De Novo Mutations in FOXP1 in Cases with Intellectual Disability, Autism, and Language Impairment

Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4–14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter

Mutations in C5ORF42 Cause Joubert Syndrome in the French Canadian Population

Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs∗31], c.4804C>T [p.Arg1602∗], and c.7477C>T [p.Arg2493∗]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS

Intellectual disability without epilepsy associated with STXBP1 disruption

STXBP1 (Munc18-1) is a component of the machinery involved in the fusion of secretory vesicles to the presynaptic membrane for the release of neurotransmitters. De novo missense mutations in STXBP1 were recently reported in patients with Ohtahara syndrome, a form of encephalopathy with severe early-onset epilepsy. In addition, sequencing of the coding region of STXBP1 in 95 patients with non-syndromic intellectual disability (NSID) revealed de novo truncating mutations in two patients who also showed severe non-specific epilepsy, suggesting that STXBP1 disruption has the potential of causing a wide spectrum of epileptic disorders in association with intellectual disability. Here, we report on the mutational screening of STXBP1 in a different series of 50 patients with NSID and the identification of a novel de novo truncating mutation (c.1206delT/ p.Y402X) in a male with NSID, but surprisingly with no history of epilepsy. This is the first report of a patient with a truncating mutation in STXBP1 that does not show epilepsy, thus, expanding the clinical spectrum associated with STXBP1 disruption

Deficiency of Asparagine Synthetase Causes Congenital Microcephaly and a Progressive Form of Encephalopathy

International audienceWe analyzed four families that presented with a similar condition characterized by congenital micro-cephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein abundance, suggesting that the mutations cause loss of function. Hypomorphic Asns mutant mice have structural brain abnormalities, including enlarged ventricles and reduced cortical thickness, and show deficits in learning and memory mimicking aspects of the patient phenotype. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate. The neurological impairment resulting from ASNS deficiency may be explained by asparagine depletion in the brain or by accumulation of aspartate/gluta-mate leading to enhanced excitability and neuronal damage. Our study thus indicates that asparagine synthesis is essential for the development and function of the brain but not for that of other organs