Psychomotor development and attention problems caused by a splicing variant of CNKSR2

Abstract

Background Mutations in CNKSR2 have been described in patients with neurodevelopmental disorders characterized by childhood epilepsy, language deficits, and attention problems. The encoded protein plays an important role in synaptic function. Case presentation Whole-exome sequencing was applied to detect pathogenic variants in a patient with clinical symptoms of psychomotor development, attention deficit, poor logical thinking ability, and an introverted personality, but without epilepsy or any significant electroencephalogram changes. Genetic study revealed a splicing mutation (c.1904 + 1G > A) and RT-PCR revealed aberrant splicing of exon 16, leading to a reading-frame shift and a truncated protein in the PH domain. Conclusions This is the first report of a splicing variant of CNKSR2, and the unique clinical features of this pedigree will help extend our understanding of the genetic and phenotypic spectra of CNKSR2-related disorders.

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

“…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].…”

CNKSR2 gene mutation leads to Houge type of X-linked syndromic mental retardation

“…2 A). In addition, eight kinds of variants in CNKSR2 had been reported in the literature, [ 1 , 5 , 7 – 10 ] there are c.452insA(p.Asp152Argfs ∗ 8), c.2024_2027delAGAG (p.Glu675Glyfs ∗ 41), c.246–247delAG(p.Thr83Lysfs ∗ 30), c.457_461del(p. Tyr153Serfs ∗ 5), c.2314 C > T(p.Arg712 ∗ ), c.2185C > T(p.Arg729 ∗ ), c.2304G > A (p.Trp768 ∗ ) and c.1904+1G > A (Fig. 2 B).Among the twenty one cases reported, nine of them have their genotype being inherited from mothers(Table 1 ).…”

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.…”