Exons deletion of CNKSR2 gene identified in X-linked syndromic intellectual disability

Abstract

Background: The Houge type of X-linked syndromic mental retardation is an X-linked intellectual disability (XLID) recently recorded in the Online Mendelian Inheritance in Man (OMIM) and only 8 cases have been reported in literature thus far. Case presentation: We present two brothers with intractable seizures and syndromic intellectual disability with symptoms consisting of delayed development, intellectual disability, and speech and language delay. The mother was a symptomatic carrier with milder clinical phenotype. Whole exome sequencing identified a small fragment deletion spanning four exons, about 9.5 kilobases (kb) in length in the CNKSR2 gene in the patients. The mutation co-segregation revealed that exon deletions occurred de novo in the proband's mother. Conclusion: Although large deletions have been reported, no small deletions have yet been identified. In this case report, we identified a small deletion in the CNKSR2 gene. This study enhances our knowledge of the CNKSR2 gene mutation spectrum and provides further information about the phenotypic characteristics of X-linked syndromic intellectual disability.

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

“…However, for another six mothers (three mothers in this cohort, family 14, [1]; family 15, [7]; family 16, [17], there were no reported seizures or intellectual disability. Skewed X-inactivation may be the underlying reason for this observed difference in penetrance (85:15 in the mother of family 25, [6] and 20:80 in family 26, [14], both with neurodevelopmental concerns, while reported to be 57:43 for the mother reported to have no neurological issues of family 15, [7]).…”

“…Of the 13 affected males in our cohort, ten represent de novo cases, while in three the variants are maternally inherited. Recent articles have indicated that females harboring heterozygous CNKSR2 pathogenic variants may have seizures, with some also manifesting neurodevelopmental concerns (family 26, [14]; family 27, [2]; mother and sister of family 19, [5]; mother of family 25, [6]; mother of family 26, [20]). However, for another six mothers (three mothers in this cohort, family 14, [1]; family 15, [7]; family 16, [17], there were no reported seizures or intellectual disability.…”

“…Since the initial characterization of a boy affected with a pathogenic variant in CNKSR2 by Houge et al [7] (mental retardation, X-linked, Houge type (MRX-SHG), MIM 301008), there have been a total of 20 affected males described in the literature, all with a consistent clinical phenotype of intellectual disability, developmental delay, and epilepsy [1,2,5,6,15,17,20]. Early developmental progress may be normal in rare instances, but global delays are observed consistently after the onset of seizures.…”

“…Approximately half of the known instances of CNKSR2-related disease are de novo in origin, and of the maternally transmitted cases, the majority of carrier mothers are neurologically without concerns. However, some females heterozygous for a CNKSR2 pathogenic variant have intellectual disability and seizures [2,5,6,14,20].…”

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.…”