3p14 deletion is a rare contiguous gene syndrome: Report of 2 new patients and an overview of 14 patients
TL;DR: Genotype–phenotype analysis revealed candidate genes for parts of the clinical features suggesting that the 3p14 deletion is a contiguous gene syndrome.
Abstract: Interstitial deletions of chromosome 3p14p12 are a rare chromosome rearrangement. Twenty-six patients have been reported in the literature to date, however, a specific clinical phenotype has not yet been delineated. We describe three patients (two new) with overlapping chromosome 3p14p12 deletions and review the clinical and molecular data of 11 well-characterized, published cases. These patients had a number of features in common, such as short stature, failure to thrive, facial dysmorphism, congenital heart defects, urogenital abnormalities, neurological problems, hearing loss, and global developmental delay, suggesting that the interstitial chromosome 3p14p12 deletion gives rise to a multiple congenital anomaly syndrome. Some of the patients show clinical overlap with other complex syndromes such as CHARGE syndrome. Genotype-phenotype analysis revealed candidate genes for parts of the clinical features suggesting that the 3p14 deletion is a contiguous gene syndrome.
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TL;DR: This review is focused on the investigation of possible links between CIN, metastasis and the host immune system in cancer development and treatment, since most cancer deaths are due to the consequences of metastasis, and immunotherapy is a rapidly expanding novel avenue of cancer therapy.
Abstract: Many cancers possess an incorrect number of chromosomes, a state described as aneuploidy. Aneuploidy is often caused by Chromosomal Instability (CIN), a process of continuous chromosome mis-segregation. CIN is believed to endow tumours with enhanced evolutionary capabilities due to increased intratumour heterogeneity, and facilitating adaptive resistance to therapies. Recently, however, additional consequences and associations with CIN have been revealed, prompting the need to understand this universal hallmark of cancer in a multifaceted context. This review is focused on the investigation of possible links between CIN, metastasis and the host immune system in cancer development and treatment. We specifically focus on these links since most cancer deaths are due to the consequences of metastasis, and immunotherapy is a rapidly expanding novel avenue of cancer therapy.
71 citations
Cites background from "3p14 deletion is a rare contiguous ..."
...Structural congenital aneuploidies can have detrimental effects on health, depending on the location and size of the structural abnormality [32, 33]....
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TL;DR: This first study to prospectively examine the genotype-phenotype relationship in multiple individuals withFOXP1 syndrome, using a battery of standardized clinical assessments, identifies novel FOXP1 mutations associated with FOXP 1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain.
Abstract: Haploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments. Genetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5–17 with mutations in FOXP1. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1. We have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections. This study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome.
59 citations
TL;DR: A review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlisting a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP 1 syndrome is presented in this paper.
Abstract: FOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.
12 citations
TL;DR: In behavior analysis, FAM19A1-deficient mice exhibited several abnormal behaviors, including hyperactive locomotor behavior, long-term memory deficits and fear acquisition failure, which provides insight into the potential contributions of FAM 19A1 to neurodevelopment and mature brain function.
Abstract: Neurodevelopment and mature brain function are spatiotemporally regulated by various cytokines and chemokines. The chemokine-like neuropeptide FAM19A1 is a member of family with sequence similarity 19 (FAM19), which is predominantly expressed in the brain. Its highly conserved amino acid sequence among vertebrates suggests that FAM19A1 may play important physiological roles in neurodevelopment and brain function. Here we used a LacZ reporter gene system to map the expression pattern of the FAM19A1 gene in the mouse brain. The FAM19A1 expression was observed in several brain regions starting during embryonic brain development. As the brain matured, the FAM19A1 expression was detected in the pyramidal cells of cortical layers 2/3 and 5 and in several limbic areas, including the hippocampus and the amygdala. FAM19A1-deficient mice were used to evaluate the physiological contribution of FAM19A1 to various brain functions. In behavior analysis, FAM19A1-deficient mice exhibited several abnormal behaviors, including hyperactive locomotor behavior, long-term memory deficits and fear acquisition failure. These findings provide insight into the potential contributions of FAM19A1 to neurodevelopment and mature brain function.
11 citations
TL;DR: From the obtained findings, "FOXP1-related intellectual disability syndrome" was considered to be clinically recognizable and is now recommended for patients with 3p13 microdeletions involving FOXP1.
Abstract: Background FOXP1 is known as the gene responsible for neurodevelopmental delay associated with language impairment. Broad clinical findings also include feeding difficulty, muscular hypotonia, and distinctive features. These findings are common between patients with loss-of-function mutations in FOXP1 and 3p13 microdeletion involving FOXP1. Thus, “FOXP1-related intellectual disability syndrome” is now recommended. Methods After obtaining informed consent, chromosomal microarray testing was performed for patients with unknown etiology. Results We identified three Japanese patients with 3p13 microdeletions involving FOXP1. One of the patients showed an additional 1q31.3q32.1 deletion as de novo, which was rather considered as a benign copy number variant. Conclusion This is the first report of patients with 3p13 microdeletions from Japan. All patients showed growth delay, moderate to severe developmental delay, hearing loss, and distinctive facial features including prominent forehead and mid facial hypoplasia. In addition, “square shaped face” commonly observed in all three patients may be a characteristic finding undescribed previously. From the obtained findings, “FOXP1-related intellectual disability syndrome” was considered to be clinically recognizable.
5 citations
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TL;DR: It is concluded that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families and a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function ofROBO1 may manifest as a specific reading disability in humans.
Abstract: Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples), the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.
357 citations
"3p14 deletion is a rare contiguous ..." refers background in this paper
...…hearing impairment, eye abnormalities, and global developmental delay in affected individuals [Bird and Show, 1978; Sundaresan et al., 2004; Hannula-Jouppi et al., 2005; Andrews et al., 2006; Lu et al., 2007; Schwarzbraun et al., 2007; Young et al., 2007; Bertoli-Avella et al., 2008;…...
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...…disabilities in a unique family (OMIM606896), while mutations in ROBO2 (OMIM 602431) were detected in approximately 5%, of patients with vesicoureteric reflux, and congenital anomalies of the urinary tract (OMIM 610878) [Hannula-Jouppi et al., 2005; Lu et al., 2007; Bertoli-Avella et al., 2008]....
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TL;DR: The results indicate that Robo1 mutants have distinct phenotypes, some of which are different from those described in Slit mutants, suggesting that additional ligands, receptors or receptor partners are likely to be involved inSlit/Robo signalling.
Abstract: The Slit genes encode secreted ligands that regulate axon branching, commissural axon pathfinding and neuronal migration. The principal identified receptor for Slit is Robo ( Roundabout in Drosophila). To investigate Slit signalling in forebrain development, we generated Robo1 knockout mice by targeted deletion of exon 5 of the Robo1 gene. Homozygote knockout mice died at birth, but prenatally displayed major defects in axon pathfinding and cortical interneuron migration. Axon pathfinding defects included dysgenesis of the corpus callosum and hippocampal commissure, and abnormalities in corticothalamic and thalamocortical targeting. Slit2 and Slit1/2 double mutants display malformations in callosal development, and in corticothalamic and thalamocortical targeting, as well as optic tract defects. In these animals, corticothalamic axons form large fasciculated bundles that aberrantly cross the midline at the level of the hippocampal and anterior commissures, and more caudally at the medial preoptic area. Such phenotypes of corticothalamic targeting were not observed in Robo1 knockout mice but, instead, both corticothalamic and thalamocortical axons aberrantly arrived at their respective targets at least 1 day earlier than controls. By contrast, in Slit mutants, fewer thalamic axons actually arrive in the cortex during development. Finally, significantly more interneurons ( up to twice as many at E12.5 and E15.5) migrated into the cortex of Robo1 knockout mice, particularly in both rostral and parietal regions, but not caudal cortex. These results indicate that Robo1 mutants have distinct phenotypes, some of which are different from those described in Slit mutants, suggesting that additional ligands, receptors or receptor partners are likely to be involved in Slit/Robo signalling.
262 citations
TL;DR: 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.
Abstract: 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.
215 citations
"3p14 deletion is a rare contiguous ..." refers background in this paper
...…[Bird and Show, 1978; Sundaresan et al., 2004; Hannula-Jouppi et al., 2005; Andrews et al., 2006; Lu et al., 2007; Schwarzbraun et al., 2007; Young et al., 2007; Bertoli-Avella et al., 2008; Garden and La Spada, 2008; Carr et al., 2010; Hamdan et al., 2010; Horn et al., 2010; Tao et al., 2011]....
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...Affected individuals had a high and broad forehead, and a small nose with depressed nasal bridge [Carr et al., 2010; Hamdan et al., 2010; Horn et al., 2010]....
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TL;DR: Results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR, and identify two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families.
Abstract: Congenital anomalies of the kidney and urinary tract (CAKUT) include vesicoureteral reflux (VUR) VUR is a complex, genetically heterogeneous developmental disorder characterized by the retrograde flow of urine from the bladder into the ureter and is associated with reflux nephropathy, the cause of 15% of end-stage renal disease in children and young adults We investigated a man with a de novo translocation, 46,X,t(Y;3)(p11;p12)dn, who exhibits multiple congenital abnormalities, including severe bilateral VUR with ureterovesical junction defects This translocation disrupts ROBO2, which encodes a transmembrane receptor for SLIT ligand, and produces dominant-negative ROBO2 proteins that abrogate SLIT-ROBO signaling in vitro In addition, we identified two novel ROBO2 intracellular missense variants that segregate with CAKUT and VUR in two unrelated families Adult heterozygous and mosaic mutant mice with reduced Robo2 gene dosage also exhibit striking CAKUT-VUR phenotypes Collectively, these results implicate the SLIT-ROBO signaling pathway in the pathogenesis of a subset of human VUR
184 citations
"3p14 deletion is a rare contiguous ..." refers background in this paper
...…disabilities in a unique family (OMIM606896), while mutations in ROBO2 (OMIM 602431) were detected in approximately 5%, of patients with vesicoureteric reflux, and congenital anomalies of the urinary tract (OMIM 610878) [Hannula-Jouppi et al., 2005; Lu et al., 2007; Bertoli-Avella et al., 2008]....
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...…global developmental delay in affected individuals [Bird and Show, 1978; Sundaresan et al., 2004; Hannula-Jouppi et al., 2005; Andrews et al., 2006; Lu et al., 2007; Schwarzbraun et al., 2007; Young et al., 2007; Bertoli-Avella et al., 2008; Garden and La Spada, 2008; Carr et al., 2010; Hamdan et…...
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TL;DR: In this paper, the authors used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications, and found three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene.
Abstract: Mental retardation affects 2-3% of the population and shows a high heritability. Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors. We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language. ©2010 Wiley-Liss, Inc.
137 citations