Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.
Genet Med
; 22(3): 610-621, 2020 03.
Article
en En
| MEDLINE
| ID: mdl-31761904
ABSTRACT
PURPOSE:
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.METHODS:
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.RESULTS:
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 ß-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 ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH).CONCLUSION:
We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Predisposición Genética a la Enfermedad
/
Enfermedades Genéticas Congénitas
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Proteínas de Neoplasias
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
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Risk_factors_studies
Límite:
Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Genet Med
Asunto de la revista:
GENETICA MEDICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Alemania