in Africans, 1:480,826 in Latino, 1:523,551 in East Asians and 1:531,118 in South Asians. These results indicate PKAN is expected to occur in approximately 2 of every 1 million live births globally outside of Africa, and has a much lower incidence 1 in 1.5 million live births in the African population.
['Brezavar|Daniel|D|', 'Bonnen|Penelope E|PE|']
D000483:Alleles D019943:Amino Acid Substitution D019295:Computational Biology D030541:Databases, Genetic D005787:Gene Frequency D056726:Genetic Association Studies D020022:Genetic Predisposition to Disease D005828:Genetics, Population D006801:Humans D015994:Incidence D006211:Pantothenate Kinase-Associated Neurodegeneration D010641:Phenotype D017853:Phosphotransferases (Alcohol Group Acceptor) D011159:Population Surveillance
Incidence PKAN PANK2 Dystonia Retinopathy Eye of the tiger Movement disorder NBIA Population genetics Variant prediction