Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by ...severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations.
Novel variants associated with chronic pancreatitis are being increasingly reported. However, most studies have so far only analyzed point mutations and small insertions or deletions. Here we report ...the characterization of two distinct deletions of the CTRC locus. Variants in four chronic pancreatitis genes, PRSS1, SPINK1, CTRC and CFTR, were systematically analyzed in the studied cases. Copy number change of the CTRC gene was analyzed by quantitative fluorescent multiplex PCR (QFM-PCR). Walking QFM-PCR followed by long-range PCR and direct sequencing were employed to identify the deletion breakpoints at the nucleotide level. A heterozygous CTRC-deleting complex rearrangement, which was co-inherited with different trans variants in SPINK1, CFTR or PRSS1, is associated with variable phenotypes (chronic pancreatitis; pancreatic cancer and chronic pancreatitis; and type 1 diabetes). Moreover, a different homozygous deletion of the CTRC locus was found in an unrelated patient with asymptomatic chronic pancreatitis. Our findings revealed a hitherto unrecognized level of complexity of genotype–phenotype correlation in chronic pancreatitis. The CTRC-deleting complex rearrangement probably resulted from LINE-1-mediated Alu insertion, which represents a novel mutational mechanism causing chronic pancreatitis.
•We characterized two distinct deletions of the CTRC locus.•We illustrated complexity of genotype–phenotype relationship in chronic pancreatitis.•A novel mutational mechanism was found to cause chronic pancreatitis.
Constitutional deficiency in factor XI (FXI) is a rare bleeding disorder in the general population, with the exception of Ashkenazi Jews. During the last decade, the detection of FXI-deficient ...patients has shifted from clinical screening identifying mostly severe bleeders to biological screening combining findings of prolonged activated partial thromboplastin time and FXI coagulation activity (FXI:C) below 50 U/dl. The goal of this study was to determine the molecular basis of FXI deficiency in western Brittany, France. Over the course of four years, we detected 98 FXI-deficient patients through biological screening, and 44 patients agreed to participate in this study corresponding to 25 index cases. We developed an efficient mutation detection strategy (combining direct sequencing and QFM-PCR to search for heterozygous rearrangements in a routine setting) that detected F11 mutations in 24 out of the 25 index cases. An unexpected allelic heterogeneity was found, with 14 different single point mutations being detected, among which nine are new. Moreover, a large heterozygous deletion of the entire F11 gene was detected, and was then further defined using a CGH array as a 4q34.2 telomeric deletion of 7 Mb containing 77 genes. We propose that the observed recurrent mutations may be considered as genetic tags of a population. This study highlights the importance of screening for large deletions in molecular studies of F11 .
Abstract We report here a de novo 16q24.1 interstitial duplication in a woman with a severe phenotype consistent with mental retardation, spastic paraplegia, severe epilepsy, a narrow and arched ...palate, malar hypoplasia, little subcutaneous fat and arachnodactyly. Although conventional karyotyping was found to be normal, array-CGH detected a small duplication on chromosome 16. Using QFM-PCR, we characterised its proximal and distal breakpoints. The duplication, which is approximately 250 kb, encompasses seven genes ( KIAA0182 , GINS2 , c16orf74 , COX4NB , COX4I1 , MIR1910 and IRF8 ). Several reports have previously described large 16q duplications, and some of these overlap with our region in 16q24.1. Due to the variability of the described phenotypes, the characterisation of small 16q duplications may help to determine critical regions and the genes they contain that are associated with the components of complex phenotypes.
Alpha‐mannosidosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in the MAN2B1 gene and characterized by a wide clinical heterogeneity. Diagnosis for this ...multisystemic disorder is confirmed by the presence of either a deficiency in the lysosomal enzyme acid alpha‐mannosidase or biallelic mutations in the MAN2B1 gene. This diagnosis confirmation is crucial for both clinical management and genetic counseling purposes. Here we describe a late diagnosis of alpha‐mannosidosis in a patient presenting with syndromic intellectual disability, and a rare retinopathy, where reverse phenotyping played a pivotal role in interpreting the exome sequencing result. While a first missense variant was classified as a variant of uncertain significance, the phenotype‐guided analysis helped us detect and interpret an in‐trans apparent alu‐element insertion, which appeared to be a copy number variant (CNV) not identified by the CNV caller. A biochemical analysis showing abnormal excretion of urinary mannosyloligosaccharide and an enzyme assay permitted the re‐classification of the missense variant to likely pathogenic, establishing the diagnosis of alpha‐mannosidosis. This work emphasizes the importance of reverse phenotyping in the context of exome sequencing.
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.
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.
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.
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.
Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants in VCP are associated with adult-onset ...multisystem proteinopathy (MSP), which manifests as myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who harbor heterozygous VCP variants (12 de novo and 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or a multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performed in vitro functional studies and in silico modeling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This cohort expands the spectrum of VCP-related disease to include neurodevelopmental disease presenting in childhood.
Valosin-containing protein (VCP) is an ATPase that assists in cellular recycling pathways. Pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), affecting the brain, muscle, and bone. This article describes 13 individuals with VCP variants associated with childhood-onset neurodevelopmental disorder, possibly mediated by a loss-of-function mechanism.
Objective
YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, ...developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG‐related epilepsy.
Methods
We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients.
Results
The phenotypic spectrum of YWHAG‐related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype–phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand‐binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001).
Significance
This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype–phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.
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