Rett (-like) syndrome: expanding the genetic sprectrum to KIF1A and GRIN1 gene

To investigate new genetic etiologies of Rett syndrome (RTT) or RTT-like syndrome, targeted next-generation sequencing (NGS) was performed on 44 Chinese patients with RTT (-like) syndrome, in whom genetic analysis of MECP2, CDKL5 and FOXG1 was negative. The mutation rate was 31.8% (14/44). Among the subjects, a de novo mutation (c.275_276ins AA, p.Cys92*) in KIF1A was identified in a girl with all core features of typical RTT. A patient with early seizure variant of RTT were discovered having  GRIN1 gene mutation (c.2337C>A, p.Val793Phe) . Additionally, a compound heterozygous PPT1 gene mutation was detected in a girl, who initially displayed typical RTT features, but progressed into neuronal ceroid lipofuscinoses (NCL) afterwards. Mutations in KCNQ2 , MEF2C, WDR45, TCF4, IQSEC2 and SDHA were also found in this study. Notably, it is the first time that mutations in GRIN1 and KIF1A were linked to RTT (-like) profiles. Our findings expand the genetic heterogeneity of RTT (-like) phenotypes, and also suggest that some patients with inherited metabolic disease such as NCL, might displayed RTT features initially.