Amelioration of the typical cognitive phenotype in a patient with the 5pter deletion associated with Cri‐du‐chat syndrome in addition to a partial duplication of CTNND2

Abstract

Cri-du-chat is a rare congenital syndrome characterized by intellectual disability, severe speech/developmental delay, dysmorphic features, and additional syndromic findings. The etiology of this disorder is well known, and is attributed to a large deletion on chromosome 5 that typically ranges from band 5p15.2 to the short arm terminus. This region contains CTNND2, a gene encoding a neuronal-specific protein, delta-catenin, which plays a critical role in cellular motility and brain function. The exact involvement of CTNND2 in the cognitive functionality of individuals with Cri-du-chat has not been fully deciphered, but it is thought to be significant. This report describes an 8-year-old African-American female with a complex chromosome 5 abnormality and a relatively mild case of cri-du-chat syndrome. Because of the surprisingly mild cognitive phenotype, although a karyotype had confirmed the 5p deletion at birth, an oligo-SNP microarray was obtained to further characterize her deletion. The array revealed a complex rearrangement, including a breakpoint in the middle of CTNND2, which resulted in a partial deletion and partial duplication of that gene. The array also verified the expected 5p terminal deletion. Although the patient has a significant deletion in CTNND2, half of the gene (including the promoter region) is not only preserved, but is duplicated. The patient's milder cognitive and behavioral presentation, in conjunction with her atypical 5p alteration, provides additional evidence for the role of CTNND2 in the cognitive phenotype of individuals with Cri-du-chat.

Multigenerational autosomal dominant inheritance of 5p chromosomal deletions

“…The presence of CTNND2 in a two-copy state may explain the milder cognitive impairment observed in Families I and III as compared to individuals who harbor larger 5p deletions. The literature supports this observation on the basis of historic CdCS studies, as well as more recent observations, in that duplication of 5 0 CTNND2 and deletion of the 3 0 portion of the gene in a CdCS patient is hypothesized to result in amelioration of the cognitive phenotype [Sardina et al, 2014]. Small exonic deletions of CTNND2 have also been reported in individuals with low normal IQ and learning problems with or without autistic features or developmental delay [Asadollahi et al, 2014].…”

Genetic alterations of δ-catenin/NPRAP/Neurojungin (CTNND2): functional implications in complex human diseases

“…Recent studies reported that the partial deletion of δ-catenin in 5p15.2 and partial duplication of its promoter region led to a mild case of Cri-du-chat syndrome (Sardina et al 2014). On the other hand, the hemizygous loss of δ-catenin is associated with severe mental retardation in Cri-du-chat children (Medina et al 2000).…”

δ-Catenin Regulates Spine Architecture via Cadherin and PDZ-dependent Interactions

“…Loss of Ctnnd2, encoding ␦-catenin, correlates with intellectual disability (17)(18)(19) in the cri du chat syndrome. Interestingly, a partial duplication of Ctnnd2 in an individual with the cri du chat syndrome with deletion of Ctnnd2 in the chromosomal deletion associated with the syndrome leads to a milder cognitive phenotype, further supporting a key role for ␦-catenin in the intellectual disability associated with this syndrome (20). In addition, copy number variations of Ctnnd2 have been implicated in schizophrenia (21) and autism (22,23).…”