| Summary: | Abstract Background Eight different deletions and point variants of the X‐chromosomal gene CNKSR2 have been reported in families with males presenting intellectual disability (ID) and epilepsy. Obligate carrier females with a frameshift variant in the N‐terminal protein coding part of CNKSR2 or with a deletion of the complete gene are not affected. Only for one C‐terminal nonsense variant, two carrier females were mildly affected by seizures without or with mild motor and language delay. Methods Exome sequencing was performed in one female child of a Dutch family, presenting seizures, mild ID, facial dysmorphisms, and abnormalities of the extremities. Potential causative variants were validated by Sanger sequencing. X‐chromosome‐inactivation (XCI) analysis was performed by methylation‐sensitive PCR and fragment‐length analysis of the androgen‐receptor CAG repeat polymorphism. Results We identified a de novo variant, c.2304G>A (p.(Trp768*)), in the C‐terminal protein coding part of the X‐chromosomal gene CNKSR2 in a female patient with seizures and mild ID. Sanger sequencing confirmed the presence of this nonsense variant. XCI analysis showed a mild skewing of X inactivation (20:80) in the blood of our patient. Our variant is the second C‐terminal–affecting CNKSR2 variant described in neurologically affected females. Conclusion Our results indicate that CNKSR2 nonsense variants in the C‐terminal coding part can result in ID with seizures in female variant carriers.
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