HAX1 mutations causing severe congenital neuropenia and neurological disease lead to cerebral microstructural abnormalities documented by quantitative MRI.
Biallelic mutations in the gene encoding HCLS-associated protein X-1 (HAX1) cause autosomal recessive severe congenital neutropenia (SCN). Some of these patients have neurological abnormalities including developmental delay, cognitive impairment, and/or epilepsy. Recent genotype-phenotype studies have shown that mutations in HAX1 affecting transcripts A (NM_006118.3) and B (NM_001018837.1) cause the phenotype of SCN with neurological impairment, while mutations affecting isoform A but not B lead to SCN without neurological aberrations. In this study, we identified a consanguineous family with two patients suffering from SCN and neurological disease caused by a novel, homozygous genomic deletion including exons 4-7 of the HAX1 gene. Quantitative MRI analyses showed generalized alterations in cerebral proton density in both of the patients, as well as in an additional unrelated patient with another HAX1 mutation (Arg86X) known to be associated with neurological manifestations. This study provides first in vivo evidence of aberrant neuroimaging findings associated with HAX1 deficiency in SCN patients.
Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany.
Kaan
K
Boztug
Xiao-Qi
XQ
Ding
Hans
H
Hartmann
Lena
L
Ziesenitz
Alejandro A
AA
Schäffer
Jana
J
Diestelhorst
Dietmar
D
Pfeifer
Giridharan
G
Appaswamy
Sonja
S
Kehbel
Thorsten
T
Simon
Abdullah
A
Al Jefri
Heinrich
H
Lanfermann
Christoph
C
Klein
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D001921:Brain / Q000002:abnormalities*; D016022:Case-Control Studies; D002648:Child; D003241:Consanguinity; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D004827:Epilepsy / Q000150:complications / Q000151:congenital / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D009154:Mutation; D009422:Nervous System Diseases / Q000150:complications / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D009503:Neutropenia / Q000150:complications / Q000151:congenital* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics; D012720:Severity of Illness Index
D048868:Adaptor Proteins, Signal Transducing; C104759:HAX1 protein, human; D020033:Protein Isoforms