Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders

Interstitial deletions of the short arm of chromosome 6 are rare and have been associated with developmental delay, hypotonia, congenital anomalies, and dysmorphic features. We used array comparative genomic hybridization in a South Carolina Autism Project (SCAP) cohort of 97 subjects with autism spectrum disorders (ASDs) and identified an ~ 5.4 Mb deletion on chromosome 6p22.3-p23 in a 15-year-old patient with intellectual disability and ASDs. Subsequent database queries revealed five additional individuals with overlapping submicroscopic deletions and presenting with developmental and speech delay, seizures, behavioral abnormalities, heart defects, and dysmorphic features. The deletion found in the SCAP patient harbors ATXN1, DTNBP1, JARID2, and NHLRC1 that we propose may be responsible for ASDs and developmental delay

Phenotypic expansion in DDX3X - a common cause of intellectual disability in females

De novo variants in DDX3X account for 1-3% of unexplained intellectual disability (ID) cases and are amongst the most common causes of ID especially in females. Forty-seven patients (44 females, 3 males) have been described. We identified 31 additional individuals carrying 29 unique DDX3X variants, including 30 postnatal individuals with complex clinical presentations of developmental delay or ID, and one fetus with abnormal ultrasound findings. Rare or novel phenotypes observed include respiratory problems, congenital heart disease, skeletal muscle mitochondrial DNA depletion, and late-onset neurologic decline. Our findings expand the spectrum of DNA variants and phenotypes associated with DDX3X disorders

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Purpose We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Deletions in chromosome 6p22.3-p24.3, including <it>ATXN1</it>, are associated with developmental delay and autism spectrum disorders

Abstract Interstitial deletions of the short arm of chromosome 6 are rare and have been associated with developmental delay, hypotonia, congenital anomalies, and dysmorphic features. We used array comparative genomic hybridization in a South Carolina Autism Project (SCAP) cohort of 97 subjects with autism spectrum disorders (ASDs) and identified an ~ 5.4 Mb deletion on chromosome 6p22.3-p23 in a 15-year-old patient with intellectual disability and ASDs. Subsequent database queries revealed five additional individuals with overlapping submicroscopic deletions and presenting with developmental and speech delay, seizures, behavioral abnormalities, heart defects, and dysmorphic features. The deletion found in the SCAP patient harbors ATXN1, DTNBP1, JARID2, and NHLRC1 that we propose may be responsible for ASDs and developmental delay.</p

Dosage Changes of a Segment at 17p13.1 Lead to Intellectual Disability and Microcephaly as a Result of Complex Genetic Interaction of Multiple Genes

Submitted by Nuzia Santos ([email protected]) on 2015-07-23T15:53:22Z No. of bitstreams: 1 Dosage Changes of a Segment at 17p13.1 Lead.pdf: 1645159 bytes, checksum: e83119eec1267cdcf9dc571d78ff4028 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-07-23T15:53:32Z (GMT) No. of bitstreams: 1 Dosage Changes of a Segment at 17p13.1 Lead.pdf: 1645159 bytes, checksum: e83119eec1267cdcf9dc571d78ff4028 (MD5)Approved for entry into archive by Nuzia Santos ([email protected]) on 2015-07-23T16:05:33Z (GMT) No. of bitstreams: 1 Dosage Changes of a Segment at 17p13.1 Lead.pdf: 1645159 bytes, checksum: e83119eec1267cdcf9dc571d78ff4028 (MD5)Made available in DSpace on 2015-07-23T16:05:33Z (GMT). No. of bitstreams: 1 Dosage Changes of a Segment at 17p13.1 Lead.pdf: 1645159 bytes, checksum: e83119eec1267cdcf9dc571d78ff4028 (MD5) Previous issue date: 2014Baylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA /Fundação Oswaldo Cruz. Centro de Pesquisas Rene Rachou. Belo Horizonte, MG, BrazilDuke University. Center for Human Disease Modeling.Durham, NC, USAWashington University . Division of Genetics and Genomic Medicine. Department of Pediatrics. St Louis, MO, USADuke University. Center for Human Disease Modeling.Durham, NC, USABaylor College of Medicine. Department of Pediatrics. Houston, TX, USA/ Texas Children’s Hospital. Houston, TX , USABaylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USA /Baylor College of Medicine. Department of Pediatrics. Houston, TX, USA/ Texas Children’s Hospital. Houston, TX , USAVejle Hospital. Clinical Genetics Department. Vejle, DenmarkVejle Hospital. Clinical Genetics Department. Vejle, DenmarkUniversidade de São Paulo. Instituto de Biociencias. Departamento de Genetica e Evolução Biologica. Sao Paulo, SP, BrazilUniversidade de São Paulo. Instituto de Biociencias. Departamento de Genetica e Evolução Biologica. Sao Paulo, SP, BrazilTexas Oncology. Austin, TX, USASpecially for Children. Austin, TX, USAPhoenix Children’s Hospital. Phoenix, AZ, USAPhoenix Children’s Hospital. Phoenix, AZ, USABaylor College of Medicine. Department of Molecular and Human Genetics. Houston, TX, USAUniversidade de São Paulo. Instituto de Biociencias. Departamento de Genetica e Evolução Biologica. Sao Paulo, SP, BrazilDuke University. Center for Human Disease Modeling. Durham, NC, USAThe 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO

Muenke syndrome (FGFR3-related craniosynostosis): expansion of the phenotype and review of the literature.

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P &lt; 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling