Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.
Alleles
Brain
/ pathology
Child
Child, Preschool
Female
Genetic Diseases, Inborn
/ genetics
Genetic Predisposition to Disease
Humans
Infant
Liver
/ pathology
Liver Transplantation
/ adverse effects
Male
Muscle, Skeletal
/ pathology
Mutation, Missense
/ genetics
Neoplasm Proteins
/ genetics
Phenotype
NBAS
RALF
SOPH syndrome
acute liver failure
infantile liver failure syndrome type 2
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
09
08
2019
accepted:
30
10
2019
revised:
30
10
2019
pubmed:
26
11
2019
medline:
4
2
2021
entrez:
26
11
2019
Statut:
ppublish
Résumé
Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.
Identifiants
pubmed: 31761904
doi: 10.1038/s41436-019-0698-4
pii: S1098-3600(21)01261-2
doi:
Substances chimiques
NBAS protein, human
0
Neoplasm Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
610-621Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK109907
Pays : United States
Organisme : Wellcome Trust
ID : 10585/B/18/Z
Pays : United Kingdom
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