title: Lessons from a pair of siblings with BPAN.
abstract: Neurodegeneration with brain iron accumulation (NBIA) encompasses a heterogeneous group of inherited progressive neurological diseases. Beta-propeller protein-associated neurodegeneration (BPAN) has been estimated to account for ~7% of all cases of NBIA and has distinctive clinical and brain imaging findings. Heterozygous variants in the WDR45 gene located in Xp11.23 are responsible for BPAN. A clear female predominance supports an X-linked dominant pattern of inheritance with proposed lethality for germline variants in hemizygous males. By whole-exome sequencing, we identified an in-frame deletion in the WDR45 gene (c.161_163delTGG) in the hemizygous state in a 20-year-old man with a history of profound neurocognitive impairment and seizures. His higher functioning 14-year-old sister, also with a history of intellectual disability, was found to carry the same variant in the heterozygous state. Their asymptomatic mother was mosaic for the alteration. From this pair of siblings with BPAN we conclude that: (1) inherited WDR45 variants are possible, albeit rare; (2) hemizygous germline variants in males can be viable, but likely result in a more severe phenotype; (3) for siblings with germline variants, males should be more significantly affected than females; and (4) because gonadal and germline mosaicism are possible and healthy female carriers can be found, parental testing for variants in WDR45 should be considered.
authors.affiliation: Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA.
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Zarate
authors.affiliation: Greenwood Genetic Center, Greenwood, SC, USA.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Jones
authors.affiliation: Greenwood Genetic Center, Greenwood, SC, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Jones
authors.affiliation: GeneDx, Gaithersburg, MD, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Millan
authors.affiliation: GeneDx, Gaithersburg, MD, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: GeneDx, Gaithersburg, MD, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Vertino-Bell
authors.affiliation: Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA.
authors.forename: G Bradley
authors.initials: GB
authors.lastname: Schaefer
authors.affiliation: Barrow Neurological Institute, Phoenix Children's Hospital, Phoenix, AZ, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kruer
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D041321:Chromosomes, Human, X / Q000235:genetics; D059472:Exome; D005260:Female; D017353:Gene Deletion; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology; D018095:Germ-Line Mutation; D057898:Hemizygote; D006579:Heterozygote; D006801:Humans; D019189:Iron Metabolism Disorders / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D008297:Male; D009030:Mosaicism; D019150:Neuroaxonal Dystrophies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C578284:WDR45 protein, human