Journal
MOLECULAR GENETICS & GENOMIC MEDICINE
Volume 7, Issue 10, Pages -Publisher
WILEY
DOI: 10.1002/mgg3.861
Keywords
CNKSR2; de novo; exome sequencing; intellectual disability; X-linked
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Funding
- Seventh Framework Programme [241995]
- Capes Fellowship [99999.013311/2013-01]
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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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