CNKSR2-related neurodevelopmental and epilepsy disorder: a cohort of 13 new families and literature review indicating a predominance of loss of function pathogenic variants

Abstract

Background Pathogenic variants in connector enhancer of kinase suppressor of Ras-2 (CNKSR2) located on the X chromosome (Xp22.12) lead to a disorder characterized by developmental delay and a characteristic seizure phenotype. To date, 20 affected males representing 13 different pathogenic variants have been published. Case presentation We identified an 8-year-old male with seizures, abnormal electroencephalogram (EEG) with epileptiform abnormalities in the right hemisphere, and developmental delay with notable loss of speech following seizure onset. Additional concerns include multiple nighttime awakenings, hyperactivity, and autism spectrum disorder. Genetic testing identified a de novo pathogenic nonsense variant in CNKSR2. Through an active family support group, an additional 12 males are described, each harboring a different CNKSR2 variant. The clinical presentation and natural history consistently show early developmental delay, sleep disturbances, and seizure onset in childhood that is initially intractable but later becomes better controlled. Virtually all of the pathogenic variants are predicted to be loss of function, including genomic deletions, nonsense variants, splice site mutations, and small insertions or deletions. Conclusions This expanded knowledge, combined with functional studies and work with animal models currently underway, will enable a better understanding and improved ability to care for individuals with CNKSR2-related neurodevelopmental and epilepsy disorder.

Functions of CNKSR2 and Its Association with Neurodevelopmental Disorders

“…Serious attention deficit and hyperactivity have frequently been observed [ 53 ]. Multiple types of variations, including deletion [ 8 , 54 , 55 , 56 , 57 ], frame shift [ 54 , 57 , 58 ], splicing [ 57 , 59 ], and nonsense variations [ 53 , 57 , 60 , 61 , 62 ] have been reported in patients suffering from MRXSHG ( Figure 2 and Table 1 ). Severely affected patients were all hemizygous males and heterozygous female carriers of variants that exhibited moderate to mild phenotype or unaffected ( Table 1 ), probably because of the production of CNKSR2 from the normal allele.…”

“…He presented attention deficit, moderate neurodevelopmental delay, hypotonia, epilepsy, and severe language delay. In another case, the deletion on Xp22.12 (21,278,397–21,678,707) was found in a male [ 57 ]. His electroencephalogram (EEG) demonstrated seizures during both day and night.…”

“…Analyses of patients with the Epilepsy-Aphasia Spectrum (EAS) revealed c.2134C > T; p.(Arg712*) (Reference sequence, NM_014927) (The authors described ’c.2314C > T; p.(Arg712*)’ in the paper [ 53 ]; but we indicated the nucleic acid number in the reference sequence), c.2185C > T; p.(Arg729*) [ 60 ] and c.2349T > G; p.(Tyr783*) [ 57 ] nonsense mutations in the CNKSR2 gene. EAS is a spectrum disorder from the severe end of Landau-Kleffner syndrome [ 65 ] and CSWS to the mild end of Childhood Epilepsy with Centrotemporal Spikes (CECTS) [ 66 ].…”

“…Recently, males who had c.625C > T; p.(Gln209*) [ 62 ], c.2545C > T; p.(Arg849*) [ 57 ] and c.1198C > T, p.(Arg400*) [ 57 ] were reported. These patients were featured with ID, language defect, epilepsy, and hyperactivity.…”

“…They exhibited seizure, mild developmental delay, and language difficulties. More recently, c.1988_1989del; p(Arg663Asnfs*2), c.1653_1656del; p.(Asn551Lysfs*4), c.2005del; p.(Ala669Glnfs*48), and c.2026_2027del; p.(Arg676Aspfs*2) variants were found in four male patients with neurodevelopmental and epilepsy disorder [ 57 ]. Two patients had EEG documenting ESES and three of them were diagnosed as autism.…”