The application of next-generation sequencing (NGS) to clinical practice is still hampered by the ability to interpret the clinical relevance of novel variants and the difficulty of evaluating their effect in specific tissues. Here, we applied integrated genomic approaches for interrogating blood samples of two unrelated individuals with neurodevelopmental disorders and identified a novel neuro-pathogenic role for the Mitogen-Activated Protein Kinase 4 gene (MAP4K4). In particular, we identified two novel frameshift variants in coding exons expressed in the blood and neuronal isoforms. Both variants were predicted to generate non-sense-mediated decay. By transcriptome analysis, we simultaneously demonstrated the deleterious effect of the identified variants on the splicing activity and stability of MAP4K4 mRNA. Therefore, we propose MAP4K4 as a novel causative gene for non-syndromic and syndromic neurodevelopmental disorders. Altogether, we prove the efficacy of an integrated approach of exome and transcriptome sequencing in the resolution of undiagnosed cases by leveraging the analysis of variants in genes expressed in peripheral blood.

Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association / Cesana, M; Vaccaro, L; Larsen, M J; Kibæk, M; Micale, L; Riccardo, S; Annunziata, P; Colantuono, C; Di Filippo, L; De Brasi, D; Castori, M; Fagerberg, C; Acquaviva, F; Cacchiarelli, D. - In: HUMAN GENETICS. - ISSN 0340-6717. - (2022). [10.1007/s00439-022-02497-y]

Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association

Cesana, M
Primo
;
Colantuono, C;De Brasi, D;Acquaviva, F;Cacchiarelli, D
Ultimo
2022

Abstract

The application of next-generation sequencing (NGS) to clinical practice is still hampered by the ability to interpret the clinical relevance of novel variants and the difficulty of evaluating their effect in specific tissues. Here, we applied integrated genomic approaches for interrogating blood samples of two unrelated individuals with neurodevelopmental disorders and identified a novel neuro-pathogenic role for the Mitogen-Activated Protein Kinase 4 gene (MAP4K4). In particular, we identified two novel frameshift variants in coding exons expressed in the blood and neuronal isoforms. Both variants were predicted to generate non-sense-mediated decay. By transcriptome analysis, we simultaneously demonstrated the deleterious effect of the identified variants on the splicing activity and stability of MAP4K4 mRNA. Therefore, we propose MAP4K4 as a novel causative gene for non-syndromic and syndromic neurodevelopmental disorders. Altogether, we prove the efficacy of an integrated approach of exome and transcriptome sequencing in the resolution of undiagnosed cases by leveraging the analysis of variants in genes expressed in peripheral blood.
2022
Integrated exome and transcriptome analysis prioritizes MAP4K4 de novo frameshift variants in autism spectrum disorder as a novel disease-gene association / Cesana, M; Vaccaro, L; Larsen, M J; Kibæk, M; Micale, L; Riccardo, S; Annunziata, P; Colantuono, C; Di Filippo, L; De Brasi, D; Castori, M; Fagerberg, C; Acquaviva, F; Cacchiarelli, D. - In: HUMAN GENETICS. - ISSN 0340-6717. - (2022). [10.1007/s00439-022-02497-y]
File in questo prodotto:
File Dimensione Formato  
s00439-022-02497-y.pdf

accesso aperto

Tipologia: Versione Editoriale (PDF)
Licenza: Dominio pubblico
Dimensione 847.51 kB
Formato Adobe PDF
847.51 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/904586
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 1
  • ???jsp.display-item.citation.isi??? 1
social impact