Agenesis of the Corpus Callosum with Facial Dysmorphism and Intellectual Disability in Sibs Associated with Compound Heterozygous KDM5B Variants.
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ABSTRACT:
SUBMITTER: Lebon S
PROVIDER: S-EPMC8467522 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundImpaired social functioning is a common symptom of individuals with developmental disruptions in callosal connectivity. Among these developmental conditions, agenesis of the corpus callosum provides the most extreme and clearly identifiable example of callosal disconnection. To date, deficits in nonliteral language comprehension, humor, theory of mind, and social reasoning have been documented in agenesis of the corpus callosum. Here, we examined a basic social ability as yet not investigated in this population: recognition of facial emotion and its association with social gaze.MethodsNine individuals with callosal agenesis and nine matched controls completed four tasks involving emotional faces: emotion recognition from upright and inverted faces, gender recognition, and passive viewing. Eye-tracking data were collected concurrently on all four tasks and analyzed according to designated facial regions of interest.ResultsIndividuals with callosal agenesis exhibited impairments in recognizing emotions from upright faces, in particular lower accuracy for fear and anger, and these impairments were directly associated with diminished attention to the eye region. The callosal agenesis group exhibited greater consistency in emotion recognition across conditions (upright vs. inverted), with poorest performance for fear identification in both conditions. The callosal agenesis group also had atypical facial scanning (lower fractional dwell time in the eye region) during gender naming and passive viewing of faces, but they did not differ from controls on gender naming performance. The pattern of results did not differ when taking into account full-scale intelligence quotient or presence of autism spectrum symptoms.ConclusionsAgenesis of the corpus callosum results in a pattern of atypical facial scanning characterized by diminished attention to the eyes. This pattern suggests that reduced callosal connectivity may contribute to the development and maintenance of emotion processing deficits involving reduced attention to others' eyes.
| S-EPMC4335392 | biostudies-literature
Project description:Six individuals of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of severe global developmental delay, positive pyramidal signs, unique dysmorphism, skeletal abnormalities, and severe failure to thrive with normal birth weights. Patients had a profound intellectual disability and cognitive impairment with almost no acquired developmental milestones by 12 months. Early-onset axial hypotonia evolved with progressive muscle weakness, reduced muscle tone, and hyporeflexia. Craniofacial dysmorphism consisted of a triangular face with a prominent forehead and midface hypoplasia. Magnetic resonance imaging (MRI) demonstrated thinning of the corpus callosum and paucity of white matter. Genome-wide linkage analysis identified a single ~4 Mbp disease-associated locus on chromosome 7q21.13-q21.3 (LOD score>5). Whole-exome and genome sequencing identified no nonsynonymous pathogenic biallelic variants in any of the genes within this locus. Following the exclusion of partially resembling syndromes, we now describe a novel autosomal recessive syndrome mapped to a ~4Mbp locus on chromosome 7.
| S-EPMC9545274 | biostudies-literature
Project description:Corpus callosum agenesis is a relatively common brain malformation. It can be isolated or included in a complex alteration of brain (or sometimes even whole body) morphology. It has been associated with a number of neuropsychiatric disorders, from subtle neuropsychological deficits to Pervasive Developmental Disorders.Etiology and pathogenetic mechanisms have been better understood in recent years, due to the availability of more adequate animal models and the relevant progresses in developmental neurosciences. These recent findings are reviewed (through a MedLine search including papers published in the last 5 years and most relevant previously published papers) in view of the potential impact on children's global functioning and on the possible rehabilitative treatment, with an emphasis on the possibility to exploit brain plasticity and on the use of the ICF-CY framework.
| S-EPMC2949675 | biostudies-literature
Project description:The corpus callosum is the largest white matter structure connecting the two cerebral hemispheres. Agenesis of the corpus callosum (ACC), complete or partial, is one of the most common cerebral malformations in humans with a reported incidence ranging between 1.8 per 10,000 livebirths to 230-600 per 10,000 in children and its presence is associated with neurodevelopmental disability. ACC may occur as an isolated anomaly or as a component of a complex disorder, caused by genetic changes, teratogenic exposures or vascular factors. Genetic causes are complex and include complete or partial chromosomal anomalies, autosomal dominant, autosomal recessive or X-linked monogenic disorders, which can be either de novo or inherited. The extreme genetic heterogeneity, illustrated by the large number of syndromes associated with ACC, highlight the underlying complexity of corpus callosum development. ACC is associated with a wide spectrum of clinical manifestations ranging from asymptomatic to neonatal death. The most common features are epilepsy, motor impairment and intellectual disability. The understanding of the genetic heterogeneity of ACC may be essential for the diagnosis, developing early intervention strategies, and informed family planning. This review summarizes our current understanding of the genetic heterogeneity in ACC and discusses latest discoveries.
| S-EPMC9562966 | biostudies-literature
Project description:BackgroundOver 500 epigenetic regulators have been identified throughout the human genome. Of these, approximately 30 chromatin modifiers have been implicated thus far in human disease. Recently, variants in BRPF1, encoding a chromatin reader, have been associated with a previously unrecognized autosomal dominant syndrome manifesting with intellectual disability (ID), hypotonia, dysmorphic facial features, ptosis, and/or blepharophimosis in 22 individuals.Patients and methodsWe report a multiply affected nonconsanguineous family of mixed Jewish descent who presented due to ID in three male siblings. Molecular analysis of the family was pursued using whole exome sequencing (WES) and subsequent Sanger sequencing.ResultsWhole exome sequencing analysis brought to the identification of a novel heterozygous truncating mutation (c.556C>T, p.Q186*) in the BRPF1 gene in the affected siblings and their mother. The four affected individuals showed varying degrees of intellectual disability, distinct facial features including downslanted palpebral fissures, ptosis, and/or blepharophimosis. Their clinical characteristics are discussed in the context of previously reported patients with the BRPF1-related phenotype.ConclusionThe reported family contributes to the current knowledge regarding this unique and newly recognized genetic disorder, and further implicates the role of BRPF1 in human brain development.
| S-EPMC6565580 | biostudies-literature
Project description:From a GeneMatcher-enabled international collaboration, we identified ten individuals with intellectual disability, speech delay, ataxia and facial dysmorphism carrying a deleterious variant in the EBF3 (Early B-cell Factor 3) gene detected by whole-exome sequencing. Five missense, two nonsense, one 9-bp duplication, and one splice-site variant in EBF3 were found; the mutation occurred de novo in eight individuals, and the missense variant c.625C>T [p.(Arg209Trp)] was inherited by two affected siblings from their healthy mother who is a mosaic. EBF3 belongs to the early B-cell factor family (also known as Olf, COE, or O/E) and encodes a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicts damaging effects of the five amino acid substitutions on DNA-binding of EBF3. Transient expression of EBF3 mutant proteins in HEK 293T cells revealed mislocalization of all but one mutant in the cytoplasm in addition to nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the CDKN1A reporter gene, and EBF3 mutant proteins were less tightly associated with chromatin as demonstrated by in situ subcellular fractionation experiments. Finally, RNA-seq and ChIP-seq experiments demonstrate that EBF3 acts as a transcriptional regulator and EBF3 mutant protein had reduced genome-wide DNA binding and gene regulatory activity. Our findings demonstrate that variants that disrupt EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay, and are present in ~0.1% of individuals with unexplained neurodevelopmental disorders.
2016-11-30 | GSE90682 | GEO
Project description:Craniosynostosis (CS) is the premature fusion of the cranial sutures,occurring either in isolated or syndromic form. CS was described in over 180 genetic syndromes that comprise 15-30% of all CS cases. Syndromic CS usually has a monogenic inheritance and originates in most of the patients from mutations within the FGFR1, FGFR2, FGFR3, and TWIST1 genes. Causative alterations in other genes, or rarely copy number variations (CNVs) were also reported. In this paper, we describe a patient with Noonan-like facial dysmorphism accompanied by intellectual disability, and compound CS, involving coronal, sagittal, and squamous sutures. We have shown that the index carried a large and rare heterozygous deletion, which encompassed 12.782 Mb and mapped to a chromosomal region of 7q32.3-q35 (HG38 – chr7:131837067-144607071). The aberration comprised 109 protein-coding genes, including BRAF, that encodes serine/threonine-protein kinase B-Raf, being a part of the RAS/MAPK signaling pathway. The RAS/MAPK pathway plays an essential role in human development, hence its dysregulation not surprisingly results in severe congenital anomalies, such as phenotypically overlapping syndromes termed RASopathies. To our best knowledge, we report here the first CNV causing haploinsufficiency of BRAF, resulting in dysregulation of the RAS/MAPK cascade, and consequently, in the phenotype observed in our patient. To conclude, with this report, we have pointed to the involvement of the RAS/MAPK signaling pathway in CS development. Moreover, we have shown that the molecular analysis based on both DNA and RNA profiling, undoubtedly constitutes a comprehensive diagnostic and research strategy for elucidating a cause of genetic diseases.
2020-06-01 | GSE150754 | GEO
Project description:From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ∼0.1% of individuals with unexplained neurodevelopmental disorders.
| S-EPMC5223027 | biostudies-literature
Project description:Corpus callosum agenesis is a relatively common brain malformation. It can be isolated or included in a complex alteration of brain (or sometimes even whole body) morphology. Etiology and pathogenetic mechanisms have been better understood in recent years due to the availability of more adequate animal models and the relevant progresses in developmental neurosciences. We present the case of a girl with a complete agenesis of the corpus callosum discovered at birth. She had mild learning difficulties, but reached satisfactory levels of autonomy after an individually tailored rehabilitative treatment. Her story is discussed in light of recent findings, which emphasize the possibility to exploit brain plasticity and the utility of an individually tailored approach, defined on the basis of a dialogue with the family and the patient.
| S-EPMC3437615 | biostudies-literature
Project description:Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder with characteristic morphological anomaly. Our patient was a 4.5-year-old girl came with features like broad thumbs, downward slanting palpebral fissures and mental retardation. Systemic abnormalities such as repeated infection, seizure with developmental delay were also associated with it. She was having head banging behavior abnormal slurring speech, incoordination while transferring things from one hand to other. Galaxy of clinical pictures and magnetic resonance imaging report helped to clinch the diagnosis as a case of "RSTS with corpus callosal agenesis" which to the best of our knowledge has never been reported in past from India.
| S-EPMC4489069 | biostudies-other