RecessiveDEAF1mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy

Abstract

A recent report has shown dominant DEAF1 mutations to occur de novo in patients with intellectual disability. Here, we demonstrate that a DEAF1-associated disorder can also be inherited as an autosomal recessive trait with heterozygous individuals being entirely healthy. Our findings expand the clinical and genetic spectrum of DEAF1 mutations to comprise epilepsy and extrapyramidal symptoms.

Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain

“…We focused on two genes, DEAF1 and CNTNAP2. DEAF1 exhibits putative DAEEs in the macaque DRN (Figure 7B) and is linked to autism, language impairment, and intellectual disability in humans (Rajab et al, 2015; Vulto-van Silfhout et al, 2014). CNTNAP2 exhibits a trend toward allele CoEEs in the macaque DRN (Figure 7B), exhibits high-confidence allele CoEEs in the mouse DRN (Figure 2G), and is also linked to autism, language impairment, and intellectual disability in humans (Alarcón et al, 2008; Arking et al, 2008).…”

Functional analysis of novelDEAF1variants identified through clinical exome sequencing expandsDEAF1-associated neurodevelopmental disorder (DAND) phenotype

“…Another inherited homozygous c.997+4A > C p.(Gly292Profs*) splice acceptor change was found in three related individuals from a consanguineous Omani family with ID, autism, hypotonia, motor and speech delay, dyskinesia of the limbs, seizures, and abnormal brain MRI. Functional analysis of this variant revealed exon skipping and a 95% reduction in DEAF1 mRNA (Rajab et al., ).…”

“…Trio-and proband-based clinical exome sequencing (CES) has greatly increased the number of candidate genetic loci contributing to ID (Rump et al, 2016), and the functional significance of these genetic variants is under active investigation. Recent CES studies have identified a potential role for deformed epidermal autoregulatory factor-1 (DEAF1; MIM# 602635; NM_021008.3) in both autosomal dominant and autosomal recessive modes of inheritance in a neurodevelopmental disorder comprising ID, speech impairment, motor developmental delay, (MRD24; MIM# 615828; MIM# 617171) (Rauch et al, 2012;Vissers et al, 2010;Vulto-van Silfhout et al, 2014), and additional phenotypes such as seizures, brain malformations, and autism (Faqeih et al, 2014;Gund, Powis, Alcaraz, Desai, & Baranano, 2016;Rajab et al, 2015;Waltl, 2014;Wenger, Guturu, Bernstein, & Bejerano, 2017), as well as a Smith-Magenis syndrome (SMS; MIM# 182290)-like phenotype that includes ID, dysmorphic features, and sleep disturbances (Berger et al, 2017). In this study, we use DEAF1-associated neurodevelopmental disorder (DAND) to describe a series of ID-related neurodevelopmental anomalies that are associated with pathogenic DEAF1 variants and share a common set of clinical features.…”

Identification of a syndrome comprising microcephaly and intellectual disability but not white matter disease associated with a homozygous c.676C>T p.R226W DEAF1 mutation

“…While this report was being prepared, a homozygous mutation in DEAF1 which caused exon skipping and generated a premature stop codon (c.997+4A>C, p.G292Pfs*) was implicated as the cause of disease in three siblings from a consanguineous Omani family [Rajab et al, ]. These three siblings had apparent intellectual disability, autism, dyskinesia, and epilepsy.…”