Next generation sequencing in nonsyndromic intellectual disability: From a negative molecular karyotype to a possible causative mutation detection

Abstract

The identification of causes underlying intellectual disability (ID) is one of the most demanding challenges for clinical Geneticists and Researchers. Despite molecular diagnostics improvements, the vast majority of patients still remain without genetic diagnosis. Here, we report the results obtained using Whole Exome and Target Sequencing on nine patients affected by isolated ID without pathological copy number variations, which were accurately selected from an initial cohort of 236 patients. Three patterns of inheritance were used to search for: (1) de novo, (2) X-linked, and (3) autosomal recessive variants. In three of the nine proband-parent trios analyzed, we identified and validated two de novo and one X-linked potentially causative mutations located in three ID-related genes. We proposed three genes as ID candidate, carrying one de novo and three X-linked mutations. Overall, this systematic proband-parent trio approach using next generation sequencing could explain a consistent percentage of patients with isolated ID, thus increasing our knowledge on the molecular bases of this disease and opening new perspectives for a better diagnosis, counseling, and treatment.

De novo mutations ofKIAA2022in females cause intellectual disability and intractable epilepsy

“…An X-inactivation pattern of 73:27 was reported. These previously reported female patients seem to be on the extreme ends of the phenotypic spectrum in comparison to our new cases, with one patient being relatively mildly affected,10 while the other two have a phenotype comparable to our most severely affected cases 911 Although we observe a comparable clinical picture in most female cases, this illustrates that the phenotypes of females affected by KIAA 2022 mutations can be very variable.…”

“…The reported phenotype was comparable to the previously described male phenotype, with severe ID, microcephaly, autistic behaviour, growth retardation and facial dysmorphia, without epilepsy. Athanasakis et al 10 reported a 13-year-old girl with mild ID and a de novo non-sense mutation of KIAA2022 (p.Arg628*) as part of a larger study which included patients with ID and absence of dysmorphic features, normal growth parameters and no seizures or malformations. The X-inactivation pattern was 65:35.…”

The H3K4me3/2 histone demethylase RBR-2 controls axon guidance by repressing the actin-remodeling gene wsp-1

“…The H3K4me3 demethylase KDM5C is mutated in X-linked mental retardation (Iwase et al, 2007;Abidi et al, 2008;Adegbola et al, 2008;Gonçalves et al, 2014). Further, mutations in KDM5B have been reported in individuals with non-syndromic intellectual disability and autism spectrum disorders (Athanasakis et al, 2014;De Rubeis et al, 2014;Iossifov et al, 2014) and mutations in KDM5A have been linked to an autosomal recessive form of intellectual disability (Najmabadi et al, 2011). Similarly, several genes implicated in cytoskeleton dynamics are mutated in intellectual disability and autism spectrum disorders (Nadif Kasri and Van Aelst, 2008;Ba et al, 2013;Hu et al, 2014;Srivastava and Schwartz, 2014).…”

Disrupted Intricacy of Histone H3K4 Methylation in Neurodevelopmental Disorders

“…Until recently, all variants in KDM5B had been described in cancer. Next-generation sequencing has since revealed a de novo splicing mutation (c.283A>G) in KDM5B in an individual with nonsyndromic ID [19] (Figure 2). Six additional variants were newly identified in exome sequencing of a large cohort of individuals with ASD [3,4].…”

“…Shen et al provided a comprehensive view on writer and eraser enzymes for H3K4me in brain disorders from a clinical perspective, including data from human samples and animal models [17]. More recently, alterations of KMT2F in schizophrenia [2], KDM1A in Kabuki/ KBG syndrome [18], and KDM5A and KDM5B in ID [1,19] have been reported, which were not covered by these earlier reviews. New exome sequencing of a large cohort of individuals with ASD also identified KMT2C and KDM5B [3,4].…”