Hidden etiology of cerebral palsy: genetic and clinical heterogeneity and efficient diagnosis by next-generation sequencing.

Autores de IIS La Fe

• Mónica Pilar Roselló Piera

  Autor

• Alfonso José Caro Llopis

  Autor

• Carmen Orellana Alonso

  Autor

• Juan Silvestre Oltra Soler

  Autor

• Marta Alemany Albert

  Autor

• Ana Victoria Marco Hernández

  Autor

• Sandra Monfort Membrado

  Autor

• Laia Pedrola Vidal

  Autor

• 

  Francisco Martínez Castellano

  Autor

• Miguel Tómas Vila

  Autor

Grupos

• Investigación Traslacional en Genética

  

  Leader

  Francisco Martínez Castellano

Abstract

Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder that causes movement and postural disabilities. Recent research studies focused on genetic diagnosis in patients with CP of unknown etiology. The present study was carried out in 20 families with one family member affected with idiopathic CP. Chromosomal microarray and exome sequencing techniques were performed in all patients. Chromosomal microarray analysis did not show any pathological or probable pathological structural variant. However, the next-generation sequencing study showed a high diagnostic yield. We report 11/20 patients (55%) with different pathogenic or potentially pathogenic variants detected by exome sequencing analysis: five patients with mutations in genes related to hereditary spastic paraplegia, two with mutations in genes related to Aicardi-Goutières syndrome, three with mutations in genes related to developmental/epileptic encephalopathies, and one with a mutation in the PGK1 gene. The accurate and precise patients' selection, the use of a high-throughput genetic platform, the selection of adequate target genes, and the application of rigorous criteria for the clinical interpretation are the most important elements for a good diagnostic performance. Based on our findings, next-generation sequencing should be considered in patients with cryptogenic CP as the first line of genetic workup. IMPACT: Sequencing techniques in CP of uncertain etiology provides a diagnostic yield of 55%. The appropriate selection of cases optimizes the diagnostic yield. NGS facilitate better understanding of new phenotypes of certain genetic diseases.