<p>A de novo <em>CTNNB1</em> Novel Splice Variant in an Adult Female with Severe Intellectual Disability</p>

Abstract

The catenin beta-1 (CTNNB1) gene, encoding a sub-unit of the cadherin/catenin protein complex that is involved in the Wnt signalling pathway important for proper interneuron development, is considered to be causative for the rare autosomal dominant mental retardation syndrome, formerly called MRD19 but later renamed neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV). Its main characteristics are moderate to severe intellectual disability (ID), disruptive autistic behaviours, microcephaly, absent or limited speech, facial dysmorphisms, peripheral hypertonia/spasticity, motor delay and visual defects. So far, 35 patients have been reported with a de novo loss-of-function variant in CTNNB1. In two other patients, a deletion comprising the full gene was found. Four out of the 37 patients were of adult age (range: 27-51 years), while the majority was infant or adolescent (range: 0-20 years). Here, a 32-year-old severely intellectually disabled female patient is described in whom exome sequencing disclosed a de novo heterozygous splice site variant in the CTNNB1 gene [Chr3(GRCh37): g.41267064G>T; NM_001904.3: 23. c.734+1G>T; r. spl?]. Somatic investigation disclosed significant microcephaly and minor facial dysmorphisms. Neurological examination demonstrated severe kyphoscoliosis, distal spastic tetraparesis, especially of the legs with increased tendon reflexes and bilateral Babinski sign, resulting in severely impaired walking capability with a broad-based gait. Apart from strabismus, no ophthalmological abnormalities were found. Here, the reported variant in the CTNNB1 gene was not published earlier nor is included in the international databases. This specific variant is considered to be causative for the severe ID, autism and the somato-neurological phenotype of the patient and corresponds with a diagnosis of NEDSDV.

Exome Sequencing Reveals Novel Variants and Expands the Genetic Landscape for Congenital Microcephaly

“…Our findings seem to confirm the existence of sex bias in the neurodevelopmental disorder with spastic diplegia and visual defects caused by variants in CTNNB1 , as all our patients are females [ 33 ]. With recent reports of eight additional patients, five of whom were male, and four patients from our study the sex ratio in this disorder is approximately 63% females to 37% males [ 34 , 35 ]. In one case (S87) we identified a frameshift variant NM_001904.4: c.1665del: p.(Thr556HisfsTer14) that had been reported only once in the literature, while the other three (S42, S63, S145) were harboring more common pathogenic variants already reported in the ClinVar database.…”

The extended clinical and genetic spectrum of CTNNB1-related neurodevelopmental disorder

“…The association between seizure and developmental delay or intellectual disability has been well established, and one study reported the prevalence of epilepsy in global developmental delay patients as high as 56% (31-33). Among the 69 patients with CTNNB1-related neurodevelopmental disorder we reviewed, none of them had apparent seizure history or abnormal electroencephalogram results (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(13)(14)(15). In addition, while structural brain abnormalities have been detected in around 30% of developmental delay patients (34, 35), there were only three patients (5.4%) showing remarkable brain abnormalities among 56 patients.…”

“…In addition, none of our patients had any seizure history during follow-up. As shown in Figure 2A, we reviewed a total of 69 patients with CTNNB1-related neurodevelopmental disorder reported in the literature, including our patients, and found that only one (1.4%) and three (5.4%) patients had seizure history and brain abnormalities, respectively (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(13)(14)(15). The patient with seizure history was suspected as having absence seizure in early childhood.…”

“…Interestingly, all three patients with autistic features were female in this study. Autistic features have been reported frequently (1,(3)(4)(5)(6)(7)(8)(9)(10)(11)(13)(14)(15), shown in around 30% of patients with CTNNB1-related neurodevelopmental disorder (Figure 2A). Consistent with our study, autistic features were significantly more frequent in female patients (54.3%, 19 out of 35) than in male patients (5.9%, 2 out of 34) with a P-value = 1.3 × 10 −5 by Fisher's exact test (Figure 2B).…”

“…This is an autosomal dominant disorder, mostly caused by loss-offunction mutations resulting in disruption of normal molecular function. Although several studies had reported additional cases of NEDSDV, their clinical presentations are different from each other (1,(3)(4)(5)(6)(7)(8)(9)(10)(11).…”